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Vaccines remain a small part of the overall drug market, just $9 billion
in sales compared to global pharmaceutical sales of $550 billion, they
make up a fast-growing segment, increasing 26% between 1999 and 2003. Large
pharmaceutical makers are attracted to vaccines because they can't be easily
replaced by generics and they provide a long-term income stream. The large
capital investment needed to manufacture vaccines also makes it difficult
for competitors to jump into the market. And vaccine development is more
predictable than other drugs, allowing companies to smooth out product
development cycles. In 1967, there were 26 vaccine manufacturers
in the US market, but by 2002 there were only 12ref,
but concern about an avian flu pandemic and flu shot shortages in 2004,
along with the development of new vaccines – including products that attack
meningitis and cervical cancer – are drawing big pharmaceutical companies'
attention back to vaccines after decades of retrenchment. Liability remains
a problem. In 1986, Congress created the Vaccine Injury Compensation Program
(VICP), a no-fault system for resolving claims, but lawsuits continue to
plague vaccine makers. The liability environment has gotten worse : there
has been a flurry of lawsuits, and the injury compensation program in the
U.S. is being circumvented in creative ways. For example, families of children
with autism who believe childhood immunizations led to their children's
condition have not filed suits that argue the vaccines themselves caused
autism. They argue instead that it is the vaccine additive thimerisol,
which is not covered by the VICP. To encourage production of pandemic vaccines,
Senators Hillary Rodham Clinton (D-NY) and Pat Roberts (R-Kan.) have introduced
legislation, known as the Influenza Vaccine Security Act, that shifts liability
from pharmaceutical companies to the federal government for personal injury
or death resulting from the manufacture, administration, or use of qualified
pandemic influenza technologies.
Perhaps in no area is the divide between the developed and developing
worlds as striking as it is for vaccines: While healthcare consumers in
economically advantaged nations worry about risk, in developing nations
compelling need forces a focus on potential benefit. People in the United
States want a quick solution, not prevention, so they prefer drugs to vaccines.
Elsewhere, people are afraid of drugs and side effects, and prefer vaccines.
Adding to the imbalance is that the same disease can have markedly different
outcomes depending on the healthcare infrastructure of a nation. Constraints
on vaccine use are complex and intertwined, involving sociology, economics,
politics, science, and technology. Success of the chickenpox vaccine highlights
the different mindset in the developed and developing worlds : the vaccine
has a very low incidence of side effects and treats a usually mild disease,
but what sells it most, though, is that if your child has chickenpox, you're
home for a week (can you afford to miss a week of work?!). Creating a vaccine
is expensive : a phase III clinical trial alone can take > 3 years and
cost $50-300 millionref.
For a company to take the plunge, a safe and effective product and a large,
continual market are critical.
Retractions :
1968 : diptheria, pertussis, tetanus (DPT)-intramuscular polio (safety
and efficacy)
1999/2000 : U.S. Public Health Service and other organizations ask for
removal of thimerosal preservative from vaccines for infants
People avoid vaccines for several reasons. The paramount reason, fear (vaccinophobia),
knows no geographic or cultural boundaries. But vaccines work : in USA
...
When a disease is caught by person-to-person contact,
as are sexually transmitted viruses, it spreads through a social network
that looks like a disorderly grid. Each person represents a node in
the grid, linked to others with whom they have had potentially infectious
contact. In recent years, researchers have realized that disease spread
can depend strongly on what this network looks like - on how the nodes
are linked. Many human networks - including some webs of sexual contacts
and the Internet - seem to take on a form called scale-free. Here a
few very highly connected nodes, dubbed 'hubs', bind the network together.
Hubs are shortcuts between any 2 nodes, giving rise to the small-world
effect popularized in the notion of us all being a maximum of six degrees
of separation from anyone else. In such networks, infection does not travel
as traditional epidemiological models imply. Even slow-spreading diseases
can reach epidemic proportions. Epidemics were long thought to occur only
if the dissemination rate exceeds a certain threshold value. In principle,
epidemics in a scale-free network can be quashed by identifying and immunizing
just the hubs. This is an appealing method, as it cuts costs. In practice,
however, hubs can be very hard to find. As a result, some epidemics, such
as the spread of computer viruses and measles, currently rely on random
immunization - virtually the entire population is treated.Rather than simply
immunizing random individuals, it might be more effective to treat a random
selection of the acquaintances of individuals picked at random. This sounds
as if it leaves just as much to chance. But it doesn't. In a scale-free
social network - a web of friendships, say - anyone connected to another
person by a friendship tie is not representative of the average. Most nodes
have very few connections. So if you know for sure that someone is part
of a friendship circle, they are more likely to be a hub than is another
person selected at random. In a standard mathematical model of the spread
of infectious disease, the strategy of random-acquaintance immunization
requires only about 50% of a population to be treated to substantially
reduce the chance of an epidemicref.
Vaccines can be made against ...
neoplastic cells (tumour immunity)
infective microorganisms
Requirements for successful specific immunotherapy :
target cell :
transcribes and translates a relevant protein antigen
protein is accessible to peptide-processing machinery
protein incorporates epitopes that can be presented by relevant MHC molecules
intact and unihibited antigen-processing pathway (including MHC presentation)
protein ineffectively cross-presented for induction of immunity (or there
would be no need for immunotherapy)
susceptible to effector mechanisms (such as apoptosis and terminal differentiation)
does not secrete or express local inhibitors of effector function
immune effector system : naive T cells with appropriate T-cell receptors
for target antigen
intervention (vaccination) induces :
sufficient quantity of effector cells
trafficking to target tissue
appropriate effector mechanisms
responses of sufficient duration
The development of
successful vaccines requires the inclusion of a mixture of epitopes for
the induction of an effective immune response that
can protect against pathogens with high mutation rates.
cover the genetic differences of the population in MHC haplotypes
Unfortunately, the application of such vaccine cocktails can lead to the
occurrence of immunodominance (ID),
indicating that the immune response is limited to one epitope or a small
portion of the bona fide T cell epitopes administered. The administration
of rIL-12
during some consecutive days initiated before immunization counteracts
immunodominance thanks to a transient depletion of B cells, T cells, macrophages,
and DCs in the spleen.
The introduction of rotavirus vaccination in developing countries is
politically difficult in light of its withdrawal from use in the USAref.
The issue goes beyond one of political correctness. The article glosses
over the moral and ethical issues involved in the trial of this vaccine
in poor countries. The question of how many serious side-effects are acceptable
to save a life has been discussed by us elsewhereref.
The risk-benefit equation answers the question "Is the cure (prevention)
worse than the disease?" It is true that developing countries, in which
the risk of death from disease is greater than in developed countries,
are more tolerant of preventive measures with side-effectsref.
We here seek to ask a more fundamental question: is it ethically justifiable
to conduct trials of expensive vaccines such as that for rotavirus in developing
countries? Glass and colleagues note that, traditionally, vaccines
are tested by multinational manufacturers in the USA and Europe and only
later in developing countries as supply and competition increase and the
cost of the vaccine decreases. We argue that ethically, too, this is the
right way to go about it. The Helsinki Declaration suggests that trials
be done in populations who are directly to use the drug, and that particular
attention must be paid when trials involve vulnerable sectors such as prisoners
and those of low socioeconomic status. It has been reported that it is
easy to recruit participants for trials in developing countries, and that
the cost of research is halvedref.
A major saving, we dare say, is in the provision of compensation for adverse
effects, which is less likely to be claimed by the indigent population
in poor countries. This is what makes drug companies press countries such
as India to change their law and allow unfettered research by foreign manufacturersref.
We suggest that if a vaccine is not affordable to the population at its
current price, trials of the vaccine in that population run counter to
the Helsinki Declaration. The rotavirus vaccine costs US$38 per dose and
is administered in three doses. For India's yearly birth cohort of 25 million,
these three doses will cost $2850 million. According to Health Information
of India 2000 and 2001, the Ministry of Health, and the Family Welfare
Government of India, the health and family welfare budget outlay for the
year 2002-03 was $1440 million. Rotavirus vaccination, which costs two
times the entire health budget, prevents just 1·5% of the deaths
that occur in children younger than 5 years (see below). The expenditure
is thus difficult to justify. It could be argued that the health budget
needs to be enlarged. However, a more absolute measure of affordability
comes from looking at the intervention against the per-capita gross national
product of the countryref.
Under-5 mortality in India is 98 per 1000 livebirths, and neonatal death
is responsible for 49 deaths. Since rotavirus vaccine given at 3 months
of age is unlikely to prevent neonatal deaths, we are potentially looking
at the remaining 49 deaths per 1000 livebirths. 15% of deaths in under-fives
in developing countries are due to diarrhoea, and 20% of them could be
due to rotavirusref.
In effect, rotavirus vaccine can prevent 1·5 deaths per 1000 livebirths.
Given the life expectancy of about 60 years in India, we can assume that
this intervention results in 90 life-years saved. The cost of the vaccine
itself (not counting the cost of administering the three doses) comes to
$1266 per life-year saved (cost of vaccines for 1000 infants divided by
90); the yearly per capita income in India is only $450. The vaccine cannot
therefore be recommended as cost-effective or affordableref
and so it is unjustifiable to test the drug in this population. The stipulations
of the Helsinki Declaration will permit the research only after its price
has come down drastically. To do otherwise is to exploit the economic vulnerability
of the population and to use them as guineapigs. In a Viewpoint,
Roger Glass and colleagues (May 8, p 1547)ref
describe how, despite the setback to children of the developing world,
withdrawal of the Rotashield vaccine (Wyerth-Ayerst, USA) from the US market
ultimately created opportunities to consolidate efforts to tackle this
important public-health problem. This situation was certainly the case
with the Pan American Health Organization and several of its partners,
including the Centers for Disease Control and Prevention, the Gates Foundation,
the National Institutes of Health, and the Albert B Sabin Vaccine Institute.
This partnership is dedicated to the reduction of morbidity and mortality
from diarrhoea caused by rotavirus infectionref1,
ref2
which is accountable for about 75 000 admissions and 15 000 deaths every
year in the Americas alone. Much work has been done in Latin America; however,
several challenges remain. As noted in a meeting held in Lima, Peru, in
September, 2003ref,
surveillance systems, similar to those developed for polio and measles,
should be strengthened. More economic studies are needed to accurately
define the cost-effectiveness of vaccine interventions. This information
will be critical for future decisions among national policy makers. Since
the Lima meeting, substantial inroads have been made. To that end, the
Pan American Health Organization and its partners held a global meeting
in Mexico City on July 7-9, 2004, to review progress towards the development
of a rotavirus vaccine and its introduction in developing countries. Several
ministers of health from Latin America and the Caribbean attended the meetingref.
Leading global experts will address a broad range of issues concerning:
rotavirus pathogenesis, epidemiology, surveillance, vaccine adverse events,
intussusception background rates in developing countries, vaccine cost-effectiveness,
the results of new rotavirus vaccines being developed, finances, and partnerships.
The aim of this meeting was not just to share technical information, but
to put forward a call to action that will ultimately benefit children in
developing countries. Therefore, a Mexico City declaration was launched
at the end of the meeting that will certainly go a long way to galvanise
the political support and commitment to do exactly that. The declaration
and proceedings of the meeting will be published in the near future.ref
Vaccines rarely provide full protection from disease. Nevertheless,
partially
effective (imperfect) vaccines may be used to protect both individuals
and whole populations. Vaccines designed to reduce pathogen growth rate
and/or toxicity diminish selection against virulent pathogens. The subsequent
evolution leads to higher levels of intrinsic virulence and hence to more
severe disease in unvaccinated individuals. This evolution can erode any
population-wide benefits such that overall mortality rates are unaffected,
or even increase, with the level of vaccination coverage. In contrast,
infection-blocking vaccines induce no such effects, and can even select
for lower virulence. These findings have policy implications for the development
and use of vaccines that are not expected to provide full immunity, such
as candidate vaccines for anthrax and malariaref.
In areas of high mortality, various vaccines might have non-specific
effects on mortality :
inactivated vaccines such as diphtheria-tetanus-pertussis (DTP) and inactivated
poliovirus (IPV) might amplify mortality from diseases other than diphtheria,
tetanus, pertussis, and polio[ref1,
ref2,
ref3,
ref4]
Non-specific effects are strongest in the first 3-6 months after immunisationref
and in girls[ref1,
ref2,
ref3,
ref4,
ref5]
and they are largely determined by the most recent vaccine received; for
example, in Guinea-Bissau, the female-male mortality ratio was 3.08 (95%
CI 1·11-8·56) for children who received DTP as their last
vaccine, but only 0.63 (0.28-1.40) for those who received measles vaccine
lastref.
Results of several studies from West Africa have shown that BCG could enhance
the response to unrelated antigensref.
Prime-boost is a 2-part process :
first, an injection of non-infectious (genetic or protein) antigen(s) primes
the immune system to respond
second, several weeks later, an injection of protein or attenuated carrier
viruses containing antigen gene(s) substantially boosts the immune response
using the same vaccine preparation (homologous
prime-boost)
using different vaccine preparations (heterologous
prime-boost) : this is used to circumvent acquired immunity to the
first vector, which precludes subsequent vaccinations with the same vector.
The boost alone produces a quicker but weaker immune response as compared
with the prime-boost strategy.
Active pharmaceutical
ingredients (API) : vaccines may consist of :
the Ag(s) against which the immune response has to be mounted
mixed or polyvalent vaccine : a vaccine prepared from cultures or
antigens of more than one strain or species.
...isolated from ...
autogenous vaccine : a vaccine prepared from microorganisms which
have been freshly isolated from the lesion of the patient who is to be
treated with it.
The antigen(s) can be ...
whole organisms
dead
or
killed or inactivated or replication-defective germs
: less risks, less effectiveness (i.e. more doses, longer latency period,
shorter protection time). They are usually administered in 2-3 sequential
doses followed by a booster after 6-12 months.
VAQTA®
(Merck
& Co.) : 50 U in 1 mL; for use in patients as young as 12 months; may
be administered concomitantly with live measles, mumps, and rubella vaccine
(MMR-II).
JE-Vax®
(distributed by Aventis Pasteur
Inc. (USA Govt license #1156), Biken (Japan) and by the Korean GreenCross).
Side effect rate (as pointed out in the
insert sheet) : local side effects >10%, systemic side effects (i.e. fever,
which is indicated may happen even up to 10-14 days after injection) <0,001%
(active reporting system in at least 66.6%: 3 shots gives 2 opportunities
to ask directly about side effects), ADEM
(a female junior high school student in east Japan's Yamanashi Prefecture
fell into critical condition after receiving an inoculation in 2004). Severe
adverse reactions after immunization with inactivated vaccines are often
reported due to mouse-brain myelin contamination. For this reason, an alternative
vaccine with a better safety profile is urgently needed. Japanese children
are usually given the vaccination 3 times: between 6 months and 7.5 years
old, 9 and 12 years old, and 14 and 15 years old. Between 4.2 million and
4.3 million children receive the encephalitis vaccine a year. The current
program of JEV vaccinations has been carried out routinely in Japan since
1994 : > 10 cases of ADEM have been linked to the vaccination since 1994.
As mouse brains are used in producing Japanese encephalitis vaccines, some
medical experts say tiny amounts of mouse brain tissue remaining in the
vaccines may have a causal link with the side effects. Surveillance of
JE vaccine-related complications in Japan during the years 1965-1973 disclosed
neurological events (principally, encephalitis, encephalopathy, seizures,
and peripheral neuropathy) among one to 2.3 per million persons vaccinatedref.
(Kitaoka M. Follow-up on use of vaccine in children in Japan. In: McDHammon
W, Kitaoka M, Downs WG, eds. Immunization for Japanese encephalitis. Amsterdam:
Excerpta Medica, 1972:275-7). The Japanese government has announced it
is suspending the government Japanese encephalitis (JE) vaccination program
which uses the inactivated mouse brain-derived JE vaccine, the only vaccine
currently licensed in Japan. The license for the vaccine is not suspended,
and vaccines are still available on an individual basis. In addition, 2
new cell culture-derived vaccines are in advanced stages of development
in Japan (undergoing Phase III trials), and licensure is expected as early
as 2006. It is reasonable to believe that the decision to suspend vaccination
was related to the short timeline for new vaccine licensure in Japan. While
the risk of any severe side effect of immunization is of concern, JE is
a disease with a fatality rate of up to 30%, and approximately one 3rd
of survivors are left with severe neurological disabilities. Recognition
of adverse events after immunization with the inactivated vaccine, including
the very rare but known cases of acute disseminated encephalomyelitis,
has been a major factor spurring the development of new JE vaccines with
improved safety profiles. The other JE vaccine currently available is the
SA
14-14-2 live, attenuated vaccine. It has an excellent safety record,
and, in studies to date, no severe adverse events have been reportedref1,
ref2,
ref3.
> 200 million children have been vaccinated with this vaccine since production
began, and the vaccine is now licensed in China, Nepal and South Korea.
In addition to the 2 new cell culture-derived Japanese vaccines, other
cell culture-derived vaccines, chimeric and other types of JE vaccine are
in development. JE is a disease that circulates in the environment, with
birds and pigs as the principal amplifying hosts, and it is, therefore,
not a disease that can be eradicated. Regular studies ascertaining the
prevalence of antibodies in humans and seroconversion in pigs demonstrate
the virus is still circulating in Japan, often with serious consequences
in those infected. In a recent outbreak of JE in the Chugoku district of
Japan in 2002, 5 of 6 patients had a severe outcome, including one deathref.
The low number of cases of JE seen in Japan is a result of their immunization
program, not a lack of circulating virus. It is anticipated the government
vaccination program and strategy will be reconsidered when a new JE vaccine
becomes available.
single-shot vaccine under development by SingVax
in Singapore and Octoplus in the
Netherlands. The work will utilise OctoPlus’ proprietary delivery systems
for the controlled release of drugs and antigens, and the PER.C6®
technology licensed by SingVax from Dutch biotechnology company Crucell,
for the manufacturing of JE viral particles
anti-Rift
Valley fever virus
vaccine : 3 injections separated by 1 month each. Effective for <
1 year.
anti-influenzaviruses
A and B
vaccine (see also protein subunit vaccine,
attenuated
vaccine and DNA
vaccine)
(Francis, T., Jr., Salk, H. E., Pearson, H. E., and Brown, P. N. Protective
effect of vaccination against induced influenza A. Proc. Soc. Exper. Biol.
& Med. 1944, 55, 104-105; Commission on Influenza. A clinical evaluation
of vaccination against influenza. Preliminary report. J. Am. Med. Assoc.
1944, 124, 982-985) : for the last 30 to 40 years, flu virus has been grown
in 8-9 days old fertilized hen eggs injected by needle with a tiny bit
of flu virus, which then grows in the egg and harvested 1-2 days later.
A single egg is needed to make one dose of vaccine containing a multitude
of flu viruses, and major flu vaccine makers like Aventis Pasteur and Chiron
Corp. need tens of millions of eggs every year (Chiron uses 100,000 a day
at the peak of production) : these have to be ordered months in advance,
which makes it difficult to produce a fresh batch of vaccine at the last
minute and sometimes, chicken disease outbreaks can kill huge numbers of
animals, hurting egg production. About 4% of the population is allergic
to eggs and many of these people can't get a flu shot : however some offices
sometimes give the flu vaccine even to patients who are allergic to eggs
because the danger to them from the flu virus is even greater than the
danger from the vaccine. To make a suitable vaccine strain, researchers
inject the circulating virus, such as Fujian, and another, fast-growing
flu strain into eggs, where the 2 mix and match their genes. From the eggs,
scientists aim to pull out a new fast-growing reassorted virus - called
a seed strain - which carries the HA and NA genes from the year's
strain. Vaccine manufacturers need to receive the seed strain in time to
grow it up in tens of millions of eggs, a process that is proven, efficient
and reliable, but takes up to 6 months. Problems growing the year's strain
could be bypassed using :
reverse genetics to rapidly engineer the seed strain in the laboratory
by stitching together the viral genes they want, and then use it to mass-produce
the vaccine in hens' eggs. Influenza vaccines made using reverse genetics
have not yet progressed through clinical trials, however, and vaccine manufacturers
might be dissuaded from using reverse genetics because they would owe licensing
fees to MedImmune, a biotechnology firm based in Gaithersburg, Maryland
that holds patents on the technique
mammalian cell cultures (Vero cell culture vaccine is in development
by Baxter and Chiron)
1 i.m. injection containing 15 µg of HA for each represented strain
per 0.5-ml dose without adjuvant induce hemagglutination-inhibition (HAI)
titers of at least 1:40. When flu vaccines are well-matched to the
prevailing flu strains, the shots can prevent flu for 1 year in 70-90%
in adultsref1,
ref2
and 30-40% in elderlies. Well-matched shots may prevent flu in only 30-40%
of nursing home residents, but they can reduce the death rate from influenza
and pneumonia in that population by 80%. As compared with an i.m. injection
of full-dose (15 µg x3) influenza vaccine, an intradermal injection
of a reduced dose (6 µg (40% of the usual dose) x3ref
or 3 µg (20% of the usual dose) x3ref)
results in similarly vigorous antibody responses among persons 18 to 60
years of age but not among those over the age of 60 years (significant
only for antigen to the H3N2 strain). Local pain
is significantly more common in the i.m. group than in the intradermal
group among subjects who were 18 to 60 years of age but not among subjects
who are over 60 years old. Signs of local inflammation are significantly
more common among subjects in the intradermal group than among those in
the intramuscular group, in both age groups.
Indications : CDC Priority groups for
vaccination with inactivated influenza vaccine :
all children aged 6-59 months : disease prevention authorities in
the USA and Canada are considering extending their influenza vaccination
programme to children under 2 years, although a recent systematic review
found little evidence to support the moveref.
A close look at data from 24 studies showed that live attenuated vaccines
work best in children, reducing the risk of confirmed influenza by 79%
(relative risk 0.21, 95% CI 0.08 to 0.52)—but only in children over
2 years. As expected, live attenuated vaccines were less effective
against unconfirmed "influenza-like" illnesses, reducing the risk by only
38% in children over 2 years (relative risk 0.62, 0.57 to 0.67). Inactivated
vaccines don't seem to work as well as live attenuated vaccines, and
in a review at least, did not work at all in children under 2. Few studies
looked at complications such as chest infections, acute otitis media, or
hospital admission, and those that did found no difference between children
who had been vaccinated and those who had not. The authors found no data
at all on mortality. Despite evidence that vaccinating schoolchildren against
influenza is effective in limiting community-level transmission, the USA
has had a long-standing government strategy of recommending that vaccine
be concentrated primarily in high-risk groups and distributed to those
people who keep the health system and social infrastructure operating.
Because of 2005 influenza vaccine shortage, a plan was enacted to distribute
the limited vaccine stock to these groups first. This vaccination strategy,
based on direct protection of those most at risk, has not been very effective
in reducing influenza morbidity and mortality. Although it is too late
to make changes for the 2005 season, the current influenza vaccine crisis
affords the opportunity to examine an alternative for future years. The
alternative plan, supported by mathematical models and influenza field
studies, would be to concentrate vaccine in schoolchildren, the
population group most responsible for transmission, while also covering
the reachable high-risk groups, who would also receive considerable indirect
protection. Vaccinating 60% of schoolchildren in the USA would dramatically
reduce the transmission of influenza. Children are the primary transmitter
and they link all the other groups in the population. In conjunction with
a plan to ensure an adequate vaccine supply, this alternative influenza
vaccination strategy would help control interpandemic influenza and be
instrumental in preparing for pandemic influenza. The effectiveness of
the alternative plan could be assessed through nationwide community studiesref.
Influenza control based on mass vaccination of schoolchildren was implemented
in Japan in the 1960s and was associated with a decrease in the overall
mortality rate. The program was discontinued in 1994. The discontinuation
was followed by a seasonal increase in the mortality rate. Lately, young
children and elderly persons have been receiving influenza vaccines. It
is likely that discontinuation of mass vaccination of schoolchildren was
responsible for the increase in influenza-associated deaths among young
children in the 1990s. The recent increase in influenza vaccinations among
young children, together with the routine therapeutic use of neuraminidase
inhibitors, has led to a decrease in the influenza-associated mortality
rateref.
Beginning with the 2004/2005 influenza season, the Advisory Committee on
Immunization Practices (ACIP) recommends that all children aged 6 to 23
months and close contacts of children aged 0 to 23 months receive annual
influenza vaccinationref.
ACIP continues to recommend that all people aged >6 months with certain
chronic underlying medical conditions, their household contacts, and health-care
workers receive annual influenza vaccinationref.
The composition is decided by consensus among an international group of
influenza experts. The decision has to be taken in February in order to
give the manufacturers sufficient time to gear up and produce the vaccine.
Data from a surveillance led the ACIP in 2005 to expand its recommendations
to include persons with conditions that compromise respiratory function,
such as neuromuscular disordersref.
In February 2006, the ACIP voted to expand annual vaccine recommendations
to include all children 6 to 59 months of age. This last recommendation
will be published in the 2006 recommendations of the ACIP on the prevention
and control of influenza..
adults aged > 65 years : over the past 4 decades, vaccines have
been used to reduce the effects of influenza in elderly individuals. In
2000, 40 of 51 developed or rapidly developing countries recommended vaccination
for all individuals aged 60–65 or olderref,
and, in 2003, 290 million doses of vaccine were distributed worldwideref.
According to Centres for Disease Control (CDC), the main aim of vaccination
in elderly individuals is to reduce the risk of complications in those
who are most vulnerableref1,
ref2.
As such, they define 2 high priority groups—individuals aged 65 years or
older, and residents of nursing homes and long-term care facilities. 2
systematic reviews of the effects of influenza vaccines in elderly people
have been publishedref1,
ref2.
The firstref
was done more than a decade ago, and the secondref
has several methodological weaknesses—namely, the exclusion of studies
with denominators of < 30 and pooling of studies of different design—and
includes only 15 studies (Rivetti D, Demicheli V, Di Pietrantonj C, Jefferson
TO, Thomas R. Vaccines for preventing influenza in the elderly. Cochrane
Database Syst Rev 2005; 1:CD004876; Thomas R, Jefferson T, Demicheli V.
Influenza vaccination for healthcare workers who work with the elderly.
Cochrane Database Syst Rev 2005; 2:CD005187)
observational studies report that influenza vaccination reduces winter
mortality risk from any cause by 50% among the elderly. Influenza vaccination
coverage among elderly persons (65 years) in the USA increased from between
15% and 20% before 1980 to 65% in 2001. Unexpectedly, estimates of influenza-related
mortality in this age group also increased during this period. Researchers
tried to reconcile these conflicting findings by adjusting excess mortality
estimates for aging
and increased circulation of influenza A(H3N2) viruses.
Researchers used a cyclical regression model to generate seasonal estimates
of national influenza-related mortality (excess mortality) among the elderly
in both pneumonia and influenza and all-cause deaths for the 33 seasons
from 1968 to 2001. Researchers stratified the data by 5-year age group
and separated seasons dominated by A(H3N2) viruses
from other seasons. For people aged 65 to 74 years, excess mortality rates
in A(H3N2)-dominated seasons fell between 1968 and
the early 1980s but remained approximately constant thereafter. For persons
85 years or older, the mortality rate remained flat throughout. Excess
mortality in A(H1N1) and B seasons did not change.
All-cause excess mortality for persons 65 years or older never exceeded
10% of all winter deaths. Researchers attribute the decline in influenza-related
mortality among people aged 65 to 74 years in the decade after the 1968
pandemic to the acquisition of immunity to the emerging A(H3N2)
virus. Researchers could not correlate increasing vaccination coverage
after 1980 with declining mortality rates in any age group. Because <
10% of all winter deaths were attributable to influenza in any season,
researchers conclude that observational studies substantially overestimate
vaccination benefitref.
Numerous studies have shown that influenza vaccination works -- including
to help protect the elderly from serious illness and hospitalizations --
but the degree to which it works varies from year to year and can be difficult
to measure. For example, influenza seasons differ each year in length and
severity, and the health status of individuals also matters. The authors
in no way imply that the elderly should not receive influenza vaccine.
Rather, the study concludes that the vaccine may prevent fewer deaths among
the elderly than previous studies would have suggested. Another reason
for the apparent relatively poor performance of influenza virus vaccines
in the elderly is semantic. Any febrile infection is described initially
as flu-like and, in the case of upper respiratory tract infections, the
assumption is that (in the absence of laboratory diagnosis) the infection
is caused by influenza virus. Whereas in the elderly in some years other
respiratory tract viruses, respiratory syncytial virus in particular, can
be the cause of extensive outbreaks described as flu
according to reliable evidence, the effectiveness of trivalent inactivated
influenza vaccines in elderly individuals is modest, irrespective of setting,
outcome, population, and study design. In view of the known variability
of incidence and effect of influenza, we constructed a large number of
comparisons and strata to reduce to a minimum possible heterogeneity between
studies and to aid comparability. Despite our attempts we noted significant
residual between-studies heterogeneity that could be explained only in
part by different study designs, methodological quality, settings, viral
circulation, vaccine types and matching, age, population types, and risk
factors. We think the residual heterogeneity could be the result of the
unpredictable nature of the spread of influenza and influenza-like illness
and the bias caused by the non-randomised nature of our evidence base.
The findings of the cohort studies that we included are likely to have
been affected to a varying degree by selection bias; differential uptake
of influenza vaccines is linked to several factors (anxiety over unwanted
effects, disease threat perception, societal and economic conditions, education,
health status) and hence to outcome. Indeed, one cohort studyref,
had real difficulties in achieving high coverage in those most at need.
Differential vaccine uptake and the resulting selection bias is the most
likely explanation for the high effectiveness of influenza vaccines in
preventing deaths from all causes. A further example of the potential effect
of such bias is the apparently counterintuitive effectiveness of the vaccines
in elderly individuals living in the community. In this population, the
vaccines are apparently ineffective in the prevention of influenza, influenza-like
illness, pneumonia, hospital admissions, or deaths from any respiratory
disease, but are effective in the prevention of hospital admission for
influenza and pneumonia and in the prevention of deaths from all causes.
That such differences are the result of a baseline imbalance in health
status and other systematic differences in the two groups of participants
cannot be discounted. Evidence from randomised controlled trials, in which
bias is reduced to a minimum, is scant and badly reported. Unfortunately,
because of the global recommendations on influenza vaccination, placebo-controlled
trials, which could clarify the effects of influenza vaccines in individuals,
are no longer possible on ethical grounds. Whatever the causes of observed
variability, we believe that the decision to vaccinate against influenza
cannot be made on the basis of the results from single studies, reporting
observations from a few seasons, but that it should be taken on the basis
of all available evidence. The conclusions drawn from studies done in individuals
who live in long-term care facilities are different to those drawn from
studies in individuals who live in the community. Whereas studies done
in residents of care homes often indicate the inevitably improvised nature
of efforts to study the effect of vaccines during an epidemic often concurrently
in several locations, the resident population is usually more consistent
than that in the community: older, with similar viral exposure and risk
levels. Despite a remaining heterogeneity and an overestimation of the
effects as a result of study design, it is possible to detect a gradient
of effectiveness, in which vaccines have little effect on cases of influenza-like
illness, but have greater effect on its complications. This finding suggests
that control through vaccination is a possibility. The effectiveness of
vaccines in the community, however, is modest, irrespective of adjustment
for systematic differences between vaccine recipients and non-recipients.
The difficulties of achieving good coverage in those who most need it,
or the diluting effect on vaccines for influenza of other agents circulating
in the community (causing influenza-like illness, clinically indistinguishable
from influenza), might be to blame. Researchers noted empirical proof of
both, with differential vaccine uptake among the same population linked
to age, sex, and health status, and a low effect on influenza-like illness
throughout our datasets, even in periods of supposedly high influenza viral
circulation when the proportion of cases of influenza-like illness caused
by influenza and the possible benefits of vaccination are highest. On the
basis of these observations, we believe efforts should be concentrated
on achieving high vaccination coverage in long-term care facilities coupled
with a systematic assessment of the effect of such a policy. One possible
way to improve this strategy might involve the vaccination of carers in
an effort to reduce transmission (Thomas R, Jefferson T, Demicheli V. Influenza
vaccination for healthcare workers who work with the elderly. Cochrane
Database Syst Rev 2005; 2:CD005187). The effect of vaccination of high
risk groups should also be further assessed (Poole PJ, Chacko E, Wood-Baker
RWB, Cates CJ. Influenza vaccine for patients with chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2000; 3:CD002733; Cates CJ,
Jefferson TO, Bara AI, Rowe BH. Vaccines for preventing influenza in people
with asthma. Cochrane Database Syst Rev 2003; 4:CD000364; Tan A, Bhalla
P, Smyth R. Vaccines for preventing influenza in people with cystic fibrosis.
Cochrane Database Syst Rev 2000; 1:CD001753). Finally, investment in the
development of better vaccines than available at present should be linked
to better knowledge of the causes and patterns of influenza-like illnesses
in different communities. This partnership could lead to the inception
of a more comprehensive and perhaps more effective strategy for the control
of acute respiratory infections, relying on several preventive interventions
that take into account the multi-agent nature of influenza-like illness
and its context (such as personal hygieneref,
and provision of electricity and adequate food, water, and sanitation)ref.ref
in homes for elderly individuals (with good vaccine match and high
viral circulation) the effectiveness of vaccines (VE=1–relative risk (RR)
or VE*=1–odds ratio (OR)) against influenza-like illness was 23% and non-significant
against influenza (RR 1.04). Well matched vaccines prevented pneumonia
(VE 46%) and hospital admission (VE 45%) for and deaths from influenza
or pneumonia (VE 42%), and reduced all-cause mortality (VE 60%). In elderly
individuals living in the community, vaccines were not significantly effective
against influenza (RR 0.19), influenza-like illness (RR 1.05), or pneumonia
(RR 0.88). Well matched vaccines prevented hospital admission for influenza
and pneumonia (VE 26%) and all-cause mortality (VE 42%). After adjustment
for confounders, vaccine performance was improved for admissions to hospital
for influenza or pneumonia (VE* 27%), respiratory diseases (VE* 22%), and
cardiac disease (VE* 24%), and for all-cause mortality (VE* 47%). In long-term
care facilities, where vaccination is most effective against complications,
the aims of the vaccination campaign are fulfilled, at least in part. However,
according to reliable evidence the usefulness of vaccines in the community
is modestref.
improvement in the immune response to influenza virus vaccination in
the elderly represents the primary unmet need in influenza virus vaccination.
A booster immunostimulating (IS) patch for transcutaneous immunization
(TCI) developed by IOMAI Corp.
in Gaithersburg, Maryland, resembles a large sticking plaster pasted over
the skin puncture left by the jab : it contains Escherichia
coli labile enterotoxin (LT) used as an adjuvant and increases
the number of antigen-specific T-lymphocytes by up to 50-foldsref.
The skin patch might also be used to boost the response to other types
of vaccination. Many other research groups are seeking ways to enhance
the influenza vaccination for the elderly, using a range of different adjuvants
and ways to deliver them. Some are adding them directly to the vaccine;
others are wafting them up the nose
ambulatory individuals 65 years and older (N = 202) were assigned randomly
to receive a single intramuscular injection of the 2001-2002 formulation
of trivalent inactivated influenza vaccine containing 15, 30, or 60 µg
of hemagglutinin per strain (up to 180 µg total per dose) or placebo.
Clinical and serologic responses were assessed during the month after immunization.
Increasing dosages of vaccine elicited significantly higher serum antibody
levels, frequencies of antibody responses, and putative protective titers
after vaccination. Mean serum hemagglutination inhibition antibody titers
1 month after immunization in groups given 0-, 15-, 30-, and 60-µg
dosages were 23, 37, 50, and 61 against influenza A/H1N1;
43, 86, 91, and 125 against influenza A/H3N2; and
10, 14, 18, and 24 against influenza B, respectively. Mean serum hemagglutination
inhibition and neutralizing antibody levels against the 3 vaccine antigens
in participants given the 60-µg dosage were 44% to 71% and 54% to
79%, respectively, higher than those in participants given the standard
15-µg dosage, and the 60-µg dosage level nearly doubled
the frequency of antibody responses in those whose preimmunization antibody
titers were in the lower half of the antibody range. Dose-related increases
in the occurrence of injection site reactions were observed (P<.001),
but all dosages were well toleratedref
persons aged 2-64 years with underlying chronic medical conditions,
all women who will be pregnant during influenza season,
residents of nursing homes and long-term care facilities,
children 6 months-18 years of age on chronic aspirin
therapy
health-care workers with direct patient care
out-of-home caregivers and household contacts of children aged <6 months.
The WHO Recommendations for Influenza Vaccine Composition for the southern
hemisphere for 2005 (southern hemisphere winter) are the following :
an A/New Caledonia/20/99(H1N1)-like virus;
an A/Wellington/1/2004(H3N2)-like virus;
a B/Shanghai/361/2002-like virus. Currently used vaccine viruses include
B/Shanghai/361/2002, B/Jilin/20/2003 and B/Jiangsu/10/2003
The composition of the trivalent inactivated vaccine (TIV) for the
2004/05 season (Northern Hemisphere winter) was announced by the WHO in
Geneva on Fri 13 Feb 2004 :
an A/New Caledonia/20/99(H1N1)-like virus will be
retained as the H1N1 component of the vaccine
an A/Fujian/411/2002(H3N2)-like virus. A/Kumamoto/102/2002
is also available as a vaccine virus. Because of the growth properties
of the A/Wyoming/3/2003 and B/Jiangsu/10/2003 viruses, US vaccine manufacturers
are using these antigenically equivalent strains in the vaccine as the
H3N2 and B components, respectively.
a B/Shanghai/361/2002-like virus : candidate vaccine viruses include B/Shanghai/361/2002
and B/Jilin/20/2003, which is a B/Shanghai/361/2002-like virus
In 2005, > 10,000 influenza viruses from all continents were isolated and
characterized by the WHO/National Influenza Centers. These laboratories,
which are located in > 80 countries, form the backbone of the global influenza
surveillance program. Based on that assembled information, WHO on Fri 10
Feb 2005 published its recommendations on the formulation of the influenza
vaccine for the Northern Hemisphere. 2005 analysis, which concluded on
Thu 9 Feb 2005, was conducted by members of the WHO Collaborating Centers
on Influenza and has recommended that vaccines to be used in the 2005-2006
season (Northern Hemisphere) should contain the followingref1,
ref2
:
an A/New Caledonia/20/99(H1N1)-like virus
an A/California/7/2004(H3N2)-like virus (candidate
vaccine viruses are being developed); The decision on A(H3N2) candidate
vaccine viruses was postponed pending the identification of a suitable
high growth reassortant. Based on the results of antigenic and genetic
analyses and growth in hens' eggs, obtained by WHO Collaborating Centers
for Reference and Research on Influenza and Reference Laboratories, a high
growth reassortant virus derived from A/New York/55/2004
(A/California/7/2004-like) virus and A/PR/8/34, is suitable as a candidate
A(H3N2) vaccine virus
a B/Shanghai/361/2002-like virus (the currently used vaccine viruses are
B/Shanghai/361/2002, B/Jiangsu/10/2003 and B/Jilin/20/2003ref).
Influenza B viruses circulating worldwide can be divided into 2 antigenically
distinct lineages: B/Yamagata/16/88 and B/Victoria/2/87. Before 1991, B/Victoria
lineage viruses circulated worldwide; from late 1991 to early 2001, no
viruses of the B/Victoria lineage were identified outside Asia. However,
since March 2001, B/Victoria-lineage viruses have been identified in many
countries outside Asia, including the USA. Viruses of the B/Yamagata lineage
began circulating worldwide in 1990 and continue to be identified. The
type-B component of the 2005-06 influenza vaccine (B/Shanghai/361/2002-like)
belongs to the B/Yamagata lineage.
On Feb 19 the FDA advisory panel voted to change the current vaccine'san
A/California/7/2004(H3N2) strain to a different H3N2
strain known as A/Wisconsin(H3N2) strain. Experts
also recommended a shift from the less common B/Shanghai/361/2002 strain
to B/Malaysia/2506/2004, antigenically equivalent to B/Ohio/1/2005. The
panel recommended no change to the current vaccine's A/New Caledonia/20/99(H1N1)
strain. < 1% of all U.S. flu cases this year were caused by Influenza
B viruses. But experts are still considering the possibility of recommending
a "quadrivalent, or 4-strain, vaccine in the future that contains two types
of Influenza B virusref1,
ref2,
ref3,
ref4,
ref5 This decision presupposes that the avian influenza A(H5N1)
virus currently circulating in East Asia will remain confined to avian
hosts and will not acquire by mutation or sub-unit reassortment properties
facilitating human-to-human transmission, thereby becoming a novel pandemic
virus. A/California influenza virus, discovered by officials in Santa Clara
County late in 2004, already represents 20% of influenza cases in USA in
the 2004/005 season. The California strain has popped up in Canada, Mexico,
Europe, Asia, Africa and Pacific islands, so that WHO is predicting that
it will be the dominant influenza virus strain next fall and winter. This
rapid spread has led WHO to recommend that the A/California strain will
replace the H3N2 component of the vaccine; i.e. the
A/Fujian/411/2002(H3N2) virus. These recommendations
are used by pharmaceutical manufacturers to update the composition of the
influenza vaccines they produce. This annual adjustment is necessary to
match the vaccine with the changing viruses expected to be circulating
during the coming influenza season. Recommendations for the composition
of the vaccine to be used in the Southern Hemisphere will be made at a
meeting in September 2005. While influenza vaccine coverage has improved
significantly in the last 10 years, the vaccine is not reaching everyone
in the high risk categories. These categories, defined by WHO, include
the elderly, those who are at increased risk because they have other respiratory
or cardiovascular disease, and health care workers. However, influenza
vaccine use in developing countries remains minimal to nonexistent. In
2004, WHO's Member States set a goal of 60% coverage for those in these
high risk groups and 75% coverage by 2010. Since young children can develop
severe disease, some countries have also started including vaccination
of children as part of their national influenza policy. Vaccinating children
may not only reduce their disease burden, but it may also reduce transmission
to the elderly and others at increased risk. The current influenza season
is now approaching its peak. All elderly persons or those with a particular
risk of influenza should be vaccinated.
For the 2005/2006 influenza vaccine, 4 manufacturers expect to provide
influenza vaccine to the U.S. population. Sanofi Pasteur, Inc., projects
production of up to 60 million doses of trivalent inactivated influenza
vaccine (TIV). Chiron Corporation projects
production of 18-26 million doses of TIV. GlaxoSmithKline, Inc. projects
production of 8 million doses of TIV. MedImmune Vaccines, Inc., producer
of the nasal-spray, live attenuated influenza vaccine (LAIV), projects
production of approximately 3 million dosesref.
Because of the uncertainties regarding production of influenza vaccine,
the exact number of available doses and timing of vaccine distribution
for the 2005/06 influenza season remain unknown. As a result, CDC recommends
that only the following priority groups receive TIV before October 24,
2005: persons aged >65 years with comorbid conditions; residents of long-term--care
facilities; persons aged 2-64 years with comorbid conditions; persons aged
>65 years without comorbid conditions; children aged 6-23 months; pregnant
women; health-care personnel who provide direct patient care; and household
contacts and out-of-home caregivers of children aged <6 months. These
groups correspond to tiers 1A-1C in the previously published table of TIV
priority groups in the event of vaccination supply disruptionref.
Beginning 24 Oct 2005, influenza vaccine should be made available to all
persons. Healthy persons aged 5-49 years who are not pregnant, including
health-care workers who are not caring for severely immunocompromised patients
in special-care units, can receive LAIV at any timeref.
Vaccination Recommendations for Persons Displaced by Hurricane Katrina
: on 6 Sep 2005, CDC issued interim vaccination
recommendations for persons displaced by Hurricane Katrinaref.
Any displaced persons aged >6 months living in crowded group settings should
be administered influenza vaccine; children aged <8 years should be
administered 2 doses, at least 1 month apart.
Influenza surveillance reports for the USA are posted online weekly
during October-Mayref.
Unperfectly matched vaccines :
as the 2003/2004 season progressed, A/Fujian/411/2002 (H3N2)
viruses, which were antigenically distinguishable from the vaccine strain
A/Panama/2007/99 (H3N2), became predominant in the
USA (the 1st cases turned up in early
October 2003 in Texas: 82% of isolatesref),
resulting in a less than optimal match. An initial study to assess the
effectiveness of the 2003/2004 influenza vaccine against ILI in health-care
workers did not demonstrate effectiveness; however, preliminary analyses
of 3 additional unpublished studies of influenza vaccine effectiveness
among children and adults in the US were presented at the ACIP meeting
on 23 Jun 2004, and all demonstrated vaccine effectiveness. Influenza experts
at the WHO knew the Fujian strain was circulating when they met in February
2003 to decide which strains to include in this season's Northern Hemisphere
shot, but laboratories in the WHO's network failed to find a Fujian strain
that would grow in fertilized hens' eggs in time to include in this season's
vaccine. Approximately 83 million doses of vaccine were administered, in
a near-record. Studies showed reduced efficacy: estimated efficacy against
ILI in those vaccinated before 1 Nov was 13% and after 1 Nov was 3%ref.
It should be noted that in a study of patients aged greater than 65 years,
TIV was effective in preventing 61% of influenza-related deaths when the
vaccine and circulating strains were well-matched and 35% when they were
not well-matchedref.
The Pneumonia & Influenza death curves (P & I) contained in 2003
report indicate that the epidemic peaks of P&I deaths were markedly
increased from the 3 prior seasons (albeit less than for the 1999/2000
peak). This can be taken as additional circumstantial evidence that last
year was more severe, probably contributed to by a less-than-efficacious
vaccine.
the predominant flu virus around the globe in 2004 is A/Fujian, and the
vaccine Americans are seeking today is a perfect match for it. But, A/Wellington/1/2004(H3N2)-like
virus is gaining ground. Tests suggest that 43% of recent New Zealand flu
cases spring from the new strain, or variants of it. A/Wellington has even
turned up about as far from the South Pacific as is geographically possible:
in Norway. The late season surge of A/Wellington was so worrying that the
WHO, on 8 Oct 2004, recommended that 2005 flu vaccine for the Southern
Hemisphere, which is shipped in March, be reformulated to protect against
it. Laboratory animal tests suggest that the current vaccine -- which targets
A/Fujian -- is about 2/3rds less effective in stirring antibodies against
A/Wellington than it is against the targeted strain. Despite the late emergence
of the new flu strain, influenza was unusually mild throughout the Southern
Hemisphere from May through October 2004.
Shortages :
CDC predicted in May 2004 that 6-8 million doses of thimerosal-free flu
vaccine would be produced for people concerned about the preservative.
90 millions of high-risk people need flu shots in USA, with only 60 million
doses available : 12 millions of doses remained unused in 2002. The average
flu shot costs 20 US$, while a year's supply of Viagra costs US$ 3,500.
Oxford-based Chiron and Aventis Pasteur are each expected to produce roughly
50% of the projected 100 million doses for USA in 2004-2005 season, while
MedImmune is likely to supply about 3 million doses of the intranasal vaccine
FluMist. Chiron Corp. announced on Aug 2004 that it was delaying release
of its flu vaccine doses until early October because some lots of vaccine
didn’t meet sterility standards. The company said it expected to ship 46-48
million doses, down from the 50 million doses predicted previously. Chiron
said its planned "late-season delivery" of 2 million Fluvirin doses for
the CDC stockpile for the Vaccines for Children program remains on schedule
: those doses are in addition to the 46-48 million produced for general
distribution. Chiron says that it then performed careful safety tests,
and showed that the problem was confined to a few batches, with the vast
majority of the vaccine is safe. But on 5 Oct, Britain's Medicines
and Healthcare products Regulatory Agency (MHRA) informed Chiron that
it had safety concerns about the entire production facility in Speke, Liverpool
and suspended the firm's licence for 3 months. UK health authorities, which
use 5 other suppliers, say they have made alternative arrangements to make
up for the loss of Chiron's near 20% share of the National Health Service's
(NHS) supplies (2.4 million out of 14 million doses). The announcement
means a huge vaccine shortfall is probable in the USA, where Chiron was
due to supply nearly half of the 100 million doses expected. To a lesser
extent, the ban will also affect Britain. Health authorities will prioritize
remaining stocks of the vaccine to those who most need them, probably health
workers, children, the elderly and those with illnesses that make them
susceptible to infection. The department is also talking to the only other
major flu vaccine manufacturer, the French company Aventis Pasteur, to
see if it can make up some of the shortfall. But experts say it will be
difficult to produce a large batch of the vaccine in time to meet demand
by the start of the flu season. Known in the industry as FDA Form 483,
the FDA warned that the plant had failed to follow its own procedures to
investigate sterility problems. For instance, bacterial contamination was
found in a room that was supposed to be sterile, even after the room was
fumigated. Even then, the company failed to document the impact of this
sterility failure on its product. The company also failed to use proper
storage temperatures for its vaccine, failed to properly follow procedures
for cleaning and maintaining equipment, failed to properly review production
records for accuracy, and failed to take corrective action after experiencing
alerts of contamination. Ultimately, the company found Serratia bacteria
in nine of its 100 flu vaccine lots. Because the plant had failed to keep
adequate records of each vaccine batch, it could not trace where the problem
started, nor determine if the other 91 lots were contaminated. As a result,
none of the batches was safe to use. The discovery meant the loss of half
of the flu shots for the United States and about 10% to 20% of the United
Kingdom's doses. Poor inspections by under-trained inspectors only make
companies feel they have done sufficient work, and that is what gives rise
to GMP noncompliance problems. On Dec 8 U.K. regulators have extended the
initial suspension of Chiron's license to make flu vaccines, scheduled
to end Jan. 4, until March 2005 to allow time to fix the manufacturing
flaws, but possibly jeopardizing 2005-2006 supply. The same day U.S. health
officials announced an agreement to buy 4 million Fluarix doses from GlaxoSmithKline
Plc.
ID Biomedical Corp. signed
distribution agreements with 3 wholesalers to supply flu vaccine to the
U.S., possibly starting as early in 2005. If the shipments start later,
the total value of the purchases under the agreements may be about $2.3
billion if the vaccine is ready for U.S. use by the 2007-2008 flu season.
As of the week ended Nov. 27, Minnesota and Washington had reported flu
cases, and New York reported more cases around the state. 35 other states,
Washington, D.C., and New York City had sporadic reports of flu cases.
The estimates are that somewhere between 42- and 50 million people would
meet high-risk, or high-priority criteria, and request vaccination. There
are currently 22.4 million doses of flu vaccine produced by Aventis Pasteur
USA that have not been shipped. In addition to the doses of flu vaccine,
there is a federal stockpile of oseltamivir, and there are plans to add
up to 5 million treatment courses of rimantadine to the stockpile as well.
High-risk children, the elderly (> 65 years of age, with a focus on institutionalized
elderly), and the military would be included in the 1st wave of vaccinations
to be offered. The implications of this current vaccine shortage/crisis
are potentially highly significant in terms of expected P&I deaths
this coming year in the USA. As a result of the vaccine shortage, the CDC
is planning to teach people how to protect themselves through hygiene and
‘cough etiquette’ : you should avoid touching your eyes, nose or mouth
and if you do get flu, stay at home so that you don’t infect others. Complete
projected figures regarding the effects of the vaccine shortage on the
UK and other countries that were dependent upon this manufacturer are not
presently available for review/discussion. The UK Department of Health
said of the 14 million doses of flu vaccine they had ordered, Chiron had
only been due to supply 2.4 millionref.
In the USA the dearth of flu vaccine is having one small, unforeseen benefit:
people are flocking to join clinical trials of new ways to defeat the disease
and, perhaps, fuelling advances in protection. But even infants, the elderly
and others at high risk are struggling to find supplies and reports abound
of long lines outside clinics. Despite the shortage, some research groups
are still able to run clinical trials that aim to figure out how best to
use the existing vaccine. And some are testing experimental drugs or vaccines
for the future. One trial, headed by virologist Pedro Piedra at Baylor
College of Medicine in Houston, Texas, is testing whether the spread of
the influenza virus can be curbed by blanket vaccination of all school-age
children in a local area. Children are the most likely to get infected
and to pass on the disease to others, so the researchers hope to discover
whether it makes sense to target this group with vaccines in the future.
Because the trial is pretty much the only way many families can find a
jab for their kids, Piedra says the group has immunized around 3,000 children
in 10 days, a process that would normally take > 6 weeks. The interest
in clinical trials is also helping those testing experimental vaccines,
such as those that are grown in cells cultured in the laboratory rather
than in hen eggs. John Treanor at the University of Rochester, New York,
is recruiting around 400 healthy adults aged < 49 who are willing to
receive a syringe-full of a vaccine grown in insect cells with the baculovirus
protein expression system (e.g. Protein
Sciences : FluBlØk™, Recombinant Neuraminidase
(rNA) and SARS), which was tested in the elderly last year. At least
one company is willing to take any number of healthy people into their
trial. GenoMed, based in St Louis,
Missouri, wants to test whether ACEI
(binding receptors on WBCs inducing apoptosis and dampening an overactive
immune response and can actually ease symptoms) can also fight flu. The
company already has preliminary evidence that the therapy wards off West
Nile virus (WNV),
and the opportunity to test it on flu during the current shot shortage
was too good to pass up. Anyone interested can enrol by printing a form
from the company's website and taking it to their doctor in order to get
a prescription for the drugs; the company then sends follow-up e-mails
to check on subjects' progress. About 100 people have shown an interest
so far. Although the approach is experimental, the drugs are widely used
and safe enough to pose little risk
Acambis is working on a vaccine based on M2 protein, which does
not mutate : so a single shot of the vaccine could protect a person against
all strains of influenza virus.
Epidemiology:
the vaccine alone costs about 7 cents per bird, not counting the labor
of injecting or the monitoring that should accompany it.
Hong Kong : in 2002 began vaccinating their poultry with an inactivated
oil-adjuvant H5N2 Mexico strain vaccine commonly
used elsewhere to protect against imported virus : it provides cross-protection
and effectiveness in 80% of chickens against infection from the the 1997
H5N1 strain. Vaccination in the region is said to
be very widespread, probably in reaction to the wholesale destruction of
Hong Kong's chickens after the H5N1 cases in people
in 1997. In that occasion at 3 farms chickens in infected sheds were culled,
but chickens in other sheds were inoculated with a vaccine based on the
H5N2 strain. The virus spread to additional sheds
on 2 of these farms, killing some of the recently vaccinated chickens,
but 18 days after vaccination, when immunity had developed, there were
no new cases of disease among the vaccinated birds; intensive monitoring
found no evidence of asymptomatic shedding. In early 2003, Hong Kong added
universal vaccination to its control measures. Unvaccinated "sentinel"
chickens are placed within each flock, and there is regular serologic and
virologic testing. When H5N1 swept through neighboring
China early this year, Hong Kong remained virus-free.Hong Kong's experience
is not easily translated to other countries, however. Hong Kong's poultry
industry is limited to just 150 farms and a handful of families raising
backyard chickens. The territory is small and has an infrastructure capable
of fully monitoring the use of vaccines. In January 2004 Hong Kong began
requiring all imported poultry to be vaccinated with an inactivated H5
vaccine.
China : currently officially applied; in 2002 poultry farmers in southern
mainland China began vaccinating their poultry with an H5N1killed
virus vaccine made at the National Veterinary Research Institute at Harbin
to protect against imported virus : it provides cross-protection and effectiveness
in 80% of chickens against infection from the the 1997 H5N1strain.
Vaccination is compulsory in a radius of 5 km around infected or suspected
premises. Several of the vaccines in use are based on the H5N1
strain itself, making it difficult to track the disease. And the use of
unvaccinated sentinels and the serological and virological monitoring is
spotty at best. The National Emergency Plan Against HPAI has inoculated
poultry flocks in areas susceptible to avian influenza infection. China
has also inoculated poultry flocks on breeding farms, large-sized egg layer
farms and in areas with a high concentration of water bodies. Poultry
in certain areas designated "no enforced inoculation areas" or "no disease
infected areas" have not been inoculated. Other areas apply voluntary
inoculation. From February 2004 to January 2005, China has inoculated
a total of 2.68 billion birds -- mainly chickens, ducks and geese. The
objective of China's poultry vaccine is to inactivate the highly pathogenic
avian influenza (HPAI) virus H5N2. During 2004, this
vaccine played an important role in HPAI elimination and prevention in
China. The vaccine is only manufactured at the plants designated by the
Chinese Government. The National Reference Laboratory has also developed
2 new vaccines. One is a recombinant AI H5N1 virus
inactivated vaccine, and the other is a H5N1 fowl
pox live virus vaccine. They are highly efficient, safe and can be produced
cost-effectively. The vaccines passed the Ministry of Agriculture's new
animal drug evaluation and verification process at the end of 2004. The
recombinant H5N1 virus inactivated vaccine even works
better against the HPAI because its protective period for chickens is longer,
and it is especially effective for waterfowl immunity. The vaccine can
efficiently stop the spread of the HPAI virus. Now, it is widely
used for waterfowl inoculation in water concentrated areas in South China.
In order to strengthen disease control and guarantee inoculation quality,
the Ministry of Agriculture has carried out regular inoculation supervision
and evaluation through sampling serum and pathogen tests among inoculated
poultry flocks. Up to now, we have not isolated any H5N1virus
from our inoculated poultry flocks. At the same time, some provinces in
South China have adopted a measure of placing inoculated poultry in highly
exposed areas to watch the result of infection. Results of 3 vaccines currently
used in China:
A. AI inactivated vaccine (H5 sub-type, N-28 strain)
(seems to be a traditional inactivated oil emulsion H5 LP vaccine.
Based upon a H5N2 LP virus, it has been widely used
in China during 2004 as a DIVA (Differentiating Infected from Vaccinated
Animals) vaccine)
1) Seed virus: A/Turkey/England/N-28/73, low virulent strain imported from
Weybridge Laboratory Lab in Britain.
2) Result: The antibody level reached the highest rate, namely 8 log2,
during the 5th week after vaccination. This rate was maintained for 4 weeks.
The antibody protective level can be sustained into the 23rd week after
vaccination.
3) Feature: The Ministry of Agriculture approved this vaccine as a new
bio-product for animal inoculation in December 2003. This vaccine
was widely used in China during the outbreaks of HPAI at the beginning
of 2004.
B. Recombinant AI virus inactivated vaccine (H5N1
sub-type, Re-1 strain)
1) Seed virus: Artificially modified conventional seed virus A/Goose/Guandong/1996
(H5N1), which is representative for the antigen in
China, to make H5N1 virus inactive through recombination
with human flu virus.
2) Result: The antibody reached highest level of 9 log2 during the 3rd
week after vaccination. This rate was maintained for 4 weeks. The
antibody protective level can be sustained into the 25th week after vaccination.
3) Feature: MOA approved this vaccine as a new bio-product for animal inoculation
in January 2005. It works efficiently for avian influenza, it helps
poultry organs generate high levels of antibodies and the protective period
lasts longer. The laboratory experiments proved that waterfowl inoculated
with this vaccine are free of AI infection or infectivity. Many countries
in the world now use this method to try to develop vaccines, but only China
has succeeded and put the vaccine into commercial production.
The inactivated H5N1 vaccine used in China was produced
from a recombinant strain of LPAI (H5N1) constructed
by reverse-genetic techniques. The HA and NA were taken from a local prevalent
dominant strain of H5N1 (the sites related to the
high pathogenicity in HA was blocked/deleted), and the other 6 genes were
taken from the PR8 strain (previously isolated from humans). This recombinant
can grow well in Vero cells and chicken embryo. The use of this recombinant
as a vaccine candidate has been subject to extensive debates among Chinese
scientists; a lot of concern was expressed regarding the potential for
a 'gene switch' for the vaccine strain and field HPAI viruses and regarding
bio-safety procedures. Detailed information on the vaccine would have allowed
a serious look at relevant potential risks. However, the vaccine has been
widely used nationwide and the outcome is not known.
C. Recombinant fowl pox virus live vaccine for AI (H5
sub-type)
1) Seed virus: Use A/Goose/Guangdong/1996 (H5N1)
as part of gene donor to make a recombinant fowl poxvirus for a live vaccine.
2) Result: The antibody reached the highest level of 7 log2
during the 2nd week after vaccination. The antibody protective level can
be sustained into the 26th week after vaccination.
3) Feature: The Ministry of Agriculture approved this vaccine as a new
bio-product for animal inoculation in January 2005. It helps create
antibodies against the antigen of specific proteins. Therefore, it
is good to differentiate immunity and field infection. Mexico also
has this kind of vaccine and widely uses it.
D. bivalent Avian influenza/Newcastle disease vaccine, has been
developed by the Harbin Veterinary
Research Institute in northeast China's Heilongjiang Province
and quickly put into production before thorough bio-safety studies. The
new vaccine is safer, more convenient to use and cannot kill newborn chicks,
attributes that made it more attractive to farmers than a vaccine they
were already using. The vaccine can be injected, given as nasal spray or
as eye drops, or put into water supplies and immunizes birds against bird
flu and Newcastle disease. China will produce 1 billion doses by the end
of 2005. Production of the live vaccine costs 20% as much as inactivated
vaccines on the market, has a longer shelf life of 18 months, and
70-80% effectiveness. The Chinese bivalent vaccine might be related to
a previously published paper on experimental recombinant NCD/AI vaccine.
A recombinant vaccine (rNDV-AIV-H7) was constructed by using
a lentogenic paramyxovirus type 1 vector (Newcastle disease virus [NDV]
B1 strain, similar to LaSota) with insertion of the hemagglutinin (HA)
gene from avian influenza virus (AIV) A/chicken/NY/13142-5/94 (H7N2).
The recombinant virus had stable insertion and expression of the H7
AIV HA gene as evident by detection of HA expression via immunofluorescence
in infected Vero cells. The rNDV-AIV-H7 replicated in 9-10 day
embryonating chicken eggs and exhibited hemagglutinating activity from
both NDV and AI proteins that was inhibited by antisera against both NDV
and AIV H7. Groups of 2-week-old white Leghorn chickens were vaccinated
with transfectant NDV vector (tNDV), rNDV-AIV-H7, or sterile
allantoic fluid and were challenged 2 weeks later with viscerotropic velogenic
NDV (vvNDV) or highly pathogenic (HP) AIV. The sham-vaccinated birds were
not protected from vvNDV or HP AIV challenge. The transfectant NDV vaccine
provided 70% protection for NDV challenge but did not protect against AIV
challenge. The rNDV-AIV-H7 vaccine provided partial protection (40%) from
vvNDV and HP AIV challenge. The serologic response was examined in chickens
that received 1 or 2 immunizations of the rNDV-AIV-H7 vaccine.
Based on hemagglutination inhibition and enzyme-linked immunosorbent assay
(ELISA) tests, chickens that received a vaccine boost seroconverted to
AIV H7, but the serologic response was weak in birds that received
only one vaccination. This demonstrates the potential for NDV for use as
a vaccine vector in expressing AIV proteinsref.
The Chinese scientists applied a similar approach starting with LaSota
strain of NDV, inserting an H5 gene (from which virus strain?)
instead of H7. It would be helpful to obtain data on their work,
particularly the methods and results of challenge trials, hopefully with
better results than the ones obtained by the experimental rNDV-AIV-H7
vaccine.
During
2005, the Chinese Government will invest over RMB 5 billion (approximately
USD 600 million) in animal disease control. China uses the 3 kinds of poultry
vaccines, approved by MOA between Dec 2003 and Jan 2005, for AI prevention.
Indonesia : currently officially selectivelyapplied in regions where the
virus has appeared. Several of the vaccines in use are based on the H5N1
strain itself, making it difficult to track the disease. And the use of
unvaccinated sentinels and the serological and virological monitoring is
spotty at best
Thailand forbids it as it is worried that vaccination might enable the
virus to circulate silently among vaccinated birds, exposing farm hands
and families to infection.
Products
:
the application of AI vaccines with a heterologous neuraminidase (not N1,
in the current case; e.g. oil-adjuvant H5N2 Mexico
strain) is meant to enable their use as natural "marker" vaccines or
differentiating infected from vaccinated animals (DIVA). This method
has been advocated and applied in recent years in several countries, initially
Northern Italy) : there will be cross protection, in theory, but the shedding
of the wild virus might not be prevented.
an inactivated vaccine, based upon an H5N2 virus
isolated from ("carrier") geese in Foshan, 1996, developed by Chinese scientists
and announced on 16 Mar 2004 by China's Ministry of Agriculture (probably
as they have done for some 5 or 6 years). It can remain effective within
an animal's immune system for as long as 10 months
An outbreak of avian influenza (AI) caused by a low-pathogenic H5N2
type A influenza virus began in Mexico in 1993 and several highly pathogenic
strains of the virus emerged in 1994-1995. The highly pathogenic virus
has not been reported since 1996, but the low-pathogenic virus remains
endemic in Mexico and has spread to two adjacent countries, Guatemala and
El Salvador. Measures implemented to control the outbreak and eradicate
the virus in Mexico have included a widespread vaccination program in effect
since 1995. Because this is the first case of long-term use of AI vaccines
in poultry, the Mexican lineage virus presented us with a unique opportunity
to examine the evolution of type A influenza virus circulating in poultry
populations where there was elevated herd immunity due to maternal and
active immunity. The coding sequence of the HA1 subunit and the NS gene
of 52 Mexican lineage viruses that were isolated between 1993 and 2002
were analyzed. Phylogenetic analysis indicated the presence of multiple
sublineages of Mexican lineage isolates at the time vaccine was introduced.
Further, most of the viruses isolated after the introduction of vaccine
belonged to sublineages separate from the vaccine's sublineage. Serologic
analysis using hemagglutination inhibition and virus neutralization tests
showed major antigenic differences among isolates belonging to the different
sublineages. Vaccine protection studies further confirmed the in vitro
serologic results indicating that commercial vaccine was not able to prevent
virus shedding when chickens were challenged with antigenically different
isolates. These findings indicate that multilineage antigenic drift, which
has not been observed in AI virus, is occurring in the Mexican lineage
AI viruses and the persistence of the virus in the field is likely aided
by its large antigenic difference from the vaccine strainref.
an (homologous?) H5N1 fowlpox vaccine (inactivated/
live-attenuated? origin? adjuvants?) developed by Chinese scientists and
announced on 16 Mar 2004 by China's Ministry of Agriculture. Probably it
is produced by taking the H5 gene from H5N1
outbreak virus and inserting it into fowlpox virus (as David Swayne did
in the USA in 1997) and using it as a live fowlpox/AI vaccine, as has been
used in Mexico since 1997. It can remain effective within an animal's immune
system for as long as 10 months
Vietnamese researchers injected a vaccine based on weakened H5N1
bird flu virus on 3 monkeys early in Feb 2005, and 3 weeks later found
the monkeys were healthy and had produced antibodies. Vietnamese researchers
hope to have a vaccine ready for testing on humans in 2004
for humans : the only difference
is that when we vaccinate with annual flu, people have one shot because
they already have some background immunity. Here, we know the population
is totally naïve, so it's difficult to raise a protective immune response.
Because H5N1 is so deadly in chicken embryos, reverse
genetics is required to prepare the prototype H5N1
virus for vaccine production, which requires growth in chicken eggs : reverse
genetics will remove a stretch of 4-5 basic amino acids at the HA cleavage
site that allows the virus to replicate in every organ of a chicken's body
(rather than only in the epithelial tissues (respiratory and intestinal)
normally infected) and merges the NA and modified HA genes from H5N1
with the other 6 viral genome segments from (A/PR8/34)[H1N1],
a rapidly growing "master" strain of virus commonly used to make vaccines.
The reassortment prototype virus can be rescued in 1 week : after that
comes amplification in embryonated hen's eggs, followed by safety testing
in chickens and in ferrets. Within 4 weeks sufficient amounts of safety-tested
prototype vaccine virus will probably be available for the necessary 1
to 2 months of clinical trials. The resulting virus is recognized by the
human immune system and causes a protective immune response but no disease.
Vaccine developers :
in 1998, an American company announced the production of an experimental
batch of an H5N1 human vaccine, and, according to
their communication, delivered > 1000 doses of the new vaccine to the NIH
for use in trials
in May 2004 the NIAID contracted 2 suppliers of the annual influenza vaccine
to prepare 16,000 doses of an investigational H5N1
avian influenza vaccine. To make the vaccine, virus was taken from a patient
who died in February 2004 in Vietnam and altered with reverse genetics
to reduce pathogenicity.
Sanofi Pasteur (USA,
France) : in March 2005, Sanofi Pasteur had 8,000 doses ready to be shipped
to the NIH to begin clinical trials. A phase I trial started in March 2005
involved 450 healthy adults in Rochester, New York; Baltimore and Los Angeles
a French vaccine company that is now part of Aventis. The government could
decide to release the product under emergency conditions if an A(H5N1)
influenza pandemic struck before the testing process was completed. Although
cautioning that the vaccine has not been fully tested, the initial test
findings have given the federal government enough confidence to start the
process of adding millions more doses of the vaccine to the 2 million it
has bought. The present supply is stored in bulk form, and they cannot
put it in vials until they find out what the right dose is. The manufacturer
needs to know the dose and regimen to determine how much more vaccine it
can produce and make available to the USA and other customers. NIH announced
on Aug 2005 preliminary results of tests in 115 people of a vaccine against
the H5N1 avian flu virus, showing that 2 large doses
should protect adults from infection. But critics point out that the large
amounts needed mean the hundreds of millions of doses needed to tackle
a pandemic could never be produced. Vaccines that work at much lower doses
are urgently needed. The NIAID tested 4 concentrations of vaccine on 452
healthy adults. The drug was made by the pharmaceutical company Sanofi
Pasteur's facility in Swiftwater, Pennsylvania. 2 shots at 90 µg
of flu antigen each were needed to produce an immune response likely to
confer protection - the highest concentration tested. Annual flu vaccines
typically use a single shot of 15µg. Needing 2 doses of 90µg
is the worst-case scenario. If the entire US vaccine production system,
which can produce 180 million seasonal flu vaccines, was devoted entirely
to making pandemic vaccine at this concentration, it could make enough
for 15 million people: barely 5% of the US population. The US government
plans to stockpile the vaccine to protect first-responders in the immediate
aftermath of a pandemic. It has bought 2 million H5N1
vaccines from Sanofi Pasteur, and says it intends to buy 20 million more.
But given the test results, these would only protect 330,000 to 3.4 million
people, far short of the 20 million US goal. Sanofi Pasteur will double
its capacity to produce flu vaccine in the USA and France in 3-4 years
time. But that would not be enough to produce sufficient vaccines unless
the dose was < 15 µg. Critics argue that the vaccine must be changed
to work at much lower doses : this is difficult, as people have no natural
immunity to avian flu. Lower doses can be used for seasonal flu jabs, as
people have a natural exposure to such viruses in their daily lives, giving
them a low level immune response. Results from earlier trials suggest that
low doses might work in combination with an adjuvant : but regulatory agencies
treat adjuvanted vaccines as new products, and so require a lengthy approval
process. NIAID will now start tests of 3 adjuvants : they will also investigate
other dose-reducing strategies such as injecting the vaccine into skin
or muscle. The institute will also test the vaccine in children and the
elderly. An immune response in healthy adults does not guarantee that the
vaccine will work in these other groups. In the meantime, experts caution
that enthusiasm over early results might do more harm than good, making
policy makers and others responsible for pandemic preparedness feel optimistic,
and reluctant to speed up urgent pandemic preparedness.
Chiron (USA)'s half of the vaccine
supply has been delayed due to problems at its Liverpool facility used
to produce its commercial flu vaccine. They are manufacturing the clinical
supply of H5N1 in Liverpool, UK, in the same location
that makes our commercial vaccine, Fluvirin, but in a different part of
the facility : the US and France have each contracted with Sanofi Pasteur
to produce 2 million doses of the prototype vaccine.. But tests of the
Chiron vaccine have not started because of delays related to prior contamination
found in Chiron's plants. The NIAID has 8000 doses of the Chiron human
A(H5N1) vaccine and hopes to start testing it in
volunteers in late fall. The tests will follow the same steps taken with
the Sanofi-Pasteur vaccine
This
approach is disadvantaged by the lapse of time between choice of vaccine
strain and appearance of a pandemic virus which may have diverged by progressive
genetic mutation, or may even have acquired non-homologous H (and/or N)
antigens by reassortment.
ID Biomedical Corp. (Canada)
announced in Jan 2005 that it had begun development of a mock vaccine against
H5N1 using the genetically modified rH5N1
reference strain from the UK's National Institute for Biological Standards
and Control
National Institute for Biological Standards
and Control (NIBSC) in Potters Bar, London, UK and St
Jude Children's Research Hospital in Memphis, Tennessee, USA : an H5N1
candidate human vaccine was developed in 2003. The strain was based on
the virus isolated in February 2003 from a human case in Hong Kong. The
candidate prototype vaccines have already undergone basic tests to ensure
safety and effectiveness, genetic stability, and antigenic homogeneity
Sinovac (China) is currently advancing
its inactivated H5N1 vaccine (Panflu®)
through the various stages of pre-clinical studies. On March 25 2004, Sinovac
received a reassortant influenza strain (NIBRG-14) for developing
a Pandemic Influenza Vaccine (H5N1) from the British
National Biological Standard and Control (NIBSC), which is the WHO International
Laboratory for Biological Standards.
Vietnam : Hanoi-based Vaccine and Biological Products No. 1 Company will
test a homegrown bird flu vaccine on humans and poultry in summer 2005
after successful tests on mice and monkeys. The trials will be conducted
in August on a group of 10 to 20 people to check the vaccine's effectiveness
and safety. The vaccine, which has been successfully tested on mice and
monkeys, will later be given to 200-300 other people who are healthy and
have close contact with poultry. The same vaccine also will be tested on
poultry in June. If the results are successful, the company hopes to mass
produce the vaccine for humans and poultry in early 2006. The trials are
expected to be completed before January 2006.
Australia ?
a subvirion influenza A (H5N1) vaccine : enrolled
in the study were 451 healthy adults 18 to 64 years of age who received
two doses of the vaccine without adjuvant, each of which contained 90,
45, 15, or 7.5 µg of hemagglutinin antigen, or placebo. The vaccine
was produced from a human isolate (A/Vietnam/1203/2004 [H5N1])
of a virulent clade 1 influenza A (H5N1) virus with
the use of a plasmid rescue system, with only the hemagglutinin and neuraminidase
genes expressed. The rest of the genes were derived from an avirulent egg-adapted
influenza A/PR/8/34 strain. The hemagglutinin gene was further modified
to replace 6 basic amino acids associated with high pathogenicity in birds
at the cleavage site between HA1 and HA2. Immunogenicity was assessed by
microneutralization and hemagglutination-inhibition assays with the use
of the vaccine virus, although a subgroup of samples were tested with the
use of the wild-type influenza A/Vietnam/1203/2004 (H5N1)
virus. Although the 1203 vaccine was safe, with an unremarkable adverse-event
profile, its immunogenicity was poor to moderate at best. In fact, in only
one group did > 50% of the subjects reach the immunogenicity threshold
(defined a priori) of an antibody titer > 1:40 (typically thought of as
seroprotective) — the subjects who received two doses of 90 µg each
28 days apart — a total dose 12 times that of seasonal influenza vaccines.
Notably, the current worldwide manufacturing capacity for influenza vaccine
is estimated at only 900 million doses (at the dose level of 15 µg).
The requirement of 2 doses of 90 µg per person means that only 75
million persons (1.2% of the world's population) could be fully immunized,
and of those, only half would achieve seroprotection. Thus, vaccines must
contain much less influenza hemagglutinin to be widely useful as a global
public health measure. And there are some additional provisos. An antibody
titer of 1:40 does not guarantee protection from infection. People with
lower titers show protection against influenza, and people with higher
titers can have symptomatic infection. Moreover, the assumption that a
titer of 1:40 is seroprotective is based on circulating strains of seasonal
influenza. Whether the same will prove to be true for new influenza viruses
in people whose immune systems have not been primed is unknown. However,
even moderate levels of seroprotection could be useful for the public health
by preventing or decreasing transmissibility, severe symptoms, complications,
or death. An important issue is whether the 1203 vaccine offers cross-protection
against other H5N1 strains of influenza Aref.
Studies of different dose levels of vaccines administered with MF59 (a
licensed adjuvant in Europe), aluminum hydroxide, or other adjuvants are
urgently neededref.
We know from previous work that new hemagglutinin proteins (including H5)
in people who have not been primed are poorly immunogenicref1,
ref2.
In recognition of this fact, the Department of Health and Human Services
and the National Institutes of Health have funded studies of > 30 candidate
vaccines. Early results from some of these trials should be available in
the next 6 to 12 months. Previous studies of a new influenza A (H5N3)
vaccine administered with MF59 adjuvant showed that vaccine administered
without adjuvant was poorly immunogenic but that vaccine administered with
MF59 adjuvant in two doses, each as low as 7.5 µg, was highly immunogenic
and resulted in cross-neutralizing antibodies against influenza A (H5N1)ref1,
ref2.
Studies of an influenza A (H2N2) vaccine administered
with alum adjuvant had similar results: hemagglutination-inhibition titers
increased significantly at doses as low as 1.9 µgref.
The immediate development and testing of such antigen-sparing vaccines
administered with adjuvant are imperative both to improve immunogenicity
and to increase the number of doses available (if lower doses are effective).
In addition, live attenuated cold-adapted influenza vaccines are safe,
are immunogenic, and have the relevant advantage of cross-protection against
heterologous influenza strains — suggesting a promising avenue to the development
of pandemic vaccines. A contract for the development of such vaccines has
been awarded to MedImmune. Other approaches to vaccine development involve
DNA, adenovirus vectorsref,
and cell-culture manufacturing techniques to increase the speed and capacity
of vaccine production. These approaches are promising, particularly since
reverse-genetics reassortant vaccine candidates can be generated within
weeksref
The
H5N1 from the outbreaks in Viet Nam and South Korea
in late 2003-2004 has a different genetic sequence and antigenicity from
the 2003 H5N1 strain in Hong Kong =>
the H5 strains currently causing disease in South-East Asia
are recognised poorly by antiserum generated against 2003's H5vaccine
strains, and so the entire process is being repeated at NIBSC, at CDC in
Atlanta, and at St Jude Children's Research Hospital in emphis. The minimum
time to generate the new strain is about 1 month. On Feb 13, 2004 the NIBSC
has generated a reassortant candidate vaccine strain containing the HA
and NA of a human H5N1 influenza virus isolated recently
in southeast Asia (A/Vietnam/1194/04) (the other 6 viral genome segments
were supplied by the laboratory virus A/PR8/34).
it seems probable that the Chinese H5N1 vaccine is
also not a very close antigenic match for the Viet Nam virus. A flu vaccine
will allow flu virus for which it is not a close antigenic match to continue
to circulate at low levels in vaccinated flocks. So the Chinese vaccine
could allow the Viet Nam virus to spread if it is present. This could continue
unnoticed, without mass disease outbreaks to give the virus's presence
away, until it reached an unvaccinated flock. These would tend to be in
smallholdings, and would probably be ducks, because they traditionally
do not get sick with flu and are probably not commonly vaccinated. So the
discovery of H5N1 in a duck smallholding in Guangxi
is interesting. The currently circulating H5N1, like
the related one that caused an outbreak in Penfold Park, Hong Kong in 2003,
is unique in that it kills ducks as well as a variety of other birds. This
might make it less likely that wild birds are mainly responsible for carrying
the virus over long distances. It is interesting to speculate what selective
pressures an H5N1 virus circulating at subclinical
levels in very large numbers of partially-immunised chickens might be subject
to, and how that might relate to the emergence of the current outbreaks
It is possible that there is cross-protection in adults to the N1
component of H5N1 that is attenuating their presentation
: the neuraminidase protein is associated with severity of influenza illness,
so it is possible that there is protection against N1 in adults
from their cumulative experience with human N1 influenza viruses
that could be resulting in milder illness from this avian strain. Perhaps
immunologically naive young children do not have the benefit of this broad
cross-protection from other N1 exposure (influenza A (H1N1)
virus first emerged in 1918 -- the most severe of known influenza pandemics
-- a highly virulent strain. N1 subtypes have been co-circulating
with other influenza viruses since 1977, but H1N1
viruses cause less extensive or widespread outbreaks. It may be that younger
persons have not had the benefit of cumulative opportunities for antigenic
exposure and resulting cross-protection. When Influenza H1N1
reached England in 1977, nearly everyone infected with it (and confirmed
by a laboratory) had been born after 1956, when the H1N1
virus had previously disappeared, having circulated from 1947-1956. In
fact, in 3 consecutive years we had infections with H1N1,
H3N2, and then both together. Age distributions of
those affected in these years showed this very nicely: H1N1
<25y, H3N2 the usual J-shaped curve, and both
an amalgam of the 2 distributions. In contrast to the neutralizing, infection-preventing
antibody induced to the major antigen of the influenza virus -- the hemagglutinin
(HA), antibody to the NA is infection-permissive, yet disease-suppressive,
and it has been repeatedly demonstrated in experimental animals that this
effect results from partial suppression of virus load over a wide range
of antibody concentrations. There is epidemiologic evidence that the impact
of the H3N2 1968 pandemic was blunted by pre-existing
encounter of humans with the N2 NA in the H2N2decade
following the pandemic introduction of H2N2 virus
in 1957. The evolutionary rate of NA antigenicity is slower than that which
occurs with the HA. This could have implications for protective/preventive
approaches : could vaccination with already on hand H1N1
human strains attenuate disease due to H5N1, if not
prevent it altogether? However, there is another possible explanation for
the greater susceptibility of children to new influenza strains and even
subtypes. Immunity can be directed to antigens conserved between viruses
that do not share neuraminidase antigens, for example nucleoprotein (NP),
matrix (M), and the polymerases. This broad cross-protection, termed heterosubtypic
immunity, has been studied in animals for decades and can be mediated
by T-cell immunity as well as in some cases antibodies (see Epstein, S.L.
Control of influenza virus infection by immunity to conserved viral features.
Expert Rev. Anti-Infect. Ther. 1(4): 89-100, 2003). Can this form of immunity
protect against highly pathogenic H5N1 viruses? Vaccination
to NP and M was indeed shown to protect mice against lethal challenge with
H5N1 virusref
: do humans have heterosubtypic immunity? Dr. Suzanne Epstein conducted
a study of archival records from the Cleveland family study during the
1957 pandemic. The antigenic shift in 1957 was from H1N1
to H2N2, thus no shared NA. Nonetheless, records
suggest an effect of prior immunity, perhaps accumulated immunity to conserved
components. In particular, adults differed from children in the effect
of prior infection, with children getting flu again in 1957 despite earlier
bouts but adults rarely getting it again. This work is not yet published.
More investigation of the multiple possible explanations for the age incidence
data is needed. Another factor to consider in relation to age-related cross-protection
is the concept of original
antigenic sin (OAS)
first described by Francis in 1953: the serological response of an individual
to influenza A virus infection is dominated throughout life by the nature
of the antibody produced in response to the first influenza A virus infection.
It is a characteristic of viruses for which there are cross-reacting antigenic
types. Consequently the cross-reacting responses of adults will vary and
relate to the serotype of influenza A virus that was predominant when they
were young. However, the relationship is not straightforward. Powers and
Belsheref
observed that elevated titers of antibodies to heterologous antigens were
present both before and after vaccination in higher proportions of middle-aged
and elderly than young adults following vaccination with a current vaccine,
whereas antibodies to more recent antigens were prevalent in all age groups.
Notably, vaccine responses to heterologous viruses were consistently reduced
in frequency and magnitude with advancing age. Also, within each age group,
antibody responses against progressively older heterologous antigens tended
to diminish. These authors concluded that preferential orientation of secondary
antibodies toward priming epitopes (OAS) is not responsible for the age-related
impairment of antibody responses to influenza vaccine
Vaccines for avian influenza typically are aimed at hemagglutinin or neuramidase
on the outside of the virus capsid. A major problem with such an approach
is that the genes coding for these proteins have a very rapid mutation
rate, forcing commercial producers to wait for mutations to occur before
developing effective new versions of standard vaccines. However, a recent
study has revealed that the 1918 flu virus, like the H5N1
AI virus, has an E627K mutation in its PB2 component, which is located
inside the virus capsid. Other research has indicated that this mutation
strongly influences the virulence of H5N1. It seems
reasonable to believe that the constancy, over > 80 years, of the E627K
mutation could be exploited to begin developing a vaccine now, rather than
waiting for new mutations. The peptide sequence, DTVQIIKLL, present in
the PB2 protein of the H5N1 virus, would be expected
to bind to HLA-A26 restricted immune system cell surface receptors. Hence,
the bound peptide might be capable of stimulating protection from CTLs.
Should the present hypothesis be confirmed in laboratory studies, and an
effective vaccine developed for individuals expressing the HLA-A26 receptor;
further research would be indicated. This research would be aimed at determining
whether molecular modifications to the DTVQIIKLL peptide could make it
effective with other members of the HLA-A1 supertype to which HLA-A26 belongs.
In addition to allowing vaccine development to begin now, this peptide-based
approach would have the advantage of avoiding the use of dangerous, live,
avian influenza virus during mass productionref.
Commercialized formulas :
split-virus
vaccine (SVV) : the inactivated virus is chemically disrupted,
and then further purified. The split virus vaccine is less reactogenic
(associated with fewer side effects) than the whole virus vaccine, especially
in children and young adults. For this reason, only split virus vaccines
are recommended for use in children under 13 years of age.
Begrivac® (Behringwerke => Chiron, globally)
preservative containing
preservative-free
Elvarix® (VEB Sachsisches Serumwerk Dresden)
Fluarix®(GlaxoSmithKline
Inc., made by its German subsidiary Sachsisches Serumwerk) : a 1,000-person
(aged 18-64) phase III clinical trial started in Dec 2004 at 4 U.S. hospital
centers -- the University of Rochester Medical Center, the University of
Maryland School of Medicine, Cincinnati Children's Hospital, and Baylor
College of Medicine. Approved by FDA for use in adults
Aventis is the 1st leading flu vaccine manufacturer worldwide, which makes
about 45-50% of the world's supply
Fluzone® (Aventis Pasteur)
Imovax Gripe® (Aventis Pasteur)
Istivac® (Aventis Pasteur)
MFV-Ject® (Aventis Pasteur)
Vaxigrip® (Aventis Pasteur)
Baxter : PreFluCel® : phase II/III clinical trial
in Europe was suspended in Dec 2004 due to a higher than expected rate
of mild fever and associated symptoms in the clinical trial participants.
Chiron, based in California, is the 2nd leading flu vaccine manufacturer
worldwide. Chiron makes 4 influenza vaccines :
Fluvirin® (Evans Medical, Servier => Chiron), the
top flu vaccine in northern Europe and the No. 2 vaccine in the US.
Adinvira A+B® (Imuna)
Admun® (Duncan)
Admune GB® (Duncan)
Alorbat® (Asta Pharma)
Biaflu Zonale® (Farmabiagini)
Flubron® (Pfizer)
Flugen® (?, UK)
Fluogen® (Parke Davis)
FluShield® (Wyeth-Ayerst)
Fluviral® (Armand-Frappier)
Gripax® (Hebrew University)
Gripe® (?, Spain)
Gripovax® (GlaxoSmithKline)
Grippe® (?, France)
HIS® (Serbian Institute)
Inflexal® V (Swiss Serum and Vaccine Institute) :
A virosomal influenza vaccine, with a composition in accordance with annual
recommendations of the WHO
Influmix® (Schiapparelli)
Influpozzi Zonale® (Ivp)
Influvac® (Duphar)
Influvirus® (Ism)
Invirin® (GlaxoSmithKline)
Isiflu Zonale® (Isi)
MFV® (Servier)
Miniflu® (Schiapparelli)
Munevan® (Medeva)
Mutagrip® (Aventis Pasteur)
Nivgrip® (Nicolau Institute of Virology)
Sandovac® (Sandoz)
Vaxihaler-Flu® (Riker) : inhaler
Side effects :
atypical lymphoid infiltrations arose within the influenza inoculation
sites of two adult female patients. One patient developed a low-grade cutaneous
marginal zone B-cell lymphoma (MZL)
that was responsive to local excision and radiation therapy despite spread
to a distant cutaneous site. The second patient's clinical course was characterized
by a locally aggressive, histologically reactive inflammatory reaction
responsive only to radiation therapy after multiple failed attempts at
surgical resectionref
false positive results in HIV
serological testing due to cross-reactivity between the transmembrane domain
of HIV-1 env protein and HAref
anti-polioviruses
1, 2 and 3
vaccine (inactivated polio vaccine (IPV)) (see also attenuated
vaccine) : developed by Jonas Salk in 1957. Viruses cultured on primary
Cercopithecus
aethiops (African green monkey) kidney (CMK) cells and killed by
formalin. 4 intramuscular injections at month 1, 2, 3, and age 1. Effective
for > 5 years in 100%.
Purivax® (Merck) : no longer in use (1956 to 1965)
IPV-Virelon® (Chiron, Italy)
Virelon C® (Chiron, Germany)
The polio vaccine used in the USA from 1955 to 1963 was found in 1960
to be contaminated with SV40,
which resists to formol inactivation of polioviruses. The tainted vaccine
was never recalled. It may have been given to 10 million to 30 million
Americans. Vaccines made after 1961 were free of the virus. There is no
doubt that SV40 causes 4 cancers in rodents (osteosarcomas, ependymoma,
mesothelioma, and non-Hodgkin's lymphoma) : the virus has been detected
in tumor cells from people with the four cancers that develop in rodents.
Further CMK cells are often contaminated by simian
cytomegalovirus (SCMV)
in lots of vaccine manufactured prior to 1992 : SCMV DNA but not infective
forms have been found in CSF from patients with encephalopathies.
anti-rabies
virus
vaccine (see also DNA
vaccine)
: intramuscular injections at day 0, 7 and 21-28. Booster every 2 year.
Effective for 2-3 years. The original rabies vaccine discovered by Louis
Pasteur was administered to Joseph Meister. It can be preparated on cultures
of :
human diploid embryo lung cells (human
diploid cell vaccine (HDCV)) : inactivated with propiolactone, much
lower incidence of adverse reactions than the previously used...
Imovax
Rabies® / Imovax Rage®
(Aventis Pasteur Swiftwater, PA) : on April 2, 2004 following the discovery
through routine testing of a non-inactivated Pitman-Moore virus (the attenuated
vaccine strain) in a single product lot which was not distributed, some
lots of Imovax® Rabies, Rabies Vaccine (Human Diploid Cell)
that were produced during the same period as the lot that contained noninactivated
Pitman-Moore virus were recalled as a precautionary measure :
Country / Lot
Angola / X0713-4
Australia / X0713-1, X0074-3, X0074-4
Botswana / X0713-4
Croatia / X0074-1
Denmark / X0253-2
Chad / X0074-1
Germany / X0071-2, X0253-4
Hong Kong (China) / X0074-1
Ireland / X0071-6, X0712-1
Italy / X0253-6, X0253-8
Malawi / X0713-4
Mozambique / X0713-4
New Zealand / X0713-1, X0074-3, X0074-4
Netherlands / X0071-3
Norway / X0253-1
Nigeria / X0074-1
Oman / X0074-1, X0074-5
Spain / X0071-1
Switzerland / X0071-7, X0253-5, X0253-7
United Arab Emirates / X0074-1, X0074-5
United Kingdom / X0071-6
United States / W1419-2 (expiration date : 12/6/2005), W1419-3 (expiration
date : 12/6/2005), X0667-2 (expiration date : 6/24/2006), X0667-3 (expiration
date : 6/24/2006), distributed in the U.S. from September 23, 2003 through
April 2, 2004
Zambia / X0713-4
Zimbabwe / X0713-4
The
lots being recalled passed all release tests, including testing to confirm
the absence of live virus. All purchasers and distributors of vaccines
from the recalled lots are being notified. Health care providers will notify
any recipients of the recalled vaccine of next steps, which may include
the recommendation that some individuals receive additional doses of vaccine
and, if appropriate, rabies immune globulin.
hamster kidney
Semple rabies vaccine is composed
of rabies virus-infected sheep or goat brain inactivated with phenol and
is administered daily after exposure for 14-21 days. It has been abandoned
because 1 case in 220 immunized individuals develop Semple rabies postvaccinial
autoimmune encephalomyelitis
(SAE) 10-14 days after vaccination : it is mediated by IgM antibodies
to myelin
basic protein (MBP), GM1 or GD1a gangliosides
and Th1 lymphocytes reactive against MBP.
primary cultures
of chicken fibroblasts (purified chick embryo cell (PCEC) vaccine (PCECV))
: a lyophilized vaccine inactivated with b-propiolactone
fetal rhesus lung : rabies
vaccine adsorbed (RVA) : the virus is inactivated by b-propiolactone
and concentrated by adsorption to aluminum phosphate
purified
vero cell rabies vaccine (PVRV)
Abhayrab® (source : Human Biologicals Institute,
Ooty, India) : pre-exposure study was undertaken on 60 healthy volunteers
(Group I) with vaccination on days 0, 7 and 21. A group of 75 patients
of category II (Group II), 67 of category III (Group III) were given post-exposure
prophylaxis and 88 patients of category III were administered with rabies
immunoglobulins (Group IV) along with post-exposure prophylaxis as per
WHO recommendations with a booster on day 90. The volunteers and patients
vaccinated showed very few adverse side effects. The blood samples collected
from volunteers (Group I) on days 14, 35 and 365 and patients (Group II–IV)
on days 14, 30, 90 and 365 showed geometric mean titres (GMT) of >0.5 IU/mlref
Sinovac Biotech Co Ltd (Beijing,
China : in collaboration with the Chinese Academy of Medical Sciences,
has been funded with $2.2 million in grants from the Chinese government)
began the world's first clinical trial on May 22, 2004 : the first person
in the world to receive the vaccine was Lan Wanli, a university student
based in Beijing. At June 2004, 4 volunteers (3 men and 1 woman, all University
students) were injected. A second batch of 36 volunteers, aged 21 to 40,
was vaccinated at the Sino-Japanese Friendship Hospital in Beijing between
22 May and August 2004, developed antibodies, and experienced only some
fever and discomfort. Phase I trials completed by end of March 2005 The
vaccine appears to be safe, but the researchers do not yet know whether
it will provide protection against SARS by stimulating the production of
protective antibodies. Scientists in Beijing will carry out the phase II
trials among volunteers aged 20 to 60 to test the effectiveness of the
vaccine in 300 human volunteers : the persistence of antibodies will be
monitored over a 9-month period after the vaccine is administered. Whether
it can conduct Phase III trials may depend on nature: Large-scale, conventional
Phase III trials can begin only if another outbreak creates a large pool
of infected people. Scientists in Singapore cloned the surface protein
of a coronavirus into Lactobacillus casei bacteria. This was then
fed to mice which developed resistance to infections.
inactivated anti-bacterial vaccines (bacterin)
polybacterial immunostimulators
oral
Alvakol®
Biostim® (source : Aventis Pharma) : a broad-spectrum
antigenic preparation from Klebsiella
pneumoniae
Broncasma Berna® (source : Swiss Serum and Vaccine
Institute, Berne) : a 1-ml dose contains 50 x 106 pneumococcal
types I, II, and III; 40 x 106 streptococci; 500 x 106
staphylococci; 60 x 106Moraxella
catarrhalis;
20 x 106Gaffkya tetragena; 250 x 106Pseudomonas
aeruginosa;
40 x 106Klebsiella
pneumoniae;
and 40 x 106Haemophilus
influenzae serotype B (Hib)
and conservans (maximum 0.4% phenol). The usual vaccine regimen consists
of 5 escalating doses: 0.1 ml, 0.3 ml, 0.5 ml, 0.7 ml, and 1.0 ml. It has
been safely used throughout the world for 30 years for the prevention or
treatment of recurrent tonsillitisref
(0.05 mL given once every 4 to 14 days (average once a week) on 3 to 20
occasions (average 8)), chronic
sinusitis
and nasal allergyref,
chronic lower respiratory infectious diseaseref,
noncholesteatomatous chronic
suppurative otitis mediaref
(7 0.05-ml injections), recurrent hordeolumref
OM-85 Broncho-Vaxom (BV)®, Imocur®(source
: Fournier or Zambon, France): lysates from eight pneumotropic
bacteria for recurrent acute respiratory tract infections (RARTIs)
Dentavax® : killed cells from Klebsiella
pneumoniae,
Streptococcus
pyogenes,
Staphylococcus
aureus,
Candida
albicans
and Lactobacillus
acidophilus
and their lysates for the prophylaxis and treatment of inflammatory periodontal
diseases. The stimulating effect of the preparation was evaluated in 12
volunteers immunized for 10 consecutive days. On days 7, 14, 21, 28 and
49 after the last immunization peripheral blood (PB) lymphocyte subsets,
T lymphocyte activation and PB phagocytic activity, were studied by flow
cytometry. PB lymphocyte proliferative responses to PHA, rIL-2, LPS and
D were evaluated radiometrically. The production of TNF-a
in supernatants of in vitro stimulated lymphocytes and specific
IgA, IgM and IgG antibodies in serum and saliva was determined by ELISA.
Ultrastructural morphologic changes in T and B lymphocyte populations were
also investigated. Although no significant changes in the levels of basic
lymphocyte subsets were detected, the early/late (CD57+/CD57-)
CD8 T effectors ratio was increased at the end of the studied period, as
were the percentage of PHA-responding (CD69+) T cells and PB
phagocytizing cells. The most prominent lymphoprolipherative responses
were measured upon costimulation with LPS+D and PHA+D on day 21. Electron-microscopic
studies demonstrated a significant effect of D on both T and B cell activity.
TNF-a concentration increased progressively
from day 7 till the end of the investigation. Maximal concentrations were
observed after stimulation with D and LPS. An increased level of specific
salivary and serum antibodies against the components of D was found, with
highest levels between days 7 and 21. Specific secretory IgA predominated
in saliva as compared to IgM and IgGref
Factor R® :
ImmunoRx® (Munogen) : killed and freeze-dried lysates
and bacterial bodies of Lactobaccillus bulgaricus and ...
OK-432 / NSC-B116209 (Picibanil®):
prepared from a strain of group A Streptococcus
pyogenesby
treatment with heat and penicillin,
its main ingredient is the lipoteichoic acid (LTA)-related molecule
(OK-PSA), which binds to TLR4
intramuscular administration 3 times at weekly intervals, booster injection
after 6 monthsref
p.o. ?
vaginal mucosal self-administration at 0, 1, 2, 6, 10 and 14 weeks : of
patients receiving 6 immunizations 55% did not experience an infection
in next 6 months, whereas 78% of primary immunization and 89% of placebo
treated women had UTIs. No women had significant adverse effects. Furthermore,
in patients who were re-infected, the median infection-free period was
160 days in the booster group versus 59 days in the primary group and 35
days in the placebo groupref.
LW 50020: multibacterial lysate vaccine for administration
consisting of antigens of 7 bacteria commonly involved in respiratory tract
infections (RTIs), including recurrent tonsillitis
Luivac® (source : Sankyo, Tokyo, Japan)
Paspat oral® (source : Altana Pharma or Luitpold
Werk, Munich))
anti-Bordetella
pertussis
vaccine : containing agglutinogens 1, 2 and 3. Each 0.5 mL dose contains
not less than 41.U of pertussis vaccine and not more than 20,000 million
organisms. Thimerosal
is added to a final concentration of 0.01%. Store between 2°C and 8°C
and protect from light. Do not freeze. This vaccine should not be used
if it has been frozen.
Protocol : 3 x 0.5 mL deep subcutaneous
or intramuscular injection at intervals of not less than 4 weeks (usually
at weeks 8, 16 and 24). Boosters after 1 and 5 years. Routine pertussis
immunization is recommended for all children under 6, except when a specific
contraindication exists.
Contraindications : history (or family
history) of convulsions, epilepsy, cerebral irritation in the neonatal
period or any other disorder of the CNS, infection, severe allergy, acute
illnesses
Side effects : mild in ~ 20% (erythema
at the site of injection during the 24 hours following vaccination, transient
fever, restlessness, irritability, crying or loss of appetite a few hours
after vaccination). About 0.1% of infants experience convulsions 10-14
days after receiving the vaccine and in a very small number of cases (1
in 20,000-50,000) postvaccinial
autoimmune encephalomyelitis
occurs : reactogenicity mainly depends on presence of pertussis toxin and
LPS.
anti-Salmonella
typhi, Salmonella paratyphi A and Salmonella paratyphi
B
vaccine (TAB vaccine) (see also attenuated
vaccine) : either acetone-dried or phenol-inactivated. 2 subcutaneous
injections separated by 1 month. Boosters every 3 yrs. It confers about
70 per cent protection, which can be overcome by a large challenge. Immunization
is recommended only for exposure due to travel, epidemic, or household
contact with a carrier. No longer used due to short protection and side
effects.
T.A.B.® (Institute Pasteur)
TAB® (Pharmaceutical Industries Corporation)
TAB Vaccine® (?, Egypt)
Titifica® (?, Italy)
Typhoid Vaccine® (Wyeth-Ayerst)
Typhopara-typhoidique® (?, France)
anti-Vibrio
cholerae
injectable vaccine (contains 4 .
109 vibrios serogroup O1 Inaba and Ogawa serovars / mL) (see
also DNA vaccine)
: 2 subcutaneous or intramuscular doses separated by 1-6 weeks. Boosters
every 6 months. Side effects within 2 dd. It doesn't protect from infection
because it doesn't induce IgA production, so does not reduce carrier status,
fecal shedding of bacteria or reduce disease transmission..
Vibriomune®
(Duncan, Flockhart)
anti-Vibrio
cholerae
oral vaccine => induces IgA production
(Cholerix®) : 1011 vibrios as
above + 1 mg B subunit of cholera toxin in a buffered solution ingested
with water. Effective in 40÷65% (no in babies and individuals with
O blood group), it protects only for 3-6 months.
cholera-toxin B subunit, killed whole-cell (rBS-WC)
oral cholera vaccine : contains inactivated
whole cells of the classic and El Tor biotypes of V. cholerae, serotypes
Inaba and Ogawa, as well as recombinant cholera-toxin B subunit. International
health experts carried out the world's first mass cholera vaccination in
Esturro (Beira, Mozambique's second-largest city, population 21,818), from
December 2003 to January 2004. 50,000 people received 2 doses of the oral
vaccine. They then assessed vaccine protection in a case–control study
during an outbreak of El Tor Ogawa cholera in Beira between January and
May 2004. A year later, researchers have determined that receipt of one
or more doses of rBS-WC vaccine was associated with 78% protection (95%
confidence interval, 39 to 92% P=0.004). The vaccine was equally effective
in children younger than five years of age and in older persons and was
90% protective against cholera of life-threatening severity. The study
could pave the way towards expanded use of vaccines against cholera, a
major public health threat in about 50 poor countries around the globe.
The vaccination was carried out by IVI, the World Health Organisation,
the Mozambique Health Ministry, Medecins Sans Frontieres and others, with
doses donated by SBL Vaccines in Sweden. The experiment also proved for
the first time that the vaccine can protect HIV-infected individuals against
cholera : it is remarkable that such a high level of protection was observed
in Beira, a population where 20-30% of adults are living with HIV. Beira
was chosen for the experiment because of the high levels of cholera - between
4,000 and 5,000 cases annually among its population of 500,000ref
anti-Yersinia
pestis
vaccine : it contains at the time of manufacture 1.8-2.2 x 109
per mL of formaldehyde-killed plague bacilli in sodium chloride injection,
USR. The product may also contain trace amounts of: beef heart extract,
yeast extract, the peptones and peptides of soya and casein, agar and not
more than 0.019% formaldehyde. It is preserved with 0.5% phenol and supplied
in a 20 mL vial. Store at 2-8°C (35-46°F). Do not freeze.
Indications :
laboratory and field personnel who are working with Y. pestis organisms
resistant to antimicrobics
persons engaged in aerosol experiments with Y. pestis
persons engaged in field operations having occupational or avocational
exposure to wild rodents in plague enzootic areas. where prevention of
exposure is not possible (such as some disaster areas) and/or at times
when regular sanitary practices are interrupted
Contraindications : hypersensitivity to any
of the product constituents, severe thrombocytopenia or any coagulation
disorder that would contraindicate intramuscular injections, severe febrile
illness, same occasion as typhoid or cholera vaccines (to avoid the possibility
of accentuated side effects), pregnants (unless clearly needed)
Protocol : intramuscular injections into
the deltoid muscle.
dose number
age <1
age 1-4
age 5-10
age >10
1
0.2 mL
0.04 mL
0.6 mL
1.0 mL
2 (after 1-3 months
0.04 mL
0.08 mL
0.12 mL
0.2 mL
3 (3-6 months after the second injection)
0.04 mL
0.08 mL
0.12 mL
0.2 mL
boosters
0.02-0.04 mL
0.04-0.08 mL
0.06-0.12 mL
0.1-0.2 mL
The series of 2 injections will produce adequate protection in the vast
majority of human beings who have never received this vaccine : however
7% of the individuals fail to produce detectable Ab even after the second
booster dose, but some may produce an adequate response following the third
injection. The mean titer of antibody to F1 capsular antigen determined
by PHA test, is 1:25, 1:140, and 1:576 at 15, 105, and 285 days, respectively.
It protects for 6-12 months and increases the chances of recovery in those
vaccinated individuals who may develop the insect-borne (bubonic) form
of the infection, but is not effective against pulmonary pestis. Booster
injections of 0.1-0.2 mL should be administered at 6-month intervals to
individuals remaining in a known plague area : the smaller dose should
be approached as the total number of such injections increases. It should
be noted, however, that booster doses at intervals > 6 months, e.g., 1-2
years, may be appropriate for persons who have received > 3 booster doses
at 6-month intervals. In persons who have an unusually high risk of infection
or who have a history of serious reactions to the vaccine, PHA should be
determined in order to govern the frequency of booster doses.
Side effects :
local (subside within 2 days)
erythema and induration at the site of injection (~ 10%)
tenderness and edema
sterile abscesses
systemic effects (~ 10%, persist for only a few days)
The increased frequency and severity of adverse reactions following repeated
doses appear to depend on the number of doses received the method by which
the doses are administered, and the reactivity of the individual.
Commercialized formulae :
Sampar® (Aventis Pasteur)
Vaksin Sampar® (Perum Bio Farma)
anti-Rickettsia
prowazekii
vaccine : a formalin-inactivated vaccine of chick embryo origin
Cox vaccine : cultivated on fertile egg membrane
Weigl vaccine : cultivated in vivo on Pediculus humanus corporis,
phenol-killed gut extract
Protocol : 2 intramuscular injections separated
by 1 month. Effective for 10 years in a limited number of vaccinated people
: booster every 6-12 months. . Efficacy of this vaccine has not been established
and it is no longer available in the United States. A live vaccine containing
the attenuated Madrid E strain is protective but can cause mild
symptomatic infection; it also is not generally available.
anti-Rickettsia
rickettsii
vaccine : grown in yolk sacs of embryonated chicken eggs; it had limited
effectiveness and is no longer available. A new chick embryo cell culture
vaccine is under investigation.
Protocol : 2 intramuscular injections
seprated by 1 month. Effective for 2 years.
Commercialized formulae :
Vax-Spiral® (Finlay Vaccunas y Sueros Centro de Investigacion)
killed
but metabolically active (KBMA) bacteria : this strategy simultaneously
takes advantage of the potency of live vaccines and the safety of killed
vaccines. Genes required for nucleotide excision repair (uvrAB)
were removed, rendering microbial-based vaccines exquisitely sensitive
to photochemical inactivation with psoralen and long-wavelength ultraviolet
light. Colony formation of the nucleotide excision repair mutants was blocked
by infrequent, randomly distributed psoralen crosslinks, but the bacterial
population was able to express its genes, synthesize and secrete proteins.
Using the intracellular pathogen Listeria monocytogenes as a model
platform, recombinant psoralen-inactivated Lm uvrAB vaccines induced
potent CD4+ and CD8+ T-cell responses and protected
mice against virus challenge in an infectious disease model and provided
therapeutic benefit in a mouse cancer model. Microbial KBMA vaccines used
either as a recombinant vaccine platform or as a modified form of the pathogen
itself may have broad use for the treatment of infectious disease and cancerref.
attenuated
live germs (live vaccine / replicative vaccine)
: a vaccine prepared from live microorganisms or viruses that have been
attenuated but that retain their ability to reproduce and immunogenic properties.
They are usually administered in a single dose. Not to administer
to immunocompromised subjects or to females that could become pregnant
within 3 months ! Virulence reversion risk, frequent side effects. They
need low temperature storage. Attenuation (lessening of virulence) may
be obtained by ...
Anyway these vaccines are actually cocktails containing complete repertoires
of antigenic forms of the corresponding germ : administering a complete
repertoire of antigenic variants confers immunity simultaneously against
all variants thus preventing the microbe varieties from persisting. Of
course, instead of an increase in antigenic heterogeneity during "attenuation",
some antigenic variants might overpower others; in any case, success in
achieving a complete repertoire will depend on the choice of experimental
conditions (e.g. duration of the disease or even the health conditions
of the animal used). This corresponds to the present severe difficulty
of empirically finding the right method of "attenuation". Understanding
vaccines as multivalent strains not only substantiates the fact of the
very existence of vaccines, but also explains some well-known phenomena
which otherwise are treated as pure paradoxes :
antigenic switching was always considered a nearly fatal obstacle to creating
vaccines. It is therefore unclear how immunologists of the past, unaware
of the existence of this problem, nevertheless succeeded in designing effective
vaccines for antigenically unstable microbes.
vaccines for rabies or smallpox were isolated from their "wild" relatives
more than century ago and have since evolved in absolutely independent
directions. This obviously led to increasing differences between 'wild'
viruses and vaccines and consequently to loss of antigenic similarity.
But, in fact, no worsening of vaccine quality over time has been reported.
any real vaccine includes different antigenic variants present in concentrations
differing by several orders of magnitude. For live vaccines this is not
significant as any small population will yield its own wave of parasitemia
providing sufficient specific immunity. But for inactivated vaccines the
quality of the immunity elicited is obviously proportional to the concentration
of antigen, so the protective effect of such vaccine will not be uniform
for different antigenic variants.
the gradual transmutation over time of virulent microbes into vaccines
is quite incompatible with what we would expect from viruses, as even a
single mutation usually means an abrupt change in virus properties, so
coexistence of various sets of viral forms with continuous change in virulence
seems a miracle. But as population overgrowth is described by an exponential
function, collecting vaccine after a few attenuation cycles ensures that
most variants are represented and the formers are still present. A classical
quantitative illustration of this transmutation phenomenon is the so-called
fixation of rabies virus described by Pasteur : after transmission from
a dog followed by sequential passages in rabbits, the duration of incubation
abruptly decreases from about 20 days to about 10 days after first 2-3
passages and then for a very long time this value approaches a stable value
of about 7 days.
Some examples :
live attenuated anti-viral vaccines
anti-flavivirus vaccines :
without effective antiviral drugs, vaccination offers the best chance of
decreasing the incidence of these diseases, and live virus vaccines are
the most promising and cost effective. However, flaviviruses can recombine,
which raises the possibility of recombination between a vaccine strain
and wild-type virus resulting in a new virus with potentially undesirable
properties, but steps can be taken to minimise risk. The development of
non-live flavivirus vaccines should be encouragedref.
anti-Japanese
encephalitis virus (JEV)
vaccine : single dose SA 14-14-2 given to children aged 1–15
years in the Terai region of Nepal in July 1999 afforded sustained high
protection ref1,
ref2
anti-dengue
virus
vaccine (see also DNA
vaccine)
: up to 90% seroconversion rates in a phase I trial of live-attenuated
dengue-virus vaccines in childrenref.
VDV3, a clonal derivative of the Mahidol live-attenuated dengue 3 vaccine
was prepared in Vero cells. Despite satisfactory preclinical evaluation,
VDV3 was reactogenic in humans. While no variations were seen in serum
IL-12 or TNF-a levels, a high IFN-g
secretion was detected from Day 8, concomitant to IFN-a,
followed by IL10. Specific Th1 and CD8 responses were detected
on Day 28, with high IFN-g/TNF-a
ratios. Vaccinees exhibited very homogeneous class I HLA profiles, and
a new HLA B60-restricted CD8 epitope was identified in NS3. Among other
factors, adaptive immunity may have contributed to reactogenicity, even
after this primary vaccination. In addition, the unexpected discordance
observed between preclinical results and clinical outcome in humans led
us to reconsider some of our preclinical acceptance criteriaref.
anti-yellow
fever virus (YFV)
vaccine : chick embryo origin, 1 subcutaneous injection with Rockefeller
17D strain. Effective for > 10 years in 100% : booster every 10 years.
Amaril® (Aventis Pasteur)
Arilvax® (Wellcome; Purdue Pharmaceuticals PLC, The
Netherlands)
There are only 4 manufacturers whose YF vaccine has been prequalified by
WHO as of 7 Jan 2005ref
::
Aventis Pasteur, France
BioManguinhos, Brazil
Institut Pasteur Dakar, Senegal
Evans Vaccines, (formerly Medeva), U.K.
Aventis Pasteur USA & the Institute of Poliomyelitis & Viral Encephalitis,
Moscow, Russia, have been removed from the list. Colombia and India produce
YF vaccines, but these have not been prequalified by WHO.
Yellow fever vaccine has been successfully used to prevent the disease
since 1937. Yellow fever vaccine associated viscerotropic disease (YFV-AVD)
and neurotropic disease (YFV-AND) have been recently identified
in various countries. Previously post-vaccination multiple
organ system failure
was recognised as a rare serious adverse event of yellow fever vaccination
and 21 cases of postvaccinial
encephalitis
had been recorded. However, reports of YFV-AVD, after administration of
17D-204
and 17DD vaccines, suggest we need to revisit the vaccine's safety
profile, specifically with attention to host-dependent risk factors. Since
1996, 9 cases of YEL-AVD, a disease clinically and pathologically resembling
naturally acquired yellow fever, have been reported in the USA; an additional
14 cases have been identified worldwide as of July 2004. 14 (61%) of these
cases have been fatal. In several cases for which tissue samples were available,
results of IHC indicated viral dissemination throughout the body, including
to the liver, lungs, spleen, lymph nodes, brain, and smooth muscle; however,
in many cases, tissue samples were not available for histopathological
review or detection of virus. In the USA, the reported incidence of YEL-AVD
is about 3 cases per million civilian doses distributed; a similar incidence
has been reported in the UK. In a review of reports made since 1990 to
the US Vaccine Adverse Event Reporting System, a passive reporting system,
advanced age was shown to be a risk factor for YEL-AVD; individuals aged
older than 60 years seem to be at increased risk. Because of the low incidence
of YEL-AVD, identifying risk factors is challenging. However, 4 (17%) of
the 23 vaccinees reported with this syndrome had a history of thymus disease,
suggesting that thymic dysfunction is an independent risk factor for YEL-AVD.
One fatal case of YEL-AVD involved a 67-year-old woman from the USA. The
patient had a history of thymectomy, for a malignant thymoma, about 2 years
before vaccination. A 2nd US case involved a 70-year-old man with a history
of hyperthyroidism, myasthenia gravis, and thymectomy for thymoma 20 years
before vaccination. This patient survived. The 3rd individual was a 50-year-old
man from Switzerland who had a history of thymectomy due to thymoma 8 years
before vaccination. He also survived. The 4th individual was a 44-year-old
man who developed fatal YEL-AVD with fulminant hepatic failure after yellow
fever vaccination in Colombia. 2 years previously, he had had a thymectomy
due to benign thymoma. The thymus is important in regulating the integrity
of T-cell and B-cell function. Thymic tumours are rare and are associated
with various autoimmune disorders. When thymectomy is undertaken
to suppress such autoimmune disorders, administration of serum immunoglobulin
is recommended to protect against infectionref.
In an adult mouse model, immune suppression induced by antithymocyte serum
potentiated lethal yellow fever 17D infectionref.
Thymomas are also associated with reduced numbers of circulating B lymphocytes
and hypogammaglobulinemia in adults. The incidence of thymoma increases
with age above 40 years up to age 80 yearsref,
and there is also thymic involution during normal aging.
This suggests that changes in the thymus may contribute, in part, to the
increased risk of YEL-AVD observed in elderly individuals. A retrospective
study looked at the effect of vaccination with live viral vaccines in children
with DiGeorge syndrome, which is associated with thymic hypoplasia and
diminished T-cell counts. These children did not have a higher rate of
adverse events when compared with reports in the general population; however,
children included in the study did not have low T-cell counts, and
yellow fever vaccine was not one of the live vaccines assessed in the studyref.
Yellow fever vaccine provides essential protection to people traveling
to, or living in, areas where yellow fever is endemic or epidemic. However,
health-care providers should carefully consider the benefits and risks
of vaccination for elderly travelers, and should ask about a history of
thymus disorder or dysfunction, irrespective of age, including myasthenia
gravis,
thymoma,
thymectomy,
or DiGeorge syndrome,
before administering yellow fever vaccine. If travel plans cannot be altered
to avoid yellow fever-endemic areas, people with a history of thymus disease
should consider alternative means of yellow fever prevention, including
use of insect repellents, containing N,N-diethyl-m-toluamide
(DEET) and permethrin, and other behaviors to reduce mosquito bites. For
countries that demand a yellow fever vaccination certificate, it is possible
for physicians to provide a letter showing that the vaccine is medically
contra-indicated. However, this does not guarantee that a country will
accept such a waiver. Health-care providers should be encouraged to report
all cases of yellow fever vaccine-associated adverse events, so more information
can be gathered about risk factors for YEL-AVDref
[ref1,
ref2,
ref3,
ref4].
A 26-year-old woman from Onuba, Spain, was admitted on 21 Oct 2004 to Juan
Ramon Jimenez Hospital in Huelva because of fever and multi-organ failure,
having had, in addition to fever, malaise, vomiting, and diarrhea during
the previous days : she died from yellow fever stemming from a post-vaccination
reaction. Since she was about to travel abroad, the patient was also vaccinated
for diphtheria and tetanus on 14 Oct 2004 at the External Sanitation Services
in Huelva. This case does not seem to correspond to problems with the vaccine
(contaminated batches), or with manufacturing problems, but is a consequence
of a special interaction between the virus in the vaccine and the host;
since, in rare cases, there might be an inability by the host to generate
an adequate immune response to the virus.
Shortages :
in February 1999, for a few weeks YF vaccine was not been available in
the UK owing to a production failure
since July 2004 in Israel
in South Africa repeated shortages since 2000 to 2005
in Italy in 2005
in New Zealand in 2005
anti-chikungunya
virus
vaccine : a phase II, randomized, double-blind, placebo-controlled,
safety and immunogenicity study of a serially passaged, plaque-purified
live chikungunya (CHIK) vaccine in 73 healthy adult volunteers. 59 volunteers
were immunized one time subcutaneously with the CHIK vaccine, and 14 were
immunized with placebo (tissue culture fluid). Vaccinees were clinically
evaluated intensively for one month and had repeated blood draws for serological
assays (50% plaque-reduction neutralization test) for 1 year. Except for
transient arthralgia in 5 CHIK vaccinees, the number and severity of local
and systemic reactions and abnormal laboratory tests after immunization
were similar in CHIK vaccinees and placebo recipients. 57 (98%) of 58 evaluable
CHIK vaccinees developed CHIK neutralizing antibody by day 28, and 85%
of vaccinees remained seropositive at one year after immunization. No placebo
recipients seroconverted. This promising live vaccine was safe, produced
well-tolerated side effects, and was highly immunogenic. Chikungunya virus
(CHIK) is an alphavirus borne by Aedes mosquitoes that produces
a dengue-like illness in humans, characterized by fever, rash, painful
arthralgia, and sometimes arthritisref1,
ref2,
ref3,
ref4
[Robinson MC, 1955. An epidemic of virus disease in Southern Province,
Tanganyika Territory in 1952 53. I. Clinical features. Trans Roy Soc Trop
Med Hyg 49: 28 32]. The virus is widely disseminated throughout sub-Saharan
Africa, Southeast Asia, India, and the Western Pacific, and numerous epidemics
have been reported in these areasref1,
ref2,
ref3
[Lumsden WHR, 1955. An epidemic disease in Southern Province, Tanganyika
Territory, in 1952-53. II. General description and epidemiology. Trans
R Soc Trop Med Hyg 49: 33-57; Halstead SB, Yammerat C, Scanlon JE, 1963.
The Thai hemorrhagic fever epidemic of 1962, a preliminary report. J Med
Assoc Thai 46:449-462; McIntosh BM, Jupp PG, Dos-Santos I, 1977. Rural
epidemic of chikungunya in South Africa with involvement of Aedes furcifer
and baboons. S Afr J Sci 73:267-269]. The widespread geographic distribution,
recurrent epidemics, and infection of military personnel, travelers, and
laboratory staff working with CHIK have indicated the need for a safe and
efficacious vaccineref1,
ref2,
ref3,
ref4.
Individual strains of CHIK are closely related antigenicallyref1,
ref2,
ref3,
and infection with one CHIK strain leads to protection against all strainsref.
Reciprocal cross-protection after infection with other alphaviruses occurs
in animal modelsref1,
ref2,
although it is unclear whether similar cross protection occurs in humans
sequentially exposed to natural infection or live alphavirus vaccinesref.
An isolate from a patient in Thailand, CHIK strain 15561, was used to develop
a small lot of vaccine 1st passaged in green monkey kidney (GMK) cells
and then formalin-inactivated before administration to 16 volunteersref.
The vaccine produced no untoward reactions and was highly immunogenic.
The current live vaccine (lot 1-85, TSI-GSD-218) was developed at the U.S.
Army Medical Research Institute of Infectious Diseases and was produced
at the Salk Institute, Swiftwater, PA from a lot of the GMK-passaged, strain
15561 inactivated vaccine by subsequent serial passage in MRC-5 cellsref.
The live vaccine proved to be safe and immunogenic in a phase I trial in
15 alphavirus-naive volunteersref.
The current phase II, randomized, double-blind, placebo-controlled trial
was designed to provide additional safety and immunogenicity data for live
CHIK vaccine TSI-GSD-21ref
FluMist® (Wyeth Lederle
+ Aviron => MedImmune
Inc.; $46 wholesale). Cold-adapted (ca) for nasal spray administration
(survives in the cool nasal passages but dies off in the warmer lung tissues).
Only for use in healthy people ages 5 to 49, as it is linked with an increase
in episodes of asthma and wheezing in children under 5.
CAIV-T is an investigational intranasal, cold-adapted trivalent
influenza vaccine. It is the next-generation, refrigerator-stable formulation
of FluMist®, which is a frozen, live attenuated cold-adapted
trivalent influenza vaccine. To date, the safety, tolerability and efficacy
of CAIV-T has been studied in both healthy and at-risk populations between
the ages of 6 weeks and 98 years.
anti-human
parainfluenza virus type 1 (rHPIV1)
live attenuated vaccine candidates was evaluated for attenuation, immunogenicity,
and protective efficacy in African green monkeys (AGMs). Temperature sensitive
(ts) and non-ts attenuating (att) mutations in the P/C and L genes were
introduced individually or in various combinations into rHPIV1, including
the CR84G and HNT553A mutations identified in the present work and the
CF170S, LY942A, and LL992C mutations identified previously. The rHPIV1
vaccine candidates exhibited a spectrum of attenuation in AGMs. One genetically
and phenotypically stable vaccine candidate, rCR84G/F170SLY942A/L992C,
was attenuated and efficacious in AGMs and is a promising live attenuated
intranasal HPIV1 vaccine candidate suitable for clinical evaluationref
human rotavirus (serotype G1, P1A[P8]) : RIX 4414 strainref
has been developed from the parent vaccine strain 89-12ref1,
ref2,
ref3
(Rotarix®; source : AVANT
Immunotherapeutics (formerly Virus Research Institute) and GlaxoSmithKline
(GSK)) is given at 2 and 4 months of age, with efficacy of 76.6%. Very
recent data obtained with Rotarix® support the suggestion
that factors other than neutralizing antibody can play important roles
in protection against rotavirus disease after live rotavirus immunizationref.
It will be rolled out without the approval of the FDA or the EMEA. Although
some of the Phase III trials involving 60,000 infants were conducted in
Finland, GSK hasn't asked Finnish authorities for approval. Instead, the
trials were done under the auspices of the Mexican government, for approval
in Mexico and other Latin American countries. GSK is trying to target an
emerging middle class that supports a private healthcare industry. The
strategy was successful in that the Phase III trial had promising results.
Of the 30,000 infants given the vaccine in the trial, only six cases of
intussusception were reported. Of the same number of children in the control
group who were given a placebo, only seven cases of intussusception were
reported. As a result, the Mexican government approved RotaRix and it went
on sale in January of 2005. It will target developing nations market (up
to 100 millions infants per year), with an estimated revenue potential
of up to $ 250 million per year. Clinical trials with the HRV vaccine in
Finnishref
and Latin Americanref
(Brazilian, Mexican, and Venezuelan) infants showed that two doses were
well tolerated and immunogenic. In phase 2 clinical trials, the efficacy
of the vaccine against severe rotavirus gastroenteritis reached 90-100%ref1,
ref2,
ref3.
Protection started as early as the first dose, lasted until the subjects
were up to 2 years of age, and was demonstrated against both G1P[8] and
G9P[8] rotavirusesref1,
ref2,
ref3.
A phase III RCT showed that the efficacy of 2 doses the vaccine against
severe rotavirus gastroenteritis and against rotavirus-associated hospitalization
was 85% and reached 100% against more severe rotavirus gastroenteritis.
Hospitalization for diarrhea of any cause was reduced by 42%. During the
31-day window after each dose, 2 vaccine recipients and 7 placebo recipients
had definite intussusception (difference in risk, –0.32 per 10,000 infants)ref
human rotavirus vaccine 89-12 (after 33 passages in cultured monkey
kidney cellsref)
is efficacious in preventing diarrhoea caused by rotavirusref.
This strain was selected because natural infections with 89-12-like rotaviruses
provided 100% protection over 2 yearsref1,
ref2,
ref3.
multivalent human-animal reassortant rotavirus vaccines (HRRV) :
reassortant rotavirus between simian rotavirus RRV or bovine rotavirus
WC3 and human strain rotaviruses have been extensively tested as candidate
vaccines
tetravalent rhesus-human reassortant rotavirus
vaccine (RRV-TV) (RotaShield® ;Wyeth
Lederle => BIOVIRx) : rhesus rotavirus
with a gene replaced by VP7 from a human strain (40% efficacy).
An estimated 1.8 million doses of rotavirus vaccine have been administered
to infants since it was licensed on August 31, 1998 to the October 15,
1999 withdrawalref1,
ref2,
ref3,
ref4,
ref5
(within the next 9 months, > 600,000 infants had received at least 1 dose
of the 3-dose vaccine : 15 cases of intussusception appeared, all of them
within 3 days of vaccinationref),
due to reports of at least 99 bowel intussusception
(with a population attributable risk of approximately 1 per 10,000 (range
of 1 in 5,000 to 1 in 12,000) vaccine recipientsref)
just 1-3 weeks following the vaccine and as many as 10-20 diarrhea episodes
a day, making them dangerously dehydratedref.
> 80% of all cases of intussusception events that were associated with
the vaccine happened with babies who received the vaccine after 4 months
of age, which was at the far end of the manufacturer's recommendations.
That's because, when the vaccine first appeared, many doctors were "catching
up" with older babies who didn't have a chance to get the vaccine in the
months before its approval. Further, overall intussusception rates of children
given the rotavirus vaccine were the same as the baseline expectation of
otherwise healthy children in the first year of life—about 1 in 3000 :
RotaShield® appears to have triggered an intussusception
response in infants who probably would have had it anyway. If a vaccine
triggers intussusception in infants who are going to get it anyway, that
means it's not only preventing rotavirus but it's providing much safer
and more watchful conditions for the intussusception to occur. Today the
consensus is that the rate of RotaShield-associated intussusception is
1 in 10,000 and probably even lower. RRV-TV was also associated with fever,
vomiting, diarrhea, abdominal pain, and bloody stoolsref1,
ref2,
ref3,
ref4.
The vaccine was voluntarily withdrawn from the market in October 1999ref
oral, live pentavalent (G1, G2, G3, G4 and P[8]) human-bovine reassortant
rotavirus vaccine (RotaTeq®; source : Merck)
is an attenuated vaccine in phase III clinical trials containing neutralization
proteins representative of dominant human serotypes. Rotavirus (RV) reassortant
strain WI79-9 consists of a human (strain WI79), G1-serotype
VP7 surface protein on a bovine (strain WC3) backgroundref1,
ref2.
Phase III trials for RotaTeq have concluded, and the preliminary results
suggest that it prevents severe rotavirus infections without causing serious
side effects such as intussusception. It had been expecting to apply for
approval by 2006, but in light of the positive trial results, it will submit
its application in the second quarter of 2005, which means it could have
a full rollout in the United States by the end of the year. It will still
be several years after a US launch before the company launches the product
in developing nations. It will target US and European market (8 million
infants per year), with an estimated revenue potential of up to $1 billion
per year
live quadrivalent rotavirus vaccine (QRV) is a precursor to the
pentavalent HRRVref
consisting of bovine-human reassortant rotavirus serotypes G1, G2, G3,
and P1aref
In the Rotavirus Efficacy and Safety Trial (REST) Study, the 34,035 infants
in the vaccine group and 34,003 in the placebo group were monitored for
serious adverse events. Intussusception occurred in 12 vaccine recipients
and 15 placebo recipients within 1 year after the first dose including
6 vaccine recipients and 5 placebo recipients within 42 days after any
dose (RR = 1.6). The vaccine reduced hospitalizations and emergency department
visits related to G1–G4 rotavirus gastroenteritis occurring 14 or more
days after the third dose by 94.5%. In a nested substudy, efficacy against
any G1–G4 rotavirus gastroenteritis through the first full rotavirus season
after vaccination was 74%; efficacy against severe gastroenteritis was
98%. The vaccine reduced clinic visits for G1–G4 rotavirus gastroenteritis
by 86.0%ref
natural bovine neonatal virus : 3 other vaccines are undergoing
Phase II trials in India and could get regulatory approval there within
3 years. Developers in India are trying a different type of vaccine, based
on strains isolated from infants in the late 1980s. M.K. Bhan, then at
the All India Institute of Indian Medical Sciences in Delhi, and C. Durga
Rao, a microbiologist at the Indian Institute of Sciences in Bangalore,
each isolated strains of a rotavirus that was sweeping through India. Babies
infected with those strains tested positive for rotavirus but had no diarrhea.
Both teams found that large portions of the strains' genetic sequence were
identical to a bovine form of the virus. Because it's a natural virus,
it should be easy to manufacture. It immunizes the child against future
severe bouts of rotavirus-related diarrhea without causing diarrhea in
the first place. Bhan notes that they do not expect intussusception as
a side effect, because no data have shown that the natural neonatal virus
leads to increased risk of intussusception. Despite the promise of the
2 strains, called 116E (Bhan's strain) and I321 (Rao's strain),
the samples sat on lab shelves for a decade, because no company was willing
to take a chance on the project. That changed in 1999, when Krishna Ella
stood up at a medical meeting and announced that his company, Hyderabad-based
Bharat
Biotech International Ltd, would create a rotavirus vaccine. It was
a bold move as the company was only 2 years old and had just begun to manufacture
its first product, a HBV vaccine. Ella had fewer than a hundred employees
and no experience in live vaccine development. Today, Bharat Technologies
employs 350, and it has a $10 million factory dedicated to cranking out
a live rotavirus vaccine. It will soon be producing 3 different vaccines,
the 2 Indian strains and a third strain (bovine reassortant) that Bharat
recently licensed from the NIH (VP7). The vaccines are being used
in clinical trials that have just begun (earlier safety trials had already
been performed in the United States). Phase II trials have just begun in
India for all 3 vaccine candidates. The best performer of those 3 will
become Bharat's new rotavirus vaccine and could be a low-cost competitor
to Rotarix and RotaTeq. A full rollout in India can begin within 3 years,
assuming that at least one of the three candidates is successful in a Phase
III trial. There used to be no infrastructure for clinical trials in India
: now that they've built that, they can complete all 3 rounds of trials
in 3 years, where it takes a minimum of 5 years in the West. And they can
do it at a fraction of the cost. Cutting expenses is crucial when it comes
to providing a vaccine for a country like India. 34 million newborns need
to be vaccinated every year in the Indian subcontinent (estimated revenue
potential up to $100 million per year), of which 24.4 in India (estimated
revenue potential up to $75 million per year), and the government can afford
to spend only a few dollars per inoculation. That's why Bhan hopes that
Bharat and other homegrown biotechs can hit the threshold of $1 per dose.
Western countries can afford to spend $40 a dose, they can't. Although
Bharat officials think they can hit the $1 mark, they don't have the same
advantages that other Indian industries offer. Salaries are cheaper in
India, but the real expense of making vaccines is in capital expenses –
equipment and buildings – and they have no competitive edge over European
or American companies there. Instead, Ella has devised a business plan
to cut development costs by doing all the clinical trials in India and
diluting the cost of equipment purchases by applying for grants from nonprofit
organizations such as the Gates Foundation. Once a rotavirus vaccine is
rolled out in India, it could then be distributed in other Asian countries
as well. The competition could drag prices down to historic lows
natural lamb virus : LLR (Chinese government) vaccine is
already in use in China (15.6 million vaccinees per year), with an estimated
revenue potential up to $10 million per year.
Animal models : to evaluate whether the rectal
route of immunization may be used to provide appropriate protection against
enteric pathogens such as rotaviruses (RV), we studied the antibody response
and the protection induced by rectal immunization of mice with RV virus-like
particles (VLP). For this purpose, 6-week-old BALBc mice were rectally
immunized twice with RV 8-2/6/7-VLP derived from the bovine RV RF81 strain
either alone or combined with various adjuvants including 4 toxins [cholera
toxin (CT) and 3 attenuated Escherichia coli-derived heat-labile
toxins (LTs), LT(R192G), LT(R72), and LT(K63)] and two Toll-like receptor-targeting
adjuvants (CpG and resiquimod). 6 weeks after the second immunization,
mice were challenged with murine RV strain ECw. RV VLP administered alone
were not immunogenic and did not protect mice against RV challenge. By
contrast, RV VLP combined with any of the toxin adjuvants were immunogenic
(mice developed significant titers of anti-RV IgA in both serum and feces
and of anti-RV IgG in serum) and either efficiently induced complete protection
of the mice (no detectable fecal virus shedding) or, for LT(K63), reduced
the amount of fecal virus shedding after RV challenge. When combined with
RV VLP, CpG and resiquimod failed to achieve protection, although CpG efficiently
induced an antibody response to RV. These results support the consideration
of the rectal route for the development of new immunization strategies
against RV infection. Rectal delivery of a VLP-based vaccine might allow
the use of adjuvants less toxic than, but as efficient as, CTref
1 subcutaneous injection. Effective for 6-10 years in 95%. Side effects
in immunocompromised. 3a5crebahnr in Russia. Vaccination for VZV has now
come of age. It is recommended for healthy children, patients with leukaemia,
and patients receiving immunosuppressive therapy or those with chronic
diseases. The protection induced by the vaccine seems, to some extent,
to include zoster and associated neuralgia.
Edmonton-Zagreb (EZ-HT) strain was derived from a clinical isolate
in 1954 and was subsequently passaged in a variety of cells in tissue culture,
resulting in attenuation of the virus and loss of pathogenicity. In 1989,
WHO recommended use of
high-titre measles vaccine (HTMV) at age
6 months for children living in countries in which the incidence of measles
before age 9 months was high. In 1992, after results of studies in Guinea-Bissau,
Senegal, and Haiti had shown raised female mortality in recipients of HTMV,
recommendation for this vaccine was rescinded. The greatly reduced mortality
after measles vaccination has been attributed to prevention of long-term
effects of measles infection. However, although morbidity might be raised
for a few months after measles infection, results have shown no increase
in mortality after the acute phase of infection. Mild measles infection
might be associated with lower mortality, thus both measles infection and
measles vaccination might provide beneficial stimulation of the immune
system, which enhances resistance to other infections. HTMVs seem to result
in a high female-male mortality ratio and an increased mortality when compared
with female recipients of
standard-titre measles vaccine (STMV).
In a meta-analysis of West African studies, girls who received HTMV had
a mortality ratio of 1.86 (95% CI) compared with those who received standard
measles vaccine, whereas boys had a mortality ratio of only 0.91. The effect
was not seen immediately, but several months later. 2 different hypotheses
have been proposed to account for these surprising observations :
Initially, HTMV was postulated to have come too close to the natural disease,
thus inducing immune suppression, as happens in natural measles infection.
This hypothesis does not account for the delayed increase in mortality
and why later, the effect was noted for girls only. Although measles mortality
might be raised in older girls and women, it is usually not higher in girls
in the first 3 years of life, which is the period when high-titre vaccines
are associated with increased female mortality. If anything, boys have
higher measles mortality in this age range. More importantly, measles infection
is usually not associated with long-term excess mortality. Hence, HTMV
does not mimic natural measles disease. Furthermore, contradictory to the
hypothesis, results of one large trial of HTMV in Zaire showed no increase
in mortality of HTMV recipients when compared with recipients of medium-titre
measles vaccine (MTMV), and no increase in female-to-male mortality
in geographical areas with high childhood mortality standard measles vaccine
was associated with a non-specific benefit on survival, which was especially
strong for girls. The detrimental effect of HTMV would only be seen in
areas with high mortality, for high-titre vaccine did not provide the non-specific
and sex-specific benefits of the standard measles vaccine. The mortality
difference would only be seen when girls in the control groups had received
the standard measles vaccine, and it would not be noted in areas with low
mortality since children in these areas had no non-specific survival benefit
from standard measles vaccine. However, in the time before vaccination,
girls did not have higher mortality than boys. Thus, our hypothesis did
not fully explain why girls had a higher mortality than boys in the high-titre
group and why these effects did not arise in the HTMV trial in Zaire
Since
both of these interpretations are unable to account for all observations,
an alternative hypothesis has been proposed. In the high-titre trials,
many children received DTP (which has been reported to be associated with
an increase in female mortality) or IPV after measles vaccination. There
is no excess mortality for high-titre recipients compared with controls
in the period between enrolment and subsequent reception of DTP or IPV
vaccines. Recipients of high-titre vaccine, after being given DTP or IPV,
have a higher female-male mortality ratio than controls receiving standard
measles vaccine at age 9-10 months, and a higher female-male mortality
ratio than high-titre recipients who did not receive additional DTP or
IPV.
M-Vax® (Lederle) : no longer in use (1963 to 1979)
NPOTHB KOPH® (?, Russia)
Odra® (?, Poland)
Pfizer Vax-Measles® (Pfizer) : no longer in use (2/65
to 1970)
Rimevax® (RIT/GlaxoSmithKline)
Rimparix® (GlaxoSmithKline)
Rougeole® (?, France)
Rouvax® (Institute Merieux)
Rubeola 'o Aifombrilla® (?, Spain)
Rubeovax® (Merck) : no longer in use (1963 to 1971)
Sarampion Comu'n® (?, Spain)
V.Rouvaux® (?, France)
Vaccinum Morbillorum Vivum® (Moscow Research Institute)
Vaksin Campak Kerig® (Pasteur Institute, Perum Bio
Farma)
VVR® (Cantacuzino Institute)
Zamovax® (Institute of Immunology - Croatia)
The secondary immune response was defined by IgG with an avidity index
>32%. A secondary response in infected children previously immunized was
considered as a secondary vaccine failure. Vaccinated children presented
higher IgG titers and IgG avidity than unvaccinated children. The proportion
of secondary immune responses in unvaccinated patients was lower than that
obtained in previously vaccinated infected patients. Avidity testing can
be a useful tool to detect secondary vaccine failure in mumpsref
... or as MMR. Recommended
for males after puberty.
anti-polioviruses
1, 2 and 3vaccine
(see also killed vaccine) : developed by
Albert Bruce Sabin in 1963 by culture on human diploid cells, then
cultured on primary Cercopithecus
aethiops (African green monkey) kidney (CMK) cells. Oral cachets
((trivalent) oral poliomyelitis vaccine (OPV / TOPV)) at month 3,
5, age 1 and 3. Obliged vaccination. This vaccine confers both humoral
and intestinal immunity. Long-life effectiveness in 100%. Reversion
to wildtype (vaccine derived poliovirus (VDPV)) and development
of
vaccine-associated paralytic poliomyelitis (VAPP) risk is estimated
as 1 in 2.5 million recipients, expecially
for polioviruses 2 and 3 :
in 1963 to 1966 in a region of the Byelorussian Republic
of the former Soviet Union a widespread circulation and evolution of independent
lineages of vaccine-derived polioviruses took place. Up to 37% of unvaccinated
children had probably been exposed to 9 strains descended from the OPV
and rapidly mutating or other vaccine-derived strains of the virus. Some
of these lineages appeared to originate from OPV given to 40 children in
the community during this period of essentially no vaccinations.
in 2000 a back mutation caused a polio outbreak in
Haiti and Dominican Republic (type-1), followed by similar incidents in
Philippines (type-1)
Egypt (type-2)
Madagascar (5 cases of acute flaccid paralysis due
to type 2 poliovirus were reported in southern Madagascar in 2001/02)
in 2005 in Madagascar 2 cases of polio were reported
: national immunisation days will be held in August-September 2005, covering
at least 600 000 children aged under 5 in Toliara's 21 districts as well
as 6 other districts bordering the province. Although no case of the disease
due to a wild polio virus has been detected in Madagascar since 1997,those
associated with the virus derived from the oral vaccine made eradication
"more complex", and had an implication for vaccination campaigns.
It would be of interest to know if the responsible virus this year is genetically
related to the one that caused the cluster of cases in 2001/2002, suggesting
continued low-level circulation of the same virus, or if this was a new
episode of reversion to neurovirulence.
If a population's immunity is boosted regularly,
the risk from stopping the vaccine is low. In Cuba, for example, where
doctors do mass vaccinations twice a year, the live virus dies out of the
population within 3 months because so few children are susceptible. Continuing
such 'pulse' vaccinations is one option for countries after worldwide eradication.
But researchers fear that diligence will dwindle once countries see the
risk as small. A second option, already taken up by many developed countries
including Italy and the USA, is cessation of vaccination with OPV, replacement
by IPV, and the creation of an OPV stockpile
for emergency response in case of the reintroduction of poliovirus into
circulation : in USA no cases of VAPP have been reported with the sequential
IPV-OPV schedule or when IPV was used exclusively from 1990 through 2003.
The injectable IPV may be safer but is much harder to deliver, expensive
and may not be 100% effective at stopping transmission of the virus in
faecal matter - both problems for developing countries. The data demonstrate
very high risks associated with both the local cessation of OPV vaccination
and the proposed use of OPV to control a possible reemergence of poliovirus
in the postvaccination period. The high transmissibility of OPV-derived
viruses in nonimmune population and the known existence of long-term OPV
excretors should be also considered in assessing risks of the synchronized
global cessation of OPV usageref.
One wonders if this is a case of "seek and ye shall find," or if this is
an emerging problem associated with the vaccine. The former seemed to have
been preliminarily ruled out by the failure of a retrospective study of
over 2000 AFP-associated poliovirus isolates (performed in the Philippines)
to identify additional VDPV. If it is truly a low-level occurrence, it
may have been missed. If this is an emerging problem, one wonders
why now, after approximately 50 years of vaccine use, we are seeing this
phenomenon. If one chooses to adjust the date to the implementation
of increased vaccination activities associated with the polio eradication
effort, the time frame for widespread use is approximately 20 years, when
polio eradication activities in the Americas region began. At the
risk of provoking our readers, this moderator wonders whether the increased
prevalence of HIV infection might be associated with this observed phenomenon.
There are now greater numbers of immune-compromised infants who may have
been exposed to the live virus, with resultant chronic infections postulated
to predispose to neurovirulence reversion. This phenomenon has now occurred
(or better stated, "been documented") in 4 different regions of the world:
the Middle East (Egypt and Israel), the Americas (Hispaniola, i.e. Haiti
& the Dominican Republic), the Western Pacific (Philippines), and now
Africa (Madagascar). In 2 of the regions (Hispaniola and the Philippines)
circulation of the wild poliovirus had been interrupted (the last reported
case of wild poliovirus-associated disease in the Americas was in 1991
and in the Philippines in 1993). In Madagascar, the last documented
case of wild poliovirus circulation was in 1997. In all 4 prior cases,
this occurred in pockets of unvaccinated or incompletely vaccinated individuals
(we do not have this information about the current case(s) in Madagascar
but one might assume this is the case). There was also a case report of
a VDPV type-1 paralytic case in Russiaref
in 1999. In the absence of total interruption of wild poliovirus circulation
worldwide, there is still a need for intensified vaccination efforts. The
risk of disease is still present, especially in today's environment with
extensive world travel. The occurrence of VDPV in association with
clinical disease is very disturbing, as it adds another factor to the risk/benefit
equation of vaccination recommendations. As mentioned in an earlier comment,
a cost-efficacy analysis of switching to the inactivated polio vaccine
(IPV) in countries that have interrupted wild virus circulation [suggests
that they cannot afford it]. Significantly, a switch to IPV would remove
the advantage of flooding the environment with the vaccine virus (the attenuated
very-low-neurovirulence virus) to further interrupt transmission of wild
poliovirus if introduced, as well as to "vaccinate" individuals who may
not have directly taken the vaccine themselvesref1Yang C-F, 8366-8377,
ref2,
ref3,ref4
Some lots of polio vaccine were found to be contaminated with SV40,
which resists to formol inactivation of polioviruses.
Web resources :
Informed Parents Against Vaccine-Associated Paralytic Polio (VAPP) (IPAV)
Golden
Rice Report : linking vitamin A distribution to the Pulse Polio Program
in India
anti-rubella
virus
vaccine : 1 subcutaneous injection expecially in never-infected fertile
females (but > 3 months before undergoing pregnancy !). Booster every 10
years. Effective for > 15 years in 95%. Side effects : reversible arthralgia
and arthritis. Administered alone.
RA 27/3 strain :
Almevax® (Evans Medical Ltd)
Cendevax® (RIT/GlaxoSmithKline) : no longer in use
(3/70 to 1976)
Ervax® (GlaxoSmithKline Mexico)
Ervevax® (GlaxoSmithKline Europe)
Ervevax RA 27/3® (GlaxoSmithKline Belgium)
Gunevax® (Sclavo => Chiron, Europe and Asia)
HarPaBreHnr B CtauOHAP® (?, Russia)
Lyovac Meruvax® (Merck) : no longer in use
Meruvax® (Merck) : no longer in use (6/69 to ?)
Meruvax II® (Merck) : 9/78
Mot Kopper® (?, Norway)
Roda Hund® (?, Sweden)
R-VAC® (Serum Institute)
Rosolia® (?, Italy)
Rosovax® (Ism)
Roteln® (?, Germany)
Rubavax® (Aventis Pasteur)
Rubeaten Berna® (Swiss Serum and Vaccine Institute)
Rubella, Generic® (Philips Roxane, Inc.) : no longer
in use (12/69 to 1972)
Rubellovac® (Sclavo => Chiron, Germany only)
Rubelogen® (Parke Davis) : no longer in use (12/69
to 1972)
Rubeola® (?, Spain)
Rubeola® (?, Norway)
Rubeola 'o Aiforbrilla® (?, Spain)
Rubilin® (Medeva)
Rudivax® (Aventis Pasteur)
Sarampion® (?, Spain)
Sarampion Aleman® (?, Spain)
Zaruvax® (Institute of Immunology - Croatia)
... or as MMR.
Side effects : arthralgia (50% of females)
or arthritis (10% of females) within 2-6 weeks.
anti-Orthopoxvirus
vaccine (variolation) [see also cross-immunization
and DNA vaccine]
: in 11th century immunity to smallpox was conferred by nasal
inhaling (Chinese and Indians) or intravenously injecting (Turks)
live variola from scabs or pustular material taken from a person with smallpox
: since scabs were usually from people who had survived smallpox, they
contained weakened or dead virus, which had been attacked by the survivor's
immune system. This practice resulted in an infection that was usually
less severe than an infection acquired naturally by inhalation of droplets
: anyway, if the recipient lacked a strong immune system (e.g. the local
Indian tribes around Fort Pitt, who were deliberately infected by British
conquerors with blankets laden with pus or fomites : using a handkerchief
was especially diabolical, since the recipient might well have used it
on his own nose, introducing the virus directly into the respiratory system)
or if the virus were not noticeably weakened, it had a mortality rate of
~ 1% - an alarming figure, but far lower than the mortality that resulted
from natural infection by the respiratory route (up to 40%). Those infected
in this manner were capable of transmitting smallpox by droplet inhalation
to others. In 1723 Lady Mary Wortley Montague (1689-1762 : wife of the
British ambassador in Constantinople, Turkey) introduced variolation to
Western Europe : she had been disfigured by smallpox and practiced variolation
to her children to protect them. Her supporting helped common people to
ignore anathemas from catholic churchmen, who believed smallpox was a divine
punishment, and hence blamed any attempt to defeat it.
anti-Salmonella
typhioralvaccine
: strain Ty21a (UDP-Gal-4-epimeraseD). 3 cachets at day
0 (no before month 3 !), 2 and 4. It replicates itself in the gut for 2÷3
dd.
Lavantuu tirokote®
(Central Public Health Lab)
Neotyf®
(Biocine) : capsules
Vivotif®(Swiss
Serum and Vaccine Institute)
Tyfoid®
(?, Sweden)
Typhoral-L®
(Swiss Serum and Vaccine Institute; Chiron, Germany)
Orochol® (Swiss Serum and Vaccine
Institute) : genetically modified strain CVD103-HgR (a Hg-resistant
derivative of classical biotype Inaba serotype strain 569B unable
to produce A subunit of CT), which has minimal reactogenicity but low colonization
potential and therefore has to be given in higher doses. 5 .
108 liophilized and buffered vibrios in water ingested at empty
stomach. No side effects. Effective (from age 2) from day 6 after vaccination
to month 6 in 60-90%
Kolera®
anti-Francisella
tularensis
vaccine : at present, no licensed tularemia vaccine is available in
the USA. However, the live vaccine strain (LVS) vaccine is available
to military personnel under an investigational new drug (IND) protocol
held by the US Army Medical Research
Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland
and is available only for at-risk US military personnel. It is administered
via 1 scarification (intradermic injection) using multiple punctures of
a bifurcated needle, similar to vaccinia inoculation for smallpox. The
availability of this vaccine in the USA for use beyond selected at-risk
groups has been hampered by several obstacles. According to Colonel David
L. Danley, Project Manager, Joint Vaccine Acquisition Program (JVAP) at
Fort Detrick, data now required for licensure were not adequately documented
during its development, prohibiting plans to license the current vaccine.
Because the "old method of growth using shaker culture does not meet current
good manufacturing processes required for FDA licensure," the manufacturing
processes and potency of the current LVS vaccine are being re-evaluated,
and "a new process using fermentation technology will be used," explained
David T. Dennis, MD, MPH, Chief, Bacterial Zoonoses Branch, CDC. Despite
the increased risk of a bioweapons threat felt after September 11th, further
vaccine development for tularemia remains slow. The projected date of a
new licensed vaccine in the USA is not until 2009. The current LVS vaccine
is based on research that goes back to the 1960s. It is a descendant of
strain
15 developed by the former Soviet Union's Institute of Epidemiology
and Microbiology, Gamalcia Institute, in Moscow, and sold to the US military
in 1956ref.
In the early 1960s, USAMRIID had isolated the LVS strain for preventive
use in at-risk US military personnelref1,
ref2.
Efficacy studies in civilian laboratory employees at Fort Detrick published
in 1977 revealed that the vaccine was safe and significantly reduced the
incidence of typhoidal tularemia from 5.70 to 0.27 cases per 1000 at-risk
employee-yearsref.
Although the incidence of ulceroglandular tularemia was unchanged by the
vaccines, the disease was found to be milder in the vaccine cohort. I am
not aware whether the vaccine is effective if given postexposure. It induces
5-10 years long CMI in a high percentage of vaccinated. Worldwide, LVS
has since been used as seed stock for tularemia vaccinesref.
Several limitations of the current LVS tularemia vaccine indicate a need
to move forward on developing an improved vaccine. One limitation is the
current mode of administration, which requires scarification that is both
cumbersome and difficult to standardize. Further limitations deal with
gaps in understanding the factors responsible for the virulence and genetic
stability of F. tularensis, as well as which antigens are needed
to produce an effective cell-mediated immunity. It is not well standardized
and contains 2 phenotypes of F. tularensis. Current research shows
that only one of the 2 phenotypes of LVS, the blue colony type, appears
to be immunogenicref1,
ref2.
A 2nd limitation is confusion over which arm of the immune system should
be targeted. Although it has been thought that the humoral immune response
is not important in protection against tularemia, a relatively recent report
from the Fort Detrick group has suggested that this may not be the caseref.
Pooled sera from humans immunized with LVS were found to fully protect
mice against a large lethal challenge of LVS organisms. New lots of LVS
produced in the USA clearly show immunogenicity in human volunteers, producing
both brisk cell-mediated and humoral immune responsesref.
In the future, techniques to optimize the appropriate humoral response
may be available. Strategies for development of a new generation of vaccines
include identification of individual components of F. tularensis,
such as the lipopolysaccharide (LPS) or various other outer surface proteins,
as potential vaccine components (either native or recombinant). After identification,
these components would then be used as immunogens, instead of using the
entire organism. In laboratory studies, some of these cell components have
been tested and found to have variable protection in mice. For instance,
one of the membrane proteins of the F. tularensis that has been
studied as a potential immunogen is a 17-kilodalton lipoprotein, TUL4.
The gene for this antigen has been cloned into a Salmonella typhimurium
mutantref.
In mice immunized with this recombinant vector, both humoral and cell-mediated
immune response to the antigen developed, and mice were protected from
an LVS challenge. The development of monoclonal antibodies for use as passively
protective agents is another possible strategy for new vaccine development,
according to Dr. Dennis of the CDC. A number of investigators are conducting
basic research into tularemia, particularly molecular and sequencing studies
aimed at identifying proteins and antigens for use as vaccine candidates.
Most of this research is being conducted at military research institutions,
including USAMRIID. As one would expect, since September 11th, information
on manufacturers actively working on a new vaccine is scarce. In the USA,
DynPort
Vaccine Company LLC was awarded a contract to develop, manufacture,
test, and license an LVS vaccine from the current vaccine material, according
to both Dr. Dennis and Col. Danley at Fort Detrick. DynPort has been under
contract to the USA Department of Defense's (DoD's) JVAP since 1997 and
acts as its executive arm, says Terry Irgens, President of DynPort. Basic
researchers from institutes such as USAMRIID work closely with DynPort,
which employs over 100 scientists, physicians, and veterinarians to conduct
preclinical and clinical testing of vaccines. Production and licensure
are also managed by DynPort, whose contract with JVAP was recently extended
to 2012. A proposed licensure date is June 2009, as previously mentionedref.
Internationally, several efforts are under way to develop new tularemia
vaccines, but with similar limited information on manufacture and licensure
dates. In the UK, 2 approaches to a new vaccine, use of defined attenuated
mutants and a subunit vaccine (Chemical
and Biological Defence Establishment, Porton Downs, England), are in
their earliest stages and are not anticipated for licensure in the UK for
more than a decade, says Col. Danley. Other development efforts are being
conducted in Sweden at the National
Defense Research Establishment, University of Umea, which recently
received a 5-year grant from the US National Institutes of Health to develop
a subunit vaccine against aerosolized forms of F. tularensis. In
collaboration with Canadian researchers, under the direction of Dr. Wayne
Conlan, Medical Research Council, Ottawa, Canada, the grant will also compare
the efficacy of these candidate vaccines to those of attenuated vaccines,
said Dr. Anders Sjostedt, who heads the research group at Umea University.
In Moscow, a project is under way at the Institute
of Immunological Engineering to develop a chemical tularemia vaccine
based on preparations of outer-membrane components of F. tularensis.
This group is also working on a project to develop a molecular vaccine
based on LPS-protein complexesrefref
X-ray irradiation-attenuated Plasmodium falciparum sporozoites has
been known for many years to protect humans from blood-stage P. falciparum
malaria infection and disease
upregulated in infectious sporozoites gene 3 (UIS3)-/-Plasmodium
berghei can be maintained as asexual stages in the red blood cells
of the host with no detrimental effects to the parasiteref.
This is crucial, as the organism has to infect the host liver to induce
a full immune response, but cannot undergo early liver-stage development.
It will be crucial to determine whether this gene deletion attenuation
is similarly effective in the most important human parasite—P. falciparumref
cross-reacting
non pathogenetic species (cross-immunization / heterotypic vaccine / heterovaccine)
: a vaccine that confers protective immunity against a pathogen not present
in the vaccine, because it contains microorganisms that possess cross-reacting
antigens which they share in common with that pathogen
anti-Mycobacterium
tuberculosis
vaccine (see also attenuated
vaccine and DNA
vaccine)
: developed by Calmette and Guérin in 1921, from a Mycobacterium
bovis
strain (Bacille Calmette-Guérin (BCG)) attenuated after >
230 transfers on glycerinated potato enriched in beef bile. It is
administered by intradermal injection or scarification to tuberculin-negative
individuals for prevention of tuberculosis. Intramuscular
injection (usually in deltoid muscle) induces formation of granuloma on
skin (easy to detect marker of effective vaccination). It is the most widely
used immunisation in the world, with 4-5 billion doses having been given
over the past decadesref.
The vaccine fails to protect against pulmonary tuberculosis in adults (0÷80%
effectiveness in South=>North gradient) : this is partly due to variability
from the original strain (nowadays most widely used strains are Tokyo,
Laos,
Copenhagen,
Pasteur,
Moscow
and Troudeau ones) and difficulties in right preservation, as well
as exposure in some patients to atypical mycobacteria infection with resultant
cross-immunity, thereby nullifying the protective effects of BCG vaccinationref.
This effect seemed to be important in those vaccine trials in tropical
or subtropical regionsref.
For the prevention of severe childhood tuberculosis (tuberculous meningitis
and miliary tuberculosis), BCG vaccination is a highly cost-effective
intervention, and should be retained in those countries with high rates
of tuberculosis. Meta-analyses of prospective trials have shown that BCG
vaccination has an overall protective efficacy of 51%, and protective efficacy
against severe forms of childhood tuberculosis of about 75%ref1,
ref2,
ref3.
However, even this protection is only relative, and might be overcome in
the presence of severe malnutrition, exposure to a large infecting dose
of tubercle bacilli from a household contact, and also after waning immunity,
many years after vaccinationref1,
ref2.
Despite these concerns, the prevention of 40 000 cases of severe childhood
tuberculosis a year worldwide is a cause for celebration. Every year about
100 million doses of BCG vaccine are given to children worldwide, which
results in the prevention of about 30,000 cases of tuberculous meningitis
and 11,000 cases of miliary tuberculosis before these children reach their
fifth birthday. This estimation translates into roughly one case of severe
childhood tuberculosis prevented for every 2500 inoculations. BCG vaccination
is thought to be nearly as cost effective as short-course chemotherapy
for active disease, which is considered good value for money. Regionally,
the highest numbers of cases prevented were in southeast Asia (46%), followed
by sub-Saharan Africa (27%), and the western Pacific (15%). These are areas
where tuberculosis infection rates and BCG coverage are highest. Cost-effectiveness
of the vaccine decreases in those richer countries where the risk of tuberculosis
infection is low (B Bourdin Trunz, PEM Fine and C Dye, Effect of BCG vaccination
on childhood tuberculous meningitis and miliary tuberculosis worldwide:
a meta-analysis and assessment of cost-effectiveness, Lancet 367 (2006),
pp. 1173–1180). BCG should be withdrawn from routine use in these countries,
and reserved for high-risk individuals : this is currently the situation
in the UK, where routine BCG vaccination of schoolchildren has now been
stopped, and the emphasis is on targeting high-risk infants and childrenref.
Contrary to the prevailing theory that BCG vaccination protects only against
tuberculosis disease, some results suggest that the vaccine also protects
against tuberculosis infection : amount of tuberculosis exposure within
the household and age (a marker of tuberculosis exposure outside the household)
were strongly associated with likelihood of infection as measured by both
TST and ELISpot. ELISpot also identified absence of BCG scar as an independent
risk factor for infection in tuberculosis-exposed children; BCG-vaccinated
children had an odds ratio of 0.60 for tuberculosis infection, compared
with unvaccinated childrenref.
So, it is not true that the entire population would have to be vaccinated
if the vaccine was to be considered efficacious. The vaccine cannot
circumvent disease reactivation in previously exposed individuals.
Vaccination may complicate the way the tuberculin skin test (TST) is read
in this country. In places that do not vaccinate, the skin test may be
used to monitor the effectiveness of antibiotic therapy. Oral vaccine is
abandoned because it would require increased bacterial charges to allow
survival in gastric juices => Th2
polarization => TNF-a => damage in host tissue
(an ideal vaccine should contain only Th1
epitopes). Anyway oral route is under clinical trial for subunit vaccine
boosters. Main model organisms for designing a novel vaccine are long-life
species : Rhesus monkey (Macaca
mulatta), cynomolgus (Macaca
fasicularis) and deer.It is used for routine vaccination of children
only in regions where there is a high incidence of tuberculosis. In the
USA it is recommended only for immunization of high-risk individuals.
Side effects : rare virulent strains cause
lymphadenitis
and osteomyelitis
as side effects. Disseminated infection in individuals with IL-12Rb1
deficiency.
In 1927 a lot of vaccine contaminated by Mycobacterium tuberculosis
caused Lubeck massacre : among 251 vaccinated newborns, 127 developed
TB and 77 died
overexpressing antigen 85 (in guinea pig trials, the vaccine yielded 10-to
100-fold better protection than BCG itself)
complemented with the complete region of deletion-1 (RD1) locus
from Mycobacterium
tuberculosis,
which contains at least 11 genes, including esxA and esxBgenes,
which encode the T-cell antigens 6-kDa early secretory antigenic target
(ESAT-6) and 10-kDa culture filtrate protein (CFP-10) respectively,
as well as a variable number of flanking genes encoding a secretory apparatus.
Mice and guinea pigs vaccinated with the recombinant strain BCG:RD1-2F9
were better protected against challenge with M. tuberculosis, showing
less severe pathology and reduced dissemination of the pathogen, as compared
with control animals immunized with BCG alone.
rBCG30 with the pMTB30 plasmid encoding the secreted 30-kDa major
secretory protein of Mycobacterium tuberculosis, the primary
causative agent of TB, affords greater survival after challenge than parental
BCG in the highly demanding guinea pig model of pulmonary TB. The parental
and recombinant vaccine strains are comparably avirulent in guinea pigs,
as they display a similar pattern of growth and clearance in the lung,
spleen, and regional lymph nodes. The plasmid is neither self-transmissible
nor mobilizable to other bacteria, including mycobacteria : it can be stably
maintained in Escherichia coli but is expressed only in mycobacteria.
The recombinant and parental strains are sensitive to the same antimycobacterial
antibioticsref
fusion-protein vaccine
The vaccines may work well in combination : modified BCG vaccines could
be given at birth and then followed up with the fusion-protein vaccine.
Different delivery methods could also help to improve the vaccines' efficacy
: at present, the BCG vaccine is injected under the skin, but it could
be introduced more directly to the lungs by delivering it by mouth or nose.
BCG vaccine is also used in cancer immunotherapy, particularly in malignant
melanoma
and bladder carcinoma;
it is thought to act as a nonspecific stimulator of cell-mediated immunity.
From autumn 2005 the long running routine programme to vaccinate schoolchildren
against tuberculosis with BCG vaccine will stop. This follows a decision
by the chief medical, nursing, and pharmaceutical officers in July that
there should be selective vaccination of high risk infants and other groups
rather than routine vaccination of adolescents negative on tuberculin testingref.
This decision comes after several years of discussion within the Joint
Committee on Vaccination and Immunisation, and it closes an important chapter
in the complex history of BCG vaccination. It comes as notifications of
tuberculosis in England and Wales are at their highest level since 1983.
The decision is well justified. This BCG programme has been unique from
its start in the mid-1950s, when a Danish vaccine (later produced by Glaxo)
was introduced on the basis of efficacy shown in a trial carried out by
the UK Medical Research Councilref.
The trial had been carried out in approximately 30 000 adolescents for
pragmatic reasons—in order to recruit participants who were still tuberculin
negative, but who were about to enter a period of high risk of disease.
That trial remains the most rigorous trial of BCG vaccination carried out
anywhere and is an important monument in the history of research in tuberculosis.
At the same time trials were carried out by the US Public Health Service
(USPHS) in Georgia, Alabama, and Puerto Rico which found that the Tice
BCG vaccines used there had little or no effectref.
Faced with these results, each nation did the locally responsible thing—the
USPHS decided not to introduce BCG vaccination because they had no evidence
that it worked among their populations, whereas the UK authorities did
introduce it, as they had good evidence of its value. This touched off
a controversy over the magnitude and determinants of the efficacy of BCG,
which still continues. Many explanations have been proposed. Perhaps the
most popular is that different populations are exposed to different environmental
mycobacteria, which can provide as much immunity as BCG or otherwise interfere
with it, and that the US trials happen to have been conducted in areas
where such environmental exposure is highly prevalentref.
Whatever the explanation for those initial trial results, they determined
the policy of vaccinating adolescents in the UK, and the efficacy of the
vaccines so given has since been confirmed repeatedly in observational
studiesref1,
ref2.
The epidemiology of tuberculosis in the UK has changed greatly over the
years since the BCG programme began. The annual risk of infection has declined
from about 2% a year in 1950 to < 1 per 1000 today, and the disease
has become increasingly restricted to identifiable segments of the population,
in particular immigrant communities: two thirds of cases in 2003 were in
people born outside the United Kingdomref.
Recent increases in the incidence of tuberculosis in the UK thus reflect
patterns and trends in the movements of populations and in the epidemiology
of tuberculosis worldwide. That non-indigenous groups were at higher risk
was first recognised in the 1960s and led to a national policy encouraging
health authorities to consider supplementary BCG programmes for neonates
or for people in contact with tuberculosis in these communities. The Joint
Committee on Vaccination and Immunisation repeatedly examined the cost
effectiveness of the routine programme in schools as an increasing proportion
of the population at high risk received the vaccine in infancy and as the
risk of disease in the general population fell. The number of cases in
people born in the United Kingdom reached an all time low in 2003.6 Although
the criteria set by the International
Union against Tuberculosis and Lung Disease for moving away from routine
BCG vaccination were achieved in the 1990sref,
policy makers were reluctant to stop the programme in schools because of
lingering concerns that increases in the prevalence of HIV and in tuberculosis
internationally might increase the risk of tuberculosis in the UK general
population. This has not occurred, and it is clear that the risk of tuberculosis
among immigrant communities declines over time once they have settled in
the United Kingdom and that the imported disease has not led to increases
in the risk of disease for the indigenous population. Under the new policy,
BCG vaccination will be offered to infants in communities with an average
incidence of tuberculosis of at least 40 per 100 000 and to unvaccinated
individuals who come from, or whose parents or grandparents come from,
countries where the incidence exceeds 40 per 100 000. Most people born
in the United Kingdom will thus probably never receive BCG vaccination,
and most will not be exposed to mycobacteria. This means that tuberculin
testing will become increasingly efficient as a means of identifying people
exposed to and latently infected with the tubercle bacillus, who may be
given prophylaxis. The change from routine to targeted vaccination is accompanied
by technical changes. The Glaxo BCG vaccine has been replaced by one from
the Danish Statens Seruminstitut and the multipuncture "Heaf" technique
for tuberculin testing is being replaced by the intradermal injection "Mantoux"
technique, which is the standard in the rest of the world. All of these
changes bring the UK's approach to preventing infection with tuberculosis
in line with policies and practice in many other countries. BCG vaccination
will continue to have an important role in protecting children in high
risk populations from tuberculosis. Coupled with vigorous efforts to identify
and appropriately treat cases, and to ascertain and offer prophylaxis to
people with latent infection, the new policy should allow more efficient
control of tuberculosis in the entire UK populationref Web resources : Aeras
Global TB Vaccine Foundation
anti-Orthopoxvirus
vaccine [see also variolation and DNA
vaccine]
: in 1774 Benjamin Jesti, a farmer in Dorset, UK, inoculated material taken
from udders of cows with cowpox to members of his family. In 1796 Edward
Jenner noticed that milkmaids infected on their hands with a self-limiting
contagious agent (Cowpox virus)
as a result of milking cows were protected subsequently against smallpox.
Once discovered cross-immunity, Jenner used fluid from a blister on the
hand of the milkmaid Sarah Nelms to confer immunity to smallpox to the
8-year-old farm boy James Phipps, whom he subsequently challenged with
Variola
virus.
Vaccination (from the Latin vacca = cow) replaced variolation,
outlawed in 1840 in Europe. Because cowpox was a relatively rare disease
of Western Europe and was absent in the Americas, live vaccine was tranported
from Cadiz (Spain) to America through arm-to-arm transfer by orphan
children on the long voyage across the Atlantic, with increased risk of
transmission of measles virus
and Treponema
pallidum subsp.pallidum
: growth of the virus on the skin of flank of a calf offered the
prospect for provision of an adequate and safer supply of vaccine material,
but the harvested vaccine remained viable for only 1 or 2 days at ambient
temperature. The solution was found in 1950 with the introduction of more
stable air-dried or freeze-dried vaccine (preserved indefinitely
at -20°C, or also at -4°C), with no need for refrigeration or loss
of potency. Multiple infection of cows with Cowpox virus, Vaccinia virus,
and Buffalopox
virus, caused Cowpox virus to be replaced by the following strains
of Vaccinia virus
:
New York
City Board of Health (NYCBH) strain ==attenuation by repeated passing
through rabbit testis, chick embryo explants, and chorioallantoic membranes
of embyonated hens' eggs==>
Rivers strain
CVI-78
highly attenuated modified Vaccinia
virus (strain Ankara)
(MVA) smallpox vaccine (source : Acambis Plc and Bavarian Nordic
A/S) was generated by > 500 passages of vaccinia virus in chick embryo
fibroblasts, during which it acquired multiple deletions and mutations
and lost the capacity to replicate efficiently in human and most other
mammalian cellsref1,
ref2,
ref3,
ref4,
ref5,ref6.
The host restriction of MVA occurs during a late stage of viral morphogenesis,
resulting in the accumulation of immature virions and the formation of
abnormal onesref1,
ref2,
ref3,
ref4.
As a result of extreme attenuation, MVA causes no adverse effects even
when high doses are injected into immune-deficient non-human primatesref.
Animal studies carried out more than 30 years ago showed that MVA protected
animals against orthopoxvirus infections, although few immune responses
were measured and those that were measured appeared lowref1,
ref2.
In a recent study, MVA and the smallpox vaccine induced a similar variety
of immune responses in miceref.
MVA seemed to be safe in humans and there was a reduction in the size of
skin lesions produced by a subsequent standard smallpox vaccinationref1,
ref2,
ref3.
MVA protects monkeys infected with monkeypox virus (the best experimental
model for human smallpox) and caused very few side-effects. After 2 doses
of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing
titres and T-cell responses were equivalent or higher than those induced
by Dryvax alone. After challenge with monkeypox virus, unimmunized animals
developed > 500 pustular skin lesions and became gravely ill or died, whereas
vaccinated animals were healthy and asymptomatic, except for a small number
of transient skin lesions in animals immunized only with MVAref.
Because an initial MVA injection may help lessen the side effects experienced
from Dryvax, MVA may serve as an important pre-vaccine for large-scale
vaccination efforts in the event of a bioterror threat involving smallpox.
Immune-compromised mice remained healthy even when given 1000 times the
usual MVA dose.
LC16m8 (source : VaxGen, Inc.) : derived from the Lister strain
of vaccinia, LC16m8 has been licensed in Japan since 1980 and forms the
basis of that country's national vaccine stockpile. In a phase I/II clinical
trial it had a 100% take rate and has been well tolerated. Intensive monitoring
for myopericarditis has not uncovered any cardiac toxicity in the first
66 volunteers
EM63
Attenuated strains have decreased incidence of complications but induce
lower neutralizing antibody titers and so lower protection
... with the following additives : fluorocarbon, phenol, peptone. Currently
it is of calf lymph or chick embryo origin.
Reconstitution of the vaccine for administration
is made by creating a solution of 50% v/v : after
reconstitution the vaccine can be preserved for > 1 weeks at 41°C.
Dilutions at 1/5 or 1/10 could be used to expand the supply of vaccine.
Administration routes :
1 scarification (without injurying skin capillaries) : both subcutaneous
and intramuscular vaccinations fail to provoke a pox reaction and do not
effecively incite neutralizing antibodies or vaccinia-virus-specific
cytotoxic T cellsref
5-15 rapid intradermally strokes injurying skin capillaries using a bifurcated
needle to inject 0.0025 mL vaccine with a titer > 108 PFU
/ mL (glycerin in McIlvaine solution is used for reconstitution)
high pressure jet injector (saline solution for reconstitution)
Succesful primary vaccination in a nonimmune person who is not immunosuppressed
results in virus proliferation in the basal cells of the dermis =>
papule with surrounding erythema (2-5 days) ==(2-3 days)=> vesicle growing
until it reaches its maximum diameter on the 9th or 10th
day=> pustule (accompanied by mild fever, swelling of the draining lymph
nodes, tenderness; maximum size after 8-12 days) => brown scab => separation
(14 to 21 days) => scar, a mark by which previous vaccinees can be recognizedref.
Protective vaccination with vaccinia virus depends on delivery of the virus
to the epidermis by a technique known as scarification, leading to an epidermal
'pox' reaction — a cutaneous T-cell-mediated delayed-type hypersensitivity
reaction presumably involving vaccinia-virus-specific skin-homing T cells.
Both subcutaneous and intramuscular vaccinations fail to provoke a pox
reaction and do not effectively incite neutralizing antibodies or vaccinia-virus-specific
cytotoxic T cellsref.
Immune response to primary vaccination
:
strong virus-specific CD4+ and CD8+ T lymphocytes
response (TNF-a and IFN-g
secretion by PBMCs), which declines slowly with an average half-life of
8-15 years.
neutralizing antibodies develop about the 10th day and remain
steady for as long as 75 yearsref
hemagglutinin-inhibiting antibodies develop about the 10th and
last < 6 months
complement-fixing antibodies develop in < 50% of the vaccinees and last
< 6 months
a DTH is detectable after 2 days
Vaccinia-specific B-cell responses are essential for protection of macaques
from monkeypox virus.
Antibody-mediated depletion of B cells, but not CD4+ or CD8+
T cells, abrogated vaccine-induced protection from a lethal intravenous
challenge with monkeypox virus. In addition, passive transfer of human
vaccinia-neutralizing antibodies protected nonimmunized macaques from severe
disease. Thus, vaccines able to induce long-lasting protective antibody
responses may constitute realistic alternatives to the currently available
smallpox vaccineref.
Multiple diagnostic techniques identify previously vaccinated individuals
with protective immunity against monkeypox : approximately 50% of the US
population received smallpox vaccinations before routine immunization ceased
in 1972 for civilians and in 1990 for military personnel. Several studies
have shown long-term immunity after smallpox vaccination, but skepticism
remains as to whether this will translate into full protection against
the onset of orthopoxvirus-induced disease. The US monkeypox outbreak of
2003 provided the opportunity to examine this issue. Using independent
and internally validated diagnostic approaches with 95% sensitivity and
90% specificity for detecting clinical monkeypox infection, we identified
3 previously unreported cases of monkeypox in preimmune individuals at
13, 29 and 48 years after smallpox vaccination. These individuals were
unaware that they had been infected because they were spared any recognizable
disease symptoms. Together, this shows that the US monkeypox outbreak was
larger than previously realized and, more importantly, shows that cross-protective
antiviral immunity against West African monkeypox can potentially be maintained
for decades after smallpox vaccinationref.
These findings are not unexpected in that vaccinia virus (i.e. smallpox
vaccine) and 21 other orthopoxviruses share the same inventory of 90 essential
genes for infection and multiplication in cellsref.
In individuals exposed at risk, boosting every 3 yrs. Mistakenly resistance
to vaccinia virus proliferation in the basal cells of the dermis after
intradermal inoculation with vaccinia (showing no major reaction) is equated
with resistance to variola virus acquired by droplet inhalation : this
is note the case, as major reactions can appear also in those who are immune.
Side effects (and hence contraindications)
in ...
... vaccinated persons : 1 every 1,000 experience severe adverse effects,
14÷52 every million experience life-threatening effect and 1÷2
every 1,000,000 dies.
... their unvaccinated contacts : 2÷6 cases every 100,000
vaccinated subjects (68.5% are < 5 years)
in December 2002, the Department of Defense (DoD) began vaccinating military
personnel as part of the pre-event vaccination programref.
Because vaccinia virus is present on the skin at the site of vaccination,
it can spread to other parts of the body (autoinoculation) or to contacts
of vaccinees (contact transfer). To prevent autoinoculation and contact
transfer, DoD gave vaccinees printed information that focused on handwashing,
covering the vaccination site, and limiting contact with infantsref1,
ref2.
This report describes cases of contact transfer of vaccinia virus among
vaccinated military personnel since December 2002; findings indicate that
contact transfer of vaccinia virus is rare. Continued efforts are needed
to educate vaccinees about the importance of proper vaccination-site care
in preventing contact transmission, especially in household settings. DoD
conducts surveillance for vaccine-associated adverse events by using automated
immunization registries, military communication channels, and the Vaccine
Adverse Events Reporting System (VAERS). Contact transfer cases are defined
as those in which vaccinia virus is confirmed by viral culture or PCR assays.
Other cases are classified as suspected on the basis of lesion description
and reported linkage to a vaccinated person 3 to 9 days before lesion development.
During the period Dec 2002 to Jan 2004, a total of 578 286 military personnel
were vaccinated; 508 546 (88%) were male, and 407 923 (71%) were primary
vaccinees (received smallpox vaccination for the 1st time). The median
age of vaccinees was 29 years (range: 17 to 76). Among vaccinees, cases
of suspected contact transfer of vaccinia were identified among
30 persons: 12 spouses, 8 adult intimate contacts, 8 adult friends, and
2 children in the same household. These cases were reported from Colorado
(4), North Carolina (4), Texas (4), Alaska (2), California (2), one in
each of Connecticut, Kansas, New Jersey, Ohio, South Carolina, Washington
state, West Virginia, and overseas. The sources of suspected contact transfer
were all male service members who were primary vaccinees. Except for 6
male sports partners, all infected contacts were female. Vaccinia virus
was confirmed in 18 (60%) of the 30 cases by viral culture or PCR. 16 of
the 18 confirmed cases involved uncomplicated infections of the skin; 2
involved the eyeref.
None resulted in eczema vaccinatum or progressive vaccinia. 12 of the 18
confirmed cases were among spouses or adult intimate contacts. The observed
rate of contact transfer was 5.2 per 100,000 vaccinees overall or 7.4 per
100,000 primary vaccinees. Among 27 700 smallpox-vaccinated DoD health-care
workers, no transmission of vaccinia from a vaccinated health-care worker
to an unvaccinated patient or from a vaccinated patient to an unvaccinated
health-care worker has been identified. 2 of the 18 confirmed cases of
transfer of vaccinia virus resulted from tertiary transfer. One involved
a service member, his wife, and their breast-fed infant; the other involved
serial transmission among male sports partners.
on May 4 2003, a service member received his primary smallpox vaccination.
About 6 to 8 days after vaccination, he experienced a major reaction (an
event that indicates a successful take; is characterized by a papule, vesicle,
ulcer, or crusted lesion, surrounded by an area of induration; and usually
results in a scar). The vaccinee reported no substantial pruritus. He slept
in the same bed as his wife (not been vaccinated against smallpox) and
kept the vaccination site covered with bandages. After bathing, he reportedly
dried the vaccination site with tissue, which he discarded into a trash
receptacle. He also used separate towels to dry himself, rolled them so
the area that dried his arm was inside, and placed them in a laundry container.
His wife handled bed linen, soiled clothing, and towels; she reported that
she did not see any obvious drainage on clothing or linen and had no direct
contact with the vaccination site. In mid-May, the wife had vesicular skin
lesions on each breast near the areola but continued to breastfeed. About
2 weeks later, she was examined at a local hospital, treated for mastitis,
and continued to breastfeed. The same day (May 29), the infant daughter
developed a papule/vesicular lesion on the upper lip/philtrum, followed
by another lesion on the left cheekref.
3 days later, the infant was examined by a pediatrician, when another lesion
was noted on her tongue. Because of possible early atopic dermatitis lesions
on the infant's cheeks, contact vaccinia infection with increased risk
for eczema vaccinatum was considered. The infant was transferred to a military
referral medical center for further evaluation. On examination, the infant
had seborrheic dermatitis and no ocular involvement. Skin lesion specimens
from the mother and infant tested positive for vaccinia by viral culture
and PCR at the Alaska Health Department Laboratory and at Madigan Army
Medical Center. Because both patients were stable clinically and the lesions
were healing without risk for more serious complications, vaccinia immune
globulin was not administered. Neither patient had systemic complications
from the infection. After being monitored in the hospital for 12 days,
the child was discharged. This is the first documented case of inadvertent
contact vaccinia transmission from a mother to her infant through direct
skin-to-skin and skin-to-mucous membrane contact while breastfeeding. The
mechanism of transfer from the vaccinee to the spouse is uncertain. This
report demonstrates that breastfeeding infants living in close contact
with smallpox vaccinees are at potential risk for contact vaccinia, even
if the vaccinee is not the breastfeeding mother, and highlights the need
for special precautions to prevent secondary transfer to breastfeeding
mothersref.
in July 2003, a service member who had been vaccinated was wrestling with
an unvaccinated service member at a military recreational function when
the bandages covering the vaccination site fell off. The unvaccinated service
member subsequently wrestled with another unvaccinated service member.
6 days later, both unvaccinated service members had lesions on their forearms,
neck, and face. Skin lesion specimens from both men tested positive for
vaccinia virus by PCR and viral culture at Tripler Army Medical Center's
microbiology laboratory.
The findings in this report indicate that the primary risk for secondary
transfer of vaccinia was among persons who shared a bed; 12 of the 18 confirmed
cases were spouses or adult intimate contacts. However, the majority of
vaccinated DoD personnel who shared a bed did not transfer vaccinia virus
to their contacts. The frequency of contact transfer in the military vaccination
program is comparable to rates observed during the 1960s, although persons
are less likely to be immune to vaccinia today and thus are more susceptible
to contact transferref.
The 1st case of tertiary transfer described in this report underscores
the need for breastfeeding mothers with household contact with vaccinees
to take precautions to prevent inadvertent transmission of vaccinia to
their infants. Direct contact is presumed to be the major mode of transmission,
but clothing and bed linen might act as vectors for secondary transmission.
Tertiary transmission, although rare, is facilitated when the secondary
infection is not recognized. Programs that educate health care workers,
vaccinees, and contacts should note that new vesicles or pustules that
appear <15 days after the vaccinia scab falls off from the vaccination
site might be vaccinia infections. Although an infant living in the home
is not a contraindication to vaccination of a family member in a non-outbreak
setting, measures to prevent transmission include having vaccinees launder
their own linens and towels and change their bandages away from other household
members. During the 1960s, the rate of unintentional infection with vaccinia
in secondary contacts was 2-6 cases per 100 000 primary vaccineesref1,
ref2,
ref3.
During that period, 2/3 of reported contact infections occurred among children,
typically siblingsref.
Such spread could manifest as an inadvertent infection or, in more severe
fashion, as eczema vaccinatum or progressive vaccinia. Infections of the
skin predominated, with rarer ocular involvement posing a risk for scarring
or keratitis. In the current DoD smallpox vaccination program, no cases
of eczema vaccinatum have occurred, although the population of atopic dermatitis
patients might have increased substantially since the 1960sref.
During the 1960s, eczema vaccinatum resulted in deaths, and 2/3 of such
cases were related to contact transfer of vaccinia virus. In the current
DoD smallpox vaccination program, careful screening of DoD vaccinees and
their household contacts for skin diseases along with targeted education
likely contributed to both screening out vaccine candidates with personal
or close-contact contraindications and educating vaccinees about proper
infection-control measures
Recommendations for covering the vaccination site vary. The World
Health Organization (WHO) does not advocate bandagingref.
The US Centers for Disease Control and Prevention (CDC) recommend a porous
gauze dressing in nonhealth care settings or a gauze dressing covered with
a semipermeable membrane for health care workersref.
The conventional methods of preventing a secondary transmission event in
the household of a smallpox vaccine recipient include the use of bandages
and long sleeves (OpSite Post-Op dressing (Smith and Nephew, Massilon,
OH, USA) to limit direct contact with the lesion and immediate hand-washing
when contact occursref.
Several recent reports have measured the presence of vaccinia virus on
the dressings or hands of vaccinated persons; however, the recovery of
vaccinia virus in the environment has not been evaluated after vaccination
in a controlled settingref1,
ref2,
ref3.
In an attempt to recover live vaccinia virus from the homes of recently
vaccinated persons, a sterile Calgiswab type 2 applicator (Harwood Products
Co., Guilford, ME, USA), moistened in sterile water, was rotated over the
linen from the study participant's bed (approximate location of sleeping
area), the middle of his or her bath towel, and the inside area of a shirt
sleeve adjacent to the vaccination bandage (before laundering). These sampling
areas were chosen on the basis of the likelihood of exposure to the semipermeable
bandage and the potential for another person to come in contact with the
vaccinia virus in these areas. An additional 129 samples from the palm
of the study participant's hand used to take the environmental samples
were taken to serve as a control mechanism. All 516 environmental samples
from designated sampling areas in the homes of recently vaccinated vaccinia-naive
persons were negative for live virus as determined by plaque infectivity
assay. Only 1 (0.78%) of 129 dressing samples tested on day 7 had measurable
titers of vaccinia. Contact with live vaccinia virus from the lesion at
the site of vaccination is the underlying cause of secondary transmission.
Common mechanisms for transmission include contact with contaminated bandages
and intimate sexual contact. Recent studies have compared a variety of
bandages used to cover the vaccination site to determine which class of
bandage provides the greatest protection against disseminated virus. Talbot
et al. observed that <1% (N = 918) of dressing samples were positive
for vaccinia (an initial semipermeable OpSite Post-Op dressing and an outer
semipermeable Tegaderm bandage)ref.
In a single-blind randomized trial design, Waibel et al. compared the presence
of vaccinia virus on the external surface of 3 different types of bandages
and noted that the unfolded 5.1 × 5.1cm gauze (Kendall Clarity
Gauze Sponge) covered by a 5.1 × 7.0 cm semipermeable membrane (Polyskin
II Transparent Dressing; Kendall) had the smallest proportion of recoverable
virus compared with the groups that used a 1.9 × 7.6cm self-adhesive
bandage (Band-Aid; Johnson & Johnson) or unfolded 5.1 × 5.1 cm
gauze (Kendall Clarity Gauze Sponge) covered by a 2.5 × 12.7 cm piece
of adherent tape (Transpore surgical tape; 3M). Viral DNA was measured
once on bandage surfaces after 8 h. In practice, however, recipients might
be instructed to change their dressing every 1-3 days for up to 3 weeks,
coinciding with reduced bandage adhesion or visible exudates. 3 weeks of
dressing changes complicate compliance, especially if a less convenient,
bulkier dressing is used. This underscores the notion that a simple plaster
adhesive containing absorbent material might increase compliance, and perhaps
reduce the risk of accidental transmissionref.
Despite the difference in types of bandages from these studies, the results
were remarkably consistent with regard to the limited dissemination of
vaccinia virus outside the dressing. The semipermeable bandage provided
significant protection from exposure to the virus on the outside of the
bandageref
In a national survey in the United States conducted after smallpox had
been eliminated, there were 66 cases, with no deaths, among 14.5 million
vaccinees.
lymphadenitis
persisting for 2÷4 weeks after blister has healed
feverof
over 100°F in ~ 70% of children and 17% of adults.
mild rash, lasting 2÷4 days
rash on entire body (1 per 4,000)
eczema vaccinatum / pyoderma varioliforme
infantum (a kind of Kaposi's
varicelliform eruption (KVE))
in individuals who have active or quiescent atopic
dermatitis (AD)
(1 per 26,000) results from an inability of the host to control the spread
of virus from the inoculation site (Th2
polarization prevents Th1-mediated
viral clearance, and increased levels of the Th2-type cytokine
IL-4 can be detected in both affected and unaffected skinref
: ectromelia virus genetically engineered to produce IL-4
results in a lethal disease in mice that are normally resistant to unmodifed
ectromelia, indicating a role for this cytokine in restricting immune responses
to pox virusesref).
After 5 days, a vaccinial eruption occurs at sites that are eczematous
or that had previously been so, sometimes spreading to normal skin => high
fever and generalized lymphadenopathy. Although usually mild and self-limited,
severe or fatal cases have been reported and are independent of the activity
of the underlying eczema at the time of vaccination : disease may cause
multiple duodenal ulcers and death by acute peritonitis and is associated
with substantial morbidity and mortalityref1,
ref2.
Production of Th1-type cytokines, such as IFN-g,
and CTL functions are also impaired in patients with ADref1,
ref2.
T-cell homing might be dysfunctional in these patients as well. In mice,
the generation of Th1-type, but not Th2-type, cytokines,
is associated with a skin-homing phenotyperef.
The presence of skin-homing Th2 cells in atopic patients might
represent an uncoupling of this associationref.
Surprisingly, even innate immunity might be impaired in these patientsref.
The production of IL-18
is increased in AD : however, serum IL-18 levels tended to correlate negatively
with serum IgE levels in patients with AD and NC/Nga miceref,
and keratinocytes from patients with AD produce a different array of cytokines
and chemokines than do keratinocytes from non-atopic individualsref1,
ref2,
ref3
progressive (or gangrenous)
vaccinia / vaccinia necrosum in individuals with agammaglobulinemia,
hypoglobulinemia, neoplasms affecting the RES, CMI
deficiencies,
or treated with immunosuppressive
drugs
(1 per 625,000). The vaccinia lesion fail to heal and metastatic
lesions sometimes appear. Methisazone is reported to be partially effective
in treatment, but 33% of such patients die from secondary visceral involvment.
generalized vaccinia (1 per 4,000)
: spread of the virus in the bloodstream cause after 6-9 days development
of vesicles and pustules resembling the initial one found at the inoculation
site (but sometimes varied in size) , sometimes covering the entire body
=> uneventful recovery without the need for specific therapy. Generalized
vaccinia is not associated with immunodeficiency, although it is more severe
in immunocompromised individuals. The rash was usually self-limiting and
thus,
little or no therapy was administered.
accidental autoinoculation to eyelids (vaccinophthalmia),
mouth, nose, genitalia, and rectum. Such lesions evolve rapidly and heal
at the same time as the primary lesion. VIG
can be used for vaccinophthalmia : however, if vaccinial
keratitis
is present, VIG is contraindicated, because it might increase corneal scaring.
circulatory encephalopathy
5-10 days after vaccination in children with age < 2 : hyperemia of
the brain, lymphocytic infiltration of the meninges, widespread degenerative
changes in ganglion cells, and perivascular hemorrhage => after 6-10 days
fever and convusions => hemiplegia and aphasia => death within few days
or recovery with some degree of mental impairment and/or paralysis.
postvaccinial
autoimmune encephalomyelitis
8-14 days after vaccination in children with age > 2 (1 per 5,000÷20,000)
: perivenous demyelination and microglial proliferation => after 11÷15
days : fever, vomiting, headache, malaise, anorexia, disorientation, drowsiness,
convulsions, coma => death (10-50%) within a week of onset, recovery with
upper spastic paralysis (25%) or full recovery within 2 weeks. In the United
States, there were 12 cases, of which one resulted in death, among the
13 million vaccinees. VIGs are useless.
fetal vaccinia in pregnant women (<
20 cases recorded)
bacterial overinfections at the vaccination site in as many as 1
per 667,000
coronary
artery diseases (CAD),
hypersensitivity
myocarditis
and pericarditis
5 to 17 days after vaccination in recipients with age from 43 to 55 and
previous heart diseases. 8 cases of cardiac adverse events [5 AMIs and
2 cases of angina, with 3 deaths] have been reported among 493,000 vaccinees
since the beginning of the US smallpox vaccination program in 2002 to 18
June 2003. As of 20 Jun 2003, a total of 21 cases of myopericarditis were
reported among civilians and another 10 cases among those in the
military. Viruses create a self-perpetuating, hypercoagulable state by
adhering directly to blood vessel walls. When this occurs, circulating
fibrin is deposited directly onto the virus creating a protective coating,
in an attempt to isolate the virus from the rest of the body. The result
is the formation of visible bumps along the inside wall of the blood vessels,
increasing the blood flow turbulence, releasing more thrombin, creating
a perpetual thrombin-fibrin-deposition cycle, leading to hypercoagulabilty
and clot formation. 2 cases of dilated
cardiomyopathy (DCM)
were diagnosed 3 months after vaccination in persons with no previous history
of cardiomyopathy, coronary artery disease (CAD), or congestive heart failure.
9 other serious events were reported, including 3 cases of chest pain,
one case of gastro-esophageal
reflux disease,
one case of cholecystitis,
one case of sudden death caused by atherosclerotic coronary
artery diseases (CAD)
69 days postvaccination. 3 neurologic cases were reported, including a
central nervous system tumor diagnosed 28 days postvaccination, a headache
evaluated for encephalitis, and a cerebral vascular accident. An additional
111 other nonserious events also were reported . Among the 610 vaccinees
with reported other nonserious adverse events during 24 Jan 2003--20 Jun
2003, the most common signs and symptoms were fever (n = 121), rash (n
= 114), headache (n = 103), pain (n = 95), and fatigue (n = 85). All of
these commonly reported events are consistent with mild expected reactions
following receipt of smallpox vaccine. Some vaccinees reported multiple
signs and symptoms.
a total of 14 cases of transmission from military personnel to civilian
contacts have been reported since the program began.
pustule at 6 to 8 days if residual CMI is low (major reaction)
antibodies rise within 7 days and reach higher levels (at least for neutralizing
ones)
Repeated vaccinations provide a short-term boost in immunity but, over
time, do not create a sustained higher level of protection compared to
those persons vaccinated only once
Status of the practice : in USA and Canada
(last Canadian case : 1946) vaccine administration has been suspended in
1971-1972 for civilians, in 1976 for healthcare workers, in 1982 for international
travelers, and in 1990 for military personnel. Part of military and healthcare
personnel has been vaccinated in 2002-2003 : the military
has inoculated 454,856 personnel (70.5 primary vaccinees), nearly 90% of
them
before the invasion of Iraq, and is now vaccinating about 1000 a week.
State health departments have inoculated only 37,608 civilian emergency
health workers in 55 jurisdictions and are adding about 100 more each week,
although the goal was 500 000. VIG was needed only 3 times. About 125 women
who were pregnant or became pregnant were inadvertently vaccinated, despite
screening : thus far, there has been no vaccinia in fetuses, and miscarriage
rates have been normal, though they are still being followed. Revaccinate
those already vaccinated in childhood and at a very low risk would be a
better strategy than risking the side effects on the population as a whole.
When revaccinated with a 1:10 dilution of smallpox vaccine, previously
immunized persons exhibit fewer side effects and a similar immune response
to that seen in vaccinia-naïve subjects : major reactions were documented
in 95% patients given undiluted vaccine, 90% given a 1:3.2 dilution, and
81% given a 1:10 dilution. Only a 1:32 dilution resulted in significantly
fewer major reactions, 52.6% compared with undiluted vaccine (p = 0.003)
Commercialized formulae :
Dryvax® (Wyeth-Ayerst; side effect : encephalitis)
: prepared from lymph collected from lesions on calves' bellies, making
it a relatively expensive and difficult endeavour. Despite its efficacy,
Dryvax's manufacture is seen as dated.
ACAM1000®ref
(OraVax, Inc. => Acambis, Ptl., USA) : a vaccinia virus was derived from
the existing Dryvax vaccine by adaptation for growth in a human diploid
cell line, providing a purer product. 6 cloned and one uncloned vaccine
candidates were produced. The ACAM1000 clone was chosen for development
based on its comparability to Dryvax when tested in mice, rabbits, and
monkeys for virulence and immunogenicity. By most measures, ACAM1000 was
less virulent than Dryvax (less likely to cause encephatis) and the vaccines
are equivalent in initial trials in their ability to produce major cutaneous
reactions ('takes') and to induce neutralizing antibody and cell-mediated
immunity against vaccinia virus
ACAM2000® (Acambis, Ptl., USA;
less likely to cause encephalitis). With the US on high terrorist
alert, Acambis fast-tracked orders for 209 million doses of the vaccine
from it before it had been fully tested. On 14 April 2004, intense monitoring
of who participated in the phase III trials has discovered that 3
suffered myopericarditis and the trial has been suspended. The drug has
not been given to anybody outside the trials. It remains to be established
whether the cell culture-derived and -produced vaccine is inferior to Dryvax,
or whether the stringency of the phase III trials procedure has been increased
in the light of more clinical assessment of the performance of the Dryvax
vaccine
La Variole® (?, France)
Lancy Vaxina® (Swiss Serum and Vaccine Institute)
Liovax® (Sclavo)
Liovaxs® (Biocine)
? (VaxGen, USA + Kaketsuken, USA)
Ospa® (?, Poland)
Pocken® (?, Germany)
Pocken-Impfstoff® (?, Germany)
Vaccinia® (?)
Vaiolo® (?, Italy)
Vaksin Cacar® (?, Indonesia)
Varicela el® (?, Spain)
Varie® (Institute of Sera and Vaccine) : lyophilized
Viruela® (?, Spain)
Vaccine production in USA has been discontinued in 1982 and reinitiated
in 2002.
Web resources :
subunit vaccines
/ acellular vaccines are cell-free vaccine prepared from purified
antigenic components of pathogenic microorganisms, thus carrying less risk
of adverse reactions than whole-cell preparations.
conventional vaccinology : biochemical, serological and microbiological
methods have been used to dissect pathogens and identify the components
useful for vaccine development. Although successful in many cases, this
approach is time-consuming and fails when the pathogens cannot be cultivated
in vitro, or when the most abundant antigens are variable in sequence.
reverse vaccinologyref
: genomic approaches allow prediction of all antigens, independent of their
abundance and immunogenicity during infection, without the need to grow
the pathogen in vitro. Candidate peptide
vaccine components representing T cell epitopes might be predicted
from the various microbial genome projects, tumor vaccine candidates from
mRNA expression profiling of tumors ("transcriptomes") and auto-antigens
from the human genome. Promising antigens are then mass-produced
in Escherichia coli, purified, and used to immunize mice. Anyway
the possibility of splicing at the protein level certainly adds to the
complexity of the possible repertoire of peptides displayed to T lymphocytes
: e.g. C2 CTLs, cloned from human CTLs infiltrating a renal cell carcinoma,
recognize HLA-A3 MHC class I molecules presenting a 9-residue FGF-5 peptide
generated by protein splicing of residues 172–176 and 199–220. This process,
previously described strictly in plants (involving reverse proteolysis)
and unicellular organisms (regulated by “inteins”), entails post-translational
excision of a polypeptide segment followed by ligation of the newly liberated
carboxy-terminal and amino-terminal residuesref.
Within 18 months of the beginning of the sequencing of Neisseria
meningitidis
serogroup B (Men B), over 600 potential vaccine candidates had been predicted
by computer analysis of the genome, and 350 of them were expressed in Escherichia
coli, purified, and used to immunize miceref1,
ref2.
Today, the genome-based approach is routine in vaccine development and
is being applied to streptococci, Chlamydiae, staphylococci, Plasmodium
falciparum, and bioterrorism-associated agents such as Yersinia
pestis.
candidate peptide vaccine components representing
B cell epitopes are typically identified by their ability to bind Abs from
subjects exposed to the relevant pathogen, which we call direct Abs.
To be useful as a vaccine component, a peptide must be not only antigenic
but also immunogenically fit : when used as an immunogen, the indirect
Abs it elicits must cross-react with native intact pathogen. Immunogenic
fitness is gauged by the fraction of indirect anti-peptide Abs that
cross-react with the pathogen : it is a property of epitope structure and
the response charactetrstics of immune cells, and does not depend on idiosyncratic
details of pathogenesis. It is distinct from immunogenicity, which is gauged
by the total anti-peptide titer of those indirect Abs, including Abs that
do not cross-react with pathogen. Peptides with excellent antigenicity
and immunogenicity frequently lack adequate immunogenic fitness and therefore
fail as potential vaccine components. A common explanation for this poor
immunogenic fitness is the conformational flexibility of most short
peptides. A flexible peptide may bind well to direct Ab and thus have
good antigenicity; indeed, flexibility may sometimes enhance antigenicity
by allowing the peptide to bind by an induced fit mechanism. Likewise,
a flexible peptide may be highly immunogenic, eliciting substantial Ab
titers. However, if the peptide has a large repertoire of conformations,
a preponderance of those Abs may fail to recognize the corresponding native
epitope on the intact pathogen. Antigenic peptides can be obtained through
a strategy called epitope discovery, in which direct Ab is used to affinity
select Ags from very large phage-displayed
libraries of peptides. The property that enables a peptide to prevail during
selection - high affinity for a prevalent subspecificity in the selecting
direct Ab population - augurs well for success as a candidate peptide vaccine
component, even though its correlation with immunogenic fitness is imperfect.
Selections can be made from 2 types of libraries :
random peptide libraries (RPLs), in which
the phage-displayed peptides are encoded by synthetic random degenerate
oligonucleotide inserts
natural peptide libraries (NPL), in which
the phage particles display fragments of natural pathogen proteins, encoded
by short DNA fragments of the pathogen genome
Ligands affinity selected from RPLs and NPLs will
be called random antigenic peptides (RAPs) and natural antigenic
peptides (NAPs), respectively. While RAPs have only marginal immunogenic
fitness, a large fraction of NAPs have excellent immunogenic fitness.
Finding efficient ways to get an antigen presented to the immune system
: pH-sensitive microspheres that seem to enhance antigen uptake and presentation
significantly. Capsules made with Eudragit 100 (E100), a methacrylate-based
polymer, remain largely stable at neutral pH, only slowly releasing their
contents over the course of several weeks. After their injection, however,
dendritic cells (DCs) readily phagocytose these capsules, which quickly
dissolve in the acidic pH of the phagosome, releasing their contents into
the vesicle. Thus released antigens enter directly into the MHC class I
pathway for presentation. Encouragingly, these capsules seem to have minimal
detrimental effect on DCs. The uptake of encapsulated antigen is considerably
greater than that of unencapsulated antigen, and uptake of antigen-laden
E100 particles significantly increases the capacity of DCs to activate
T cell response relative to antigen alone or antigen encapsulated in a
non-pH-sensitive methacrylate polymer. In vivo, splenocytes from
mice injected with E100 capsules containing an influenza-derived peptide
antigen proved capable of stimulating more robust cytotoxic activity than
cells from mice treated with soluble antigen alone. Data indicate that
these microparticles do not induce DC maturation by themselves. It is possible
that the inflammatory reaction to the particles may be involved in enhancing
the T cell response in vivoref To counter highly mutable pathogens, a number of vaccines are being
developed to deliver multiple mutant forms of antigens to provoke multivalent
CTL. However it is uncertain whether such multiple mutant epitope vaccines
will generate the diverse CTL responses desired or will instead create
immune
interference.
At least some immune intereferences can be avoided by delivering mutant
Ags to the immune system simultaneously.
homologous Ags
transfer factors
(TF) : a dialyzable extract obtained from lysates of peripheral
blood lymphocytes that is capable of transferring antigen-specific cell-mediated
immunity (delayed-type hypersensitivity) from donor to recipient and also
has nonspecific immunostimulatory activity. TF is nonantigenic and does
not transfer humoral immunity. It has been used in the treatment of a variety
of immunodeficiency diseases. It comes
from ...
dried cow colostrum (Transfer Factor®,
Transfer Factor Plus®, Transfer
Factor XF®) concentrated 30
times, devoid of allergens.
Transfer factor contains :
RNA
protein : a mix of > 200 different peptides with
4 < molecular weight < 10 kDa, about 44-amino acids long, from
which antibodies have been eliminated (probably because they could interfere
with induction of adaptive immune response),
and hence containing mainly :
cytokine are normally
produced from all species with an adaptive immune system (i.e. Vertebrates).
These cytokines can be administered even by oral route as natural(i.e.
in mammary gland or eggs) hyperglycosylation allows them to resist
gastric pH and digestive proteases.
antigens are present thanks to (multiple) vaccination
(with adjuvants) of the experimental animal
It doesn't contain :
DNA
viable cells can't account for the protective role
of transfer factor as it can be effectively
administered even in powdered or freeze-dried
forms.
Transfer factors are said to be able to elicit a
secondary immune response just because they
also already contain those cytokines that require
some days in humans to be produced after primary exposure : hence we should
more properly say transfer factors induce
a fastened primary immune response, as for most
vaccinations (in this case transfer are just like subunit vaccines
and cytokines are the adjuvants).
Even if transfer factors can pass protective
immunity to mice (patent data support this,
hoping they're serious), this doesn't mean they
can pass protective immunity to humans. Cytokines effects depends on their
ability to bind receptors on immune system cells : the greater
the phylogenetic distance between the producer species and humans
(hen > cow > human), the higher the likelihood that these cytokines can't
bind human receptors. Human cytokines have a molecular weight between 6
and 60 kDa : 4-5 kDa could be the weight of intact avian / bovine cytokines,
otherwise if they were the result of a proteolytic cleavage these peptides
would have reduced likelihood of retaining an active receptor-binding domain.
Not all human diseases are zooanthoroponoses
(e.g. human herpesviruses are human-restricted). Anyway when
an antigen from an heterologous infectious organism is injectedtogether
with adjuvant, the unusual host can develop an adaptive immune
response against it. Anyway for antigens to be found in yolk orcolostrum
they have to reach a significant concentration in blood and this
seems quite difficult if they can't replicate in such unusual
host, unless high amount of antigens are directly injected intothe bloodstream
of the producer species : this let scientists doubtful about the
effectiveness of the anti-EBV patented transfer factor, even because
eggs are collected 175 days after immunization, where antigens have been
reasonably cleared.
microorganism
Ags
Some examples :
broad-spectrum antibacterial vaccine : injection of low-dose LPS
to mice prior to induction of GVHD
with allogeneic spleen cells saved > 40% of the recipients, whereas all
mice in the untreated control group died. The survival of recipients of
spleen cells from immunized donors rose to 54% and clinical signs of GVHD
were attenuated as compared to control mice inoculated with spleen cells
obtained from unimmunized donors. This immunization protocol suggests that
immunization of the donor or the recipient against LPS prior to transplantation
may be protective against gram-negative bacteriaref
protein antigens
anti-viral
subunit vaccines / subvirion vaccines
anti-human
papillomaviruses (HPV)
vaccines (see also DNA
vaccine):
virus-like
particles (VLP) consist of the capsid proteins L1 or L1 and L2. Chimeric
VLP, which have the E7 protein fused to either L1 or L2, are being developed
for immunotherapeutic vaccine strategies against cervical cancer. The constitutive
expression of high-risk HPV E6 and E7 proteins, which bind and inactivate
tumor suppressors p53 and pRb, respectively, in cervical cancer cells,
makes them attractive targets for immunotherapy. A 2002 double-blind study
on 768 women of ages 16-23 who received 3 doses of an HPV16 VLP vaccine
has shown 100% effectiveness against infection and preinvasive cervical
cancer. Both women taking and not taking
oral
contraceptives
develop detectable titres of anti-HPV16L1 VLP immunoglobulins in their
cervical secretions after immunization : anyway these titres were fairly
constant in the contraceptive group throughout the mentrual cycle, but
titres of both vaccine-specific and total IgG decreased by about 9-fold
during ovulation in the no contraceptive group, then rose again in the
luteal phase of the cycle. Sex hormones might have a role in regulating
antibody concentration in the cervix, and the decrease in antibody concentration
at ovulation might be a protective mechanism to reduce the level of antisperm
antibodies in the genital tract at a time when conception is most likely
: it is unclear whether the decrease in antibody production will affect
the ability of this vaccine to protect against cervical cancer.
no objective clinical response
open-label uncontrolled trial
bivalent HPV-16/18 (that have been linked to 70% of cervical cancers)
L1 VLP (Cervarix®) (not yet been submitted for regulatory
approvals)
a study of 1,113 women aged 15 to 25 years old in North America and
Brazil has found it is 100% effective at preventing the persistent infections
that cause cervical cancer. It was 91.6% effective at reducing incident
or new infections for as long as 2 years among 366 women (65% of the total
1,113 patients) who received all 3 doses according to schedule. In the
intention-to-treat analyses, vaccine efficacy was 95.1% against persistent
cervical infection with HPV-16/18 and 92.9% against cytological abnormalities
associated with HPV-16/18 infectionref.
A Glaxo-financed phase III trial, conducted in Europe and Russia showed
that 158 healthy girls aged 10 to 14 who received the vaccine had immune
responses twice as strong as 458 women 15-25 years old given the vaccine
HPV 16 and 18, cause about 70% of cervical cancer cases, while HPV
6 and 11 cause about 90% of genital warts cases (Gardasil®,
Merck & Co.) (already awaiting approval from U.S. and European regulators)
over 2 1/2 years of follow-up, the vaccine blocked about 90% of infections
with the 4 HPV types. None of the vaccine recipients developed cervical
cancer, precancerous lesions or genital warts related to those HPV types
The goal would be to give the vaccine to girls before they are sexually
active. The vaccine prompts the body to produce high numbers of antibodies
to fight the HPV infection and the only side effects were some redness
and irritation at the vaccine site. Although the vaccine won't prevent
all cervical cancers because it doesn't protect against all cancer-producing
strains, a quadrivalent vaccine that also protects against types 6 and
11 is already under study. Merck presented results that showed its vaccine,
which targets just the HPV16 form of virus, continued to protect against
the disease for 4 years. Merck is testing a more advanced vaccine that
targets 4 forms of the virus in a study of 25,000 women. Although teenagers
and adults took part in the trials, in practice the vaccine is likely to
be administered to girls as young as 10 to 13. Because HPV is transmitted
through sexual intercourse, older sexually active girls are more likely
to be infected. Some critics have argued that treating young girls with
the vaccine might encourage under-age sex
anti-HAV
vaccines (see also killed vaccine)
: 2 intramuscular injections separated by 6-12 months
Avaxim® (Aventis Pasteur)
160 U in 0.5 mL
80 U in 0.5 mL or 800 U / 5 mL (for pediatric use)
Apaxal® : 0.5 mL
Epaxal® (Swiss Serum and Vaccine Institute) : the
first product based on the virosome technology developed and patented by
Berna Biotech. The innovative carrier system provides rapid, long lasting
protection and exhibits good tolerability.
There is no worldwide consensus on how long protection will last or whether
there will be a need for HAV booster vaccinations in the future. In most
countries, booster-vaccination policy is guided by manufacturers' recommendations,
national authorities, or both. In June, 2002, a panel of international
experts met to review the long-term immunogenicity and protection conferred
by HAV vaccine in different population groups. Data have shown that after
a full primary vaccination course, protective antibody amounts persist
beyond 10 years in healthy individuals, and underlying immune memory provides
protection far beyond the duration of anti-HAV antibodies. The group concluded
that there is no evidence to lend support to HAV booster vaccination after
a full primary vaccination course in a healthy individual. However, further
investigations are needed before deciding if boosters can be omitted in
special patient-groupsref
anti-HBV
vaccine (HBV) (see also DNA
vaccine)
for immunization of persons at high risk, e.g., medical and dental personnel,
immunocompromised patients and patients requiring hemodialysis or frequent
transfusions, residents and staff of closed institutions, contacts of carriers,
and male homosexuals : it protects also from HDV.
4 intramuscular injections (not on gluteus !) at months 0, 1, 2, and 8-14;
effective ([Ab] > 10 mU/mL) for 3-5 yrs in 90-99%. 1-2 boosters may be
required only after age 60. If titer has never been measured after vaccination,
practice a booster : if titer rises sharply the patient was already protected,
otherwise patient is classified as non-responder (rather he/she has an
undetectable but still protective titer). The HBV vaccine market outside
of the USA is approximately $500 million
formalin-treated HBsAg isolated from plasma of human carriers of hepatitis
B
H-B-Vax® (MSD-Behringwerke) : serum
Heptavax B® (Merck) : plasma derived, no longer in
use
Biken-HB® (Research Foundation for Microbial Disease)
Bimmugen® (Chemo-Sero-Therapeutic Research Institute)
a new HBV vaccine (source : Dynavax)
combines immunostimulatory
(ISS) oligodeoxynucleotides (ODN) / TLR9 agonists
with rHBsAg induced more rapid immunogenicity and more durable protective
response compared to Engerix-B in healthy young adults 4 weeks after administration
of the third dose in a phase II/III trial
Engerix-B®
(RIT/GlaxoSmithKline Inc., Dong Shin Pharmaceuticals Co.) : 20 mg
/ mL for adults, 10 mg / mL for babies. 12.5
mg
mercury per dose (0.005% thimerosal).
Strong immunological memory persists more than 10 years after immunisation
of infants and adolescents with a primary course of vaccination. Protective
anti-HBs concentrations were retained in 64% of children and 89% of recruits.
Antibody amounts < 10 IU/L were recorded in 36% of children and 11%
of recruits. 1 child and 4 recruits were positive for anti-HBc, but negative
for HBsAg and hepatitis B viral DNA. Antibody concentrations were higher
in recruits than in children. 97% of children and 96% of recruits who received
a booster showed an anamnestic response, whereas 3% of children and 4%
of recruits remained negative for anti-HBs or had antibody concentrations
of less than 10 IU/L. Prebooster and postbooster antibody titres were strongly
correlated with each other in both groups. All individuals given 2 additional
vaccine doses showed anti-HBs amounts > 10 IU/L at 1 month after vaccination.
Booster doses of vaccine do not seem necessary to ensure long-term protectionref
Hepacare® (Medeva) : recombinant, 20 mg
S, pre-S1 and pre-S2 Ags in 1 mL
Hepavax-Gene® is a DNA recombinant HBV vaccine with
a proven safety and efficacy record. The vaccine is produced using the
highly-efficient proprietary Hansenula polymorpha technology.
Heprecomb® (Berna) : yeast derived
Hepatitis tipo B® (?, Spain)
Recombivax
HB® (Merck & Co.; royalties : Chiron) : preservative-free;
LIQ(5 mg / 0.5 mL) IM (10 mg
for adults, 5 mg for babies). No mercury added.
rHBsAg cloned in mammalian cell
GenHevac B® (Aventis Pasteur)
R-HB Vaccine® (Mitsubishi Chemical Corp.) : precipitated,
CHO derived
anti-influenzaviruses
A and B
vaccine (see also kllled vaccine,
attenuated
vaccine and DNA
vaccine)
: 2 intramuscular injections. Current vaccines are highly effective for
4-6 months in children and adults (70%–90%), although not in those >65
years of age (30%–50%)ref
: booster every year. Counterindicated in individuals allergic to egg proteins.
universal influenza vaccineref
based on invariant proteins that confer heterotypic or heterosubtypic
immunity. Incorporation of several conserved targets in a universal
vaccine may decrease the likelihood and rate of emergence of escape mutants
and increase the strength of protection. They have been studied extensively
in animals and found to be mediated predominantly by virus-specific memory
T cellsref1,
ref2,
antibodiesref1,
ref2,
ref3,
or a combination of bothref1,
ref2
(Gerhard W, Mozdzanowska K, Furchner M. The nature of hetero-subtypic immunity.
In: Brown LE, Hampson AW, Webster RG, editors. Options for the control
of influenza III. Amsterdam: Elsevier Science; 1996. p. 235–43). The reason
for these differences in the relative strength of T-cell and antibody-mediated
protection is not clear but could be attributable to differences in vaccination
procedures, virus challenge, and read out (how protection was measured)
between the various studies. A large number of memory T cells may also
result in immunopathologic manifestationsref1,ref2,
which tend to be associated with excessive inflammatory responses in acute
infections : antibody-mediated protection is the accessibility of the viral
antigen to antibody on infectious virus particles, intact infected cells,
or both. This accessibility restricts the potential targets to conserved
structures of the ectodomains of viral transmembrane proteins HA, NA, and
M2, in the case of influenza A viruses, and HA, NA, NB, and BM2, in the
case of influenza B viruses. In the elderly, another high-risk population,
a universal vaccine may be particularly advantageous because the protective
antibodies are generated by memory B cells that tend to be maintained into
old age and can be recalled by booster vaccination. In contrast, the efficacy
of current inactivated vaccines depends greatly on the ability to mount
a strong response to novel (strain-specific) determinants generated through
antigenic drift and shift on HA and NA. This response requires naive
B cells, whose frequency tends to decrease with increasing age. When all
factors are taken into account, protection against influenza virus infection
likely can be improved by a universal vaccine.
intersubunit region of hemagglutinin : The protective potential
of antibodies directed to this region of HA0 has been explored
in 2 studies by immunization of mice with synthetic peptides spanning the
cleavage siteref1,
ref2.
Both studies found that mice vaccinated with a peptide spanning the HA1/HA2
joining region exhibited less illness and fewer deaths on virus challengeref1,
ref2.
Most importantly, HA1/HA2 joint-specific antibodies
were undetectable in virus-immune human seraref.
These findings make the HA1/HA2 joining region another
promising candidate for inclusion in a universal vaccine. Indeed, the authors
of 1 study, some of whom had been involved in an M2e-vaccine study, commented
that joint-specific immunity in the mouse model was more robust than M2e-specific
immunityref.
Although the HA1/HA2-joining region is the most broadly
conserved HA sequence, other determinants on HA2 are shared between a restricted
number of subtypes. For instance, a MAb that reduced illness and death
in passively immunized mice against viruses of the H1, H2,
and H5 subtypes has been describedref1,
ref2.
This MAb was shown to recognize a conformational epitope of HA2ref,
but no immunogen that could selectively induce this response has been described.
A search for determinants shared by a more restricted number of closely
related subtypes such as H2 and H5, which display
85% sequence homology in HA2, or shared by members of the same
subtype, which typically display >95% sequence homology in HA2ref,
would be worthwhile, particularly since the HA2-specific antibody
response appears to be induced less effectively than the HA1-specific
response by infection in humansref.
That many HA2-specific antibodies do not display substantial
antiviral activities in vitro does not preclude protective activity
in vivo because the mere binding of antibody to native HA expressed on
infected cells and infectious virus could mediate protective activity by
targeting FcR expressing cells or complement deposition to these structures
ectodomain of matrix protein 2 (M2e) : M2e-specific antibodies,
while they did not prevent infection, restricted subsequent virus replication
and reduced illness and proportion of deathsref1,
ref2,
ref3,
ref4,
ref5.
This antibody response was only poorly induced by infection, both in miceref
and humansref1,
ref2.
A likely reason for the poor M2e-specific antibody response is extensive
antigenic competition with HA- and NA-specific responsesref.
Thus, in view of the >10-fold difference in ectodomain size, the frequency
of M2e-specific precursor B cells must be orders of magnitude lower than
the frequencies of HA- and NA-specific precursor B cells. Assuming that
most immunogenic entities generated in the course of infection contain
a mixture of all 3 transmembrane proteins, most M2e may be taken up by
HA- and NA-specific B cells, leaving little or none for B-cell receptor–mediated
uptake and processing by M2e-specific precursor B cells. Note that the
same phenomenon results also in a suppression of the NA-specific antibody
response by immunodominant HA-specific B cellsref.
Such competition can be avoided by presenting individual antigens on physically
distinct immunogenic entities to the immune systemref.
The substantial M2e-specific antibody responses seen in mice after vaccination
with dedicated M2e vaccines (20–24) supports the above explanation. In
view of the poor or absent M2e-specific antibody response in humans, confirming
the genetic stability of M2e was essential when the virus was propagated
in an immune environment. Replication of A/PR/8/34(H1N1)
(PR8) virus for >3 weeks in severe combined immunodeficient (SCID) mice
that were chronically treated with M2e-specific monoclonal antibodies (MAbs)
resulted in the emergence of M2e-escape mutantsref.
However, only 2 distinct escape mutants emerged, 1 with a replacement of
Pro at position 10 by Leu (P10L) and the other with a replacement of the
same Pro by His (P10H)ref.
Each of these mutants was isolated repetitively from many distinct mice
treated with distinct M2e-specific MAbs, which indicates that they represented
essentially the entire range of escape mutants capable of arising from
the PR8 wild-type virus under the given experimental conditions. No escape
mutants emerged after 11 consecutive passages of PR8 in BALB/c mice that
had been actively vaccinated with M2e. In addition, incorporating determinants
of potential escape mutants into a polyvalent universal M2e vaccine would
likely further impede emergence of escape mutants. Indeed, preliminary
studies have shown that no escape mutants emerged in SCID mice treated
with a combination of MAbs specific for M2e of wild-type PR8 and the P10H
and P10L escape mutants. Thus, although M2e is not totally invariant, it
is remarkably stable, even under immune pressure. Several vaccination strategies
have been evaluated in mouse and ferret models, including M2-expressing
recombinant viruses, M2 recombinant proteinsref1,
ref2,
M2-encoding plasmid DNAref,
and synthetic M2e peptides that were chemically linked to carrier proteins
or synthetically linked to defined helper T-cell determinantsref1,
ref2,
ref3.
In most studies in which induction of an antibody response was confirmed,
M2e-specific immunity reduced illness, but did not entirely prevent it.
The best protection was reported for mice vaccinated by the intranasal
route with an M2e-hepatitis B core fusion protein construct and detoxified
heat-labile Escherichia coli enterotoxin adjuvant; almost none of these
mice died after a virus challenge that killed 90% of control miceref.
However, in contrast to the significant protection seen in most mouse models,
pigs vaccinated with recombinant M2e-hepatitis B core protein or plasmid
DNA encoding an M2e-nucleoprotein fusion protein showed no protection or
even had higher death rates, respectively, after virus challengeref.
This finding needs to be confirmed, and the explanation for it remains
unknown. At this time, it serves as a reminder that immune phenomena are
complex and that observations made in 1 species may not apply to another.
By the same token, good protection in an animal model does not guarantee
protection in humans. Taken together, the observations that M2e shows minimal
antigenic variability, even under antibody-mediated pressure in vivo, that
M2e-specific antibodies typically restrict virus replication in vivo, and
that humans exhibit low or undetectable M2e-specific antibody titers provide
a strong rationale for further exploration of an M2e-based vaccine.
i.n. synthetic multiple antigen peptide (MAP) constructs that contain covalently
linked M2e and Th-determinant peptides. M2e are highly conserved
amongst human influenza type A viruses and the new vaccine may obviate
repetitive immunizations with updated strains to maintain protectionref
BM2 of influenza B virus, the homolog of M2, has only a 6-aa-long
ectodomainref.
This ectodomain is most likely too small for formation of a BM2-specific
epitope because protein epitopes have usually been found to comprise 12–17
contact residues. NB of influenza B virus also shows structural similarities
with M2 of influenza A virus, including ion channel activityref,
and has an 18-aa-long ectodomain. However, NB2 has 2 attached carbohydrate
chains that can be expected to mask the protein core from recognition by
antibody. NA, however, is a good and not sufficiently explored target for
cross-protective antibodies. Like HA, it displays a large ectodomain of
420 aa. Nine subtypes are recognized among influenza A viruses, while influenza
B virus contains 1 subtype. The C-terminal of the polypeptide (380 aa)
forms a globular head that is anchored to the viral membrane by a flexible
stalk. The globular domain contains the enzyme-active site and all known
antigenic sites.
Although no cross-protective NA-specific antibody population has
been identified, indirect evidence supports the existence of cross-reactive
determinants on N1 and N2, the subtypes found in
classic human strains. Thus, mice vaccinated first with a mixture of purified
N1 and N2 proteins and subsequently boosted with
the individual antigens showed a small memory response also against the
heterologous subtyperef.
Given the ample expression and accessibility of NA on infectious virus
and infected host cells, a search for determinants shared between or within
subtypes would be worthwhile.
Fluvirin®
FluBlØk™ (source : Protein
Sciences) consists of 3 rHA proteins corresponding to the flu strains
selected by the WHO and the CDC for each year's vaccine. These proteins
are produced in serum free insect cells and formulated in PBS without preservatives
or adjuvants. Clinical trials have shown safety and efficacy in healthy
adults and the elderly population:
several Phase I and II trials conducted by the NIAID involving over 600
subjects demonstrated safety and efficacy as reported in four published
studies in the Journal of Infectious Diseases. A significantly higher percentage
of elderly subjects receiving a higher dose of our vaccine develop protective
antibody titers compared to the licensed vaccine.
a Phase II(b) trial conducted by NIAID in 399 elderly subjects was completed
in November, 2003. The trial involved 3 different doses of FluBlØk™
(containing 15, 45 and 135µg, respectively, of each antigen) compared
to the licensed inactivated vaccine (15µg of each antigen).
a pivotal Phase III efficacy study of FluBlØk™ is scheduled to take
place in the fall of 2004. The vaccine initially includes 45µg of
each antigen.
an rHA cloned from a highly pathogenic avian H5 strain has also been tested
as a vaccine for the potential "bird flu" threat. The rHA vaccine provided
complete protection against a lethal viral challenge in chickens (PDF file).
In a human clinical trial of our vaccine 52% of the subjects had a 4-fold
increase in serum titers. (Treanor et al., 2002, PDF file). Significantly
improved results can be anticipated with the use of an adjuvant, and such
studies are being scheduled.
recombinant neuraminidase (rNA) has potential for use as an efficacy-enhancing
additive to influenza vaccines. rNA has completed Phase II(b) challenge
studies conducted by NIAID. Clinical data demonstrated safety and, when
combined with the current vaccine, a significant increase in the level
of antibodies and, for vaccinated people who become ill, less viral shedding,
less severe and shorter duration of illness compared to the licensed vaccine
alone.
FSME Immun® (FSME is the German abbreviation of "Early
Summer Meningo-Encephalitis", a name that in fact is misleading, since
there is another peak in the fall) by Baxter, Austrai
The conventional vaccination schedule consists of 3 doses at day 0, 1-3
months
and 9-12 months after the 2nd dose. After 30 years of development,
both vaccines are now available in adult and paediatric formulations that
cause few adverse side effects. Encepur is licensed for rapid immunisation
at days 0, 7 and 21, and this provides protection 2 weeks after the 2nd
dose of vaccine. The FSME-IMMUN rapid schedule involves 2 vaccine doses
given 2 or 3 weeks apart. This 2-dose rapid schedule is only recommended
for immunisation protection over the summer months because, unlike the
Encepur schedule, its protection is only optimal for 6 months. The difference
of the products is found in the frequency of adverse side effects only.
The Japanese strain was sequenced, and vaccination trials in Japanese volunteers
showed no difference in the neutralization test using different antigensref.
Neutralizing antibodies between different strains have a Spearman rank
correlation was between 0.6 and 0.76, comparing the neutralizing antibodies
against 3 different strains, namely, NDF # 04/94, which is the strain used
for FSME Immun®, 12 Loop.ill and N 132 2BMP. Encepur®
should have the same efficacy against the Russian and Far Eastern strain
as the above-mentioned vaccine. Encepur is used in Germany, in former Eastern
countries (now new members of the EU), and in Austria. Patients can be
immunized, or boostered, with one or the other vaccine.
anti-HTLV-1
vaccine : Although HTLV-1 Tax is the most dominant antigen for HTLV-1-specific
CD8+ CTLs in HTLV-1-infected individuals, few epitopes recognized
by CD4+ Th lymphocytes in HTLV-1 Tax protein have
been described. The aim of the present study was to study Th-cell
responses to HTLV-1 Tax and to identify naturally processed MHC class II-restricted
epitopes that could be used for vaccine development. An MHC class II binding
peptide algorithm was used to predict potential Th cell epitope
peptides from HTLV-1 Tax. The ability of the corresponding peptides to
elicit helper T-cell responses was assessed by in vitro vaccination of
purified CD4+ T lymphocytes. Peptides Tax191-205
and Tax305-319 were effective in inducing Th-cell
responses. Although Tax191-205 was restricted by the HLA-DR1
and DR9 alleles, responses to Tax305-319 were restricted by
either DR15 or DQ9. Both these epitopes were found to be naturally processed
by HTLV-1+ T-cell lymphoma cells and by autologous antigen-presenting
cells that were pulsed with HTLV-1 Tax+ tumor lysates. Notably,
the two newly identified helper T-cell epitopes are found to lie proximal
to known CTL epitopes, which will facilitate the development of prophylactic
peptide-based vaccine capable of inducing simultaneous CTL and T-helper
responses. HTLV-1 Tax protein could serve as TAA for CD4+ helper
T cells and that the present epitopes might be used for T-cell-based immunotherapy
against tumors expressing HTLV-1ref.
Since 1987, researchers have studied about 60 potential HIV vaccines
to help stem the AIDS epidemic. So far, no vaccine has won FDA approval
as
safe and effective. The rapid antigenic variation of HIV virus is frequently
presented as the main scientific obstacle for developing vaccine. To be
true, such opinions quite frequently are followed by honest remarking that
a number of effective vaccines are already available against other viruses
who also display high rates of antigenic variation (poliovirus is usually
mentioned). Therefore, the actual problem is to understand how existing
vaccines overcome antigenic variation. Drug users are attractive for trials
because incidence is so high and because they'd benefit from a vaccine
but it may be more difficult to protect people who've been infected by
injection than those infected sexually, in which the first challenge is
mucosal.
recombinant Tat IIIB toxoid vaccine : with or without an adjuvant
it induces high avidity anti-Tat antibodies with neutralizing activity.
Because of the toxic effects of the Tat protein, an inactivated recombinant
Tat IIIB protein is used.
IR103, which combines the company's patented HIV-1 immunogen with
Amplivax®,
an immunostimulatory oligonucleotide adjuvant, with or without incomplete
Freund's adjuvant (IFA)
gp120-based vaccines :
AIDSVax® (source : VaxGen)
designed to produce antibodies : clinical trials in 5,400 men and women
considered at high risk in the USA and Netherlands reported in February
have shown that the vaccine only reduces the rate of HIV-1
infection by 3.8%, while Blacks and Asians had a 67% lower rate of infection.
It failed to prevent HIV infection or even slow the development of disease
in its second phase III clinical trial, conducted in Thailand and reported
on November 2003 : the results were even worse than those from the first
trial. Antibody induced by this vaccine against gp120 is not protective
: now there are already several groups working on second generation gp120,
or other envelope vaccines, using deglycosylation or tinkering with deletions,
making trimers as in the natural protein and so on. One option is to develop
more immunogenic antibody vaccines, possibly vaccines that induce antibodies
that neutralize primary or clinical isolates of HIV, which the VaxGen candidate
couldn't do. Lab isolates of the virus have been adapted to grow in tissue
culture and tend to bind to CXCR4 (X4) coreceptors rather than CCR5 (R5),
which are used by clinical isolates : initially, most of the gp120 vaccines
were based on X4 strains. Bob Gallo has some hybrid constructs, a chimeric
protein of gp120 and CD4, that can induce antibodies that seem to be able
to neutralize primary isolates and different subtypes. This is probably
because gp 120 complexed with CD4 opens up and exposes cryptic regions
another approach is to induce cytotoxic T lymphocytes (CTLs). A number
of candidates use a prime-boost combination, for example DNA followed by
modified Vaccinia Ankara virus (MVA). Other CTL candidates are in the pipeline
using prime boost with adenovirus, or boosting with Semliki forest virus
or Venezuelan equine encephalitis replicons. Other groups, like Merck and
Aventis, are now working together to combine vaccines.
prime-boost regimen using Merck's replication-defective adenovirus type
5 vector (Ad5) vaccine candidate first, followed by the canarypox virus
vector (ALVAC vCP1452 on weeks 0, 4, 8 and 12 + daily low-dose IL-2)
vaccine candidate from Aventis Pasteur
Epitopes of the HIV-1 envelope glycoproteins that
induce neutralizing antibodies:
cluster I of gp41 (clone 3, 246-D) : highly immunogenic epitope, but clone
3 is the only one of many mAb specific for this epitope that has neutralizing
activityref1,
ref2,
ref3
transmembrane-proximal region of gp41 (2F5, 4E10, Z13) : poorly immunogenic,
but antibodies to this region are broadly neutralizingref1,
ref2,
ref3
CD4-binding domain of gp120 (IgG1b12, 559/64D, 15e) : highly immunogenic,
but IgG1b12 is the only mAb of many specific for this epitope that has
broad neutralizing activityref1,
ref2,
ref3
CD4-induced epitope of gp120 (17b, 48D) : only antigen-binding fragments
of antibodies specific for this epitope are neutralizing. Intact IgG molecules
specific for this epitope do not neutralize primary isolatesref1,
ref2,
ref3
a1=>2 mannose residues of gp120 (2G12) : poorly
immunogenic, but at least one mAb to this region is broadly neutralizingref1,
ref2
V2 loop of gp120 (697-D) : highly immunogenic, but antibodies to these
epitopes are isolate specificref1,
ref2
V3 loop of gp120 (447/52-D, 19b, 2182) : highly immunogenic, but antibody
specificity broadens only after extended antigenic stimulationref1,
ref2,
ref3
Lessons for HIV-1 vaccine design :
it might be useul to target the antibody response to neutralizing epitopes
rather than to immunize with native molecules or constructs based on whole
molecules bearing many neutralizing and non-neutralizing epitopes
most, if not all, neutralizing epitopes are conformation sensitive, indicating
that the peptide immunogens might not present the optimal "shapes" to the
immune system.
the V3 loop should be considered as a "semi-conserved region" due to its
structural and conformational conservation, and might therefore be as valuable
a target for vaccines as envelope constant regions for the induction of
neutralizing antibodies
an increased emphasis should be placed on the design of immunogens that
will induce antibodies specific for the various constant and variable domains
that interact with chemokine receptors
an increased emphasis should be placed on inducing antibodies that interfere
with the required conformational changs in gp41
virus diversity poses a challenge to vaccine development. This might be
addressed by recognizing the need for a polyvalent HIV-1 vaccine, by identifying
representative viruses to include in such a vaccine, and by recognizing
that, despite virus diversity, there are constnt features on the virus
envelope that are required for interaction with its receptor and co-receptors
induction and maintenance of antibody and T cell responses will be critical
for developing a successful vaccine against HIV. A rational approach for
generating such responses is to design vaccines or adjuvants that have
the capacity to activate specific antigen-presenting cells. In this regard,
DCs are the most potent antigen-presenting cells for generating primary
T cell responses. TLR agonists and ligands that activate DCs in vitro influence
the magnitude and quality of the cellular immune response in nonhuman primates
(NHPs) when administered with HIV Gag protein. NHPs immunized with HIV
Gag protein and a TLR7/8 agonist or a TLR9 ligand had significantly increased
Gag-specific Th1 and antibody responses, compared with animals
immunized with HIV Gag protein alone. Importantly, conjugating the HIV
Gag protein to the TLR7/8 agonist (Gag-TLR7/8 conjugate) dramatically enhanced
the magnitude and altered the quality of the Th1 response, compared
with animals immunized with HIV Gag protein and the TLR7/8 agonist or CpG
ODN. Furthermore, immunization with the Gag-TLR7/8 conjugate vaccine elicited
Gag-specific CD8+ T responses. Collectively, our results show
that conjugating HIV Gag protein to a TLR7/8 agonist is an effective way
to elicit broad-based adaptive immunity in NHPs. This type of vaccine formulation
should have utility in preventive or therapeutic vaccines in which humoral
and cellular immunity is requiredref
A vaccine delivered to maturing dendritic cells in lymphoid tissue by engineering
protein antigen into an antibody to DEC-205, a receptor for antigen presentation.
The CD4+ T cell immune response to HIV gag was characterized
and efficacy compared with other vaccine strategies in a single dose. DEC-205-targeted
HIV gag p24 or p41 induces stronger CD4+ T cell immunity relative
to high doses of gag protein, HIV gag plasmid DNA, or recombinant adenovirus-gag.
High frequencies of IFN-g- and IL-2-producing
CD4+ T cells are elicited, including double cytokine-producing
cells. In addition, the response is broad because the primed mice respond
to an array of peptides in different MHC haplotypes. Long-lived T cell
memory is observed. After subcutaneous vaccination, CD4+ and
IFN-g-dependent protection develops to a challenge
with recombinant vaccinia-gag virus at a mucosal surface, the airway. A
DEC-targeted vaccine, in part because of an unusually strong and protective
CD4+ T cell response, will improve vaccine efficacy as a stand-alone
approach or with other modalitiesref.
Web resources :
BHPIV3 is being developed for intranasal paediatric
immunisation against HPIV3 infection and diseaseref1,
ref2.
BHPIV3 was derived from bovine (B)PIVref1,
ref2,
ref3
a closely-related bovine counterpart of HPIV3 that is attenuated in primates
because of a natural host range-restriction. It has also been shown to
be attenuated and immunogenic in humans, and is a candidate vaccine against
HPIVref1,
ref2,
ref3.
BPIV3 was modified previously with recombinant DNA methods to replace its
F and HN protective surface antigen genes with their HPIV3 counterparts,
yielding BHPIVref1,
ref2.
BHPIV3 was an improved HPIV3 vaccine, since it bears protective antigens
that exactly match HPIV3ref
Protein Sciences was awarded
a $2.7M grant by NIAID to produce 2,000 doses of a recombinant S-protein
sub-unit vaccine. The product has shown to induce virus neutralizing antibodies
in preliminary mouse studies. Expanded animal studies are underway and
the Company expects to test the material in human clinical trials in late
2004 or early 2005.
6 rhesus macaques (Macaca mulatta) immunised i.m. with a combination
of 3 Ad5 vectors (early regions 1 and 3 had been deleted by use of Cre-lox
recombination; 1x1011 viral particles each) expressing codon-optimised
SARS-CoV strain Urbani structural antigens (spike protein S1 fragment,
membrane protein, and nucleocapsid protein) and given a booster vaccination
on day 28 all had strong neutralising antibody responses against spike
protein S1 fragment and T-cell responses against the nucleocapsid proteinref.
There is no date set for clinical trials
poxvirus vectors
the American vectored mucosal vaccine was made by inserting the Urbani
strain spike (S) protein into a recombinant live attenuated BHPIV3
(a hybrid between bovine parainfluenza virus 3 and human
parainfluenza virus 3 (HPIV3).
It was sprayed i.n. (the nose is where the infection attacks) once each
of 4 African green monkeys (Cercopithecus aethiops) that, 4 weeks
later, were deliberately exposed to the coronavirus that causes SARS. The
monkeys showed no sign of the disease in their respiratory tracts, and
blood tests showed that they had developed a type of protein known as neutralizing
antibodies that best correlate with protection of disease, while SARS virus
replicated in all 4 monkeys in a control group that receive the BHPIV3/Ctrl.
The current form would presumably be most effective in young children because
most adults have suffered respiratory infections caused by the parainfluenza
virus. So the researchers are seeking to develop a different vaccine by
using another virus into which the S protein could be insertedref.
Leishmune® vaccine is the first licensed vaccine
against canine visceral leishmaniasis. It contains the Fucose–Mannose-ligand
(FML) antigen of Leishmania donovani. The potential Leishmune®
vaccine effect on the interruption of the transmission of the disease,
was assayed by monitoring, in untreated (n = 40) and vaccinated dogs (n
= 32) of a Brazilian epidemic area: the kala-azar clinical signs, the FML-seropositivity
and the Leishmania parasite evidence by IHC of skin and PCR for
Leishmanial DNA of lymph node and blood samples. On month 11 after vaccination,
untreated controls showed: 25% of symptomatic cases, 50% of FML-seropositivity,
56.7% of lymph node PCR, 15.7% of blood PCR and 25% of immunohistochemical
positive reactions. The Leishmune®-vaccinated dogs showed
100% of seropositivity to FML and a complete absence of clinical signs
and of parasites (0%) in skin, lymph node and blood PCR samples (p
< 0.01). The positivity in FML-ELISA in untreated dogs significantly
correlates with the PCR in lymph node samples (p < 0.001) and
with the increase in number of symptoms (p = 0.006) being strong markers
of infectiousness. The absence of symptoms and of evidence of Leishmania
DNA and parasites in Leishmune®-vaccinated animals indicates
the non-infectious condition of the Leishmune®-vaccinated
dogsref
anti-Plasmodium
spp.
vaccine : it is unlikely that a vaccine directed against a single antigen
will be protective, so multivalent vaccines that combine antigens
expressed at different stages of the parasite life cycle have been developed.
Most of these jabs create conditions in which, although the parasites can
still infect people, the immune system slows their multiplication so they
do not cause disease. Parasites that moved from one vaccinated animal to
another evolved into nastier strains than those grown in non-vaccinated
animals : the vaccinated animals stayed healthy, but when the parasite
they carried was transferred into other mice, it killed more red blood
cells and made them lose more weight than the original malaria strain.
Researchers might also avoid types of vaccine that allow the parasite to
survive at low levels, he suggests. Instead, they could focus on classes
of vaccine that hobble the parasite before it infects red blood cells or
which cripple it in the mosquito and so stop it passing from one person
to another. Many of the vaccines under trial already take the latter approach.
In fact experts predict that an effective malaria vaccine will probably
trigger the immune system into attacking the parasite at several different
stages of its life cycleref.
The cultured ELISPOT assay, in which cells are restimulated and clonally
expanded in vitro prior to measuring IFN-g
production, might measure the central-memory T-cell population, which was
recently proposed to be more important in protective immunity to malaria
than the short-lived effector-memory cell population measured in standard
ex
vivo ELISPOTref.
APT2683®
is based on a malaria parasite protein called MSP1.19, which stimulates
a very weak immune reaction. Adprotech is working on genetically modified
versions of MSP1.19 which elicit a greater immune reaction and it is further
enhancing the immunogenicity of MSP1.19 by binding to C3d.
Ab to MSP1.19 prevent the processing of MSP1.42 and stop the merozoite
invading the RBC.
pre-erythrocytic vaccines directed against Plasmodium falciparum
circumsporozoite
(CS) protein. Their effectiveness can be studied in rodents thanks
to hybrid parasites generated by targeting a CS-deficient form of the rodent
malaria parasite Plasmodium
berghei with a plasmid encoding Plasmodium falciparum
CS repeat regions (CS(Pf)).
RTS,S/AS02A vaccine specifically targets
the pre-erythrocytic stage of Plasmodium falciparum and confers
protection against infection by P falciparum sporozoites delivered
via laboratory-reared infected mosquitoes in malaria-naive adult volunteers
and against natural exposure in semi-immune adultsref1,
ref2,
ref3,
ref4.
RTS,S consists of a hybrid molecule recombinantly expressed in yeast, in
which the circumsporozoite proteinref,
central tandem repeat, and carboxyl-terminal regions are fused to the N
terminal of the S antigen of hepatitis B virus (HBsAg) in a particle that
also includes the unfused S antigen. A full adult dose of RTS,S/AS02A (GSK
Biologicals, Rixensart, Belgium) contains 50 µg of lyophilised RTS,S
antigen reconstituted in 500 µL of AS02A adjuvant (proprietary oil
in water emulsion with the immunostimulants monophosphoryl lipid A and
QS21).
The adult dose is a 250 µL dose containing 25 µg of RTS,S antigen
in 250 µL AS02A adjuvant. It is administered intramuscularly in the
deltoid region of alternating arms according to a 0, 1, 2 month vaccination
schedule. A trial in 2000 children in Mozambique showed it reduced the
risk of infection by only 37% compared with a control vaccine (11.9% vs
18.9%) - far better than any previous result. Even more impressive is that
the vaccine reduced the risk that the children - aged 1-4 - would develop
the most severe and lethal form of malaria by 57.7%. Better still, the
risk of severe disease in recipients aged < 2 saw a 77% reductionref.
But it might take until 2010 to get the vaccine cleared and ready for use.
And the price -estimated at $10 to $20 per vaccination - may be too much
for some poorer nations unless richer countries help foot the bill.
SPf66 peptide
CD4+ T cells specific for a circumsporozoite-protein-derived
peptide were found to be strongly associated with protection against naturally
acquired infection and disease : individuals in the unvaccinated group
who showed similar responses to this peptide (resulting from previous natural
exposure) are also found to be protectedref.
oral immunization : oral feeding of a malaria protein induced serum
antibody levels similar to those induces by intraperitoneal immunization
with Freund's adjuvant. Further, responses to conformational epitopes are
induced. In the rodent challenge system, significant levels of protection
to lethal challenge with malaria are induced in mice. The protective efficacy
is highly correlated with antibody levels, which depend on the antigen
dosage and require cholera toxin subunit B as an oral adjuvantref
anti-bacterial protein vaccines : a
proteomic
approach has been described for identifying bacterial surface-exposed proteins
quickly and reliably for their use as vaccine candidates. Whole cells are
treated with proteases to selectively digest protruding proteins that are
subsequently identified by mass spectrometry analysis of the released peptides.
When applied to the sequenced M1_SF370 group A Streptococcus strain,
68 PSORT-predicted surface-associated proteins were identified, including
most of the protective antigens described in the literature. The number
of surface-exposed proteins varied from strain to strain, most likely as
a consequence of different capsule content. The surface-exposed proteins
of the highly virulent M23_DSM2071 strain included 17 proteins, 15 in common
with M1_SF370. When 14 of the 17 proteins were expressed in E. coli and
tested in the mouse for their capacity to confer protection against a lethal
dose of M23_DSM2071, one new protective antigen (Spy0416) was identified.
This strategy overcomes the difficulties so far encountered in surface
protein characterization and has great potential in vaccine discoveryref.
alum-precipitatedPA
recovered
from the culture of the avirulent, nonencapsulated Sterne strain of Bacillus
anthracis, rendered sterile by filtration and containing 0.005%W/v
thimerosal
as preservative. Kept at temperatures between 2°C and 8°C. Freezing
must be avoided. According to FDA the licensed anthrax vaccine is safe
and effective for preventing all forms of anthrax regardless of the route
of exposure (including inhalational anthrax), thereby undermining the rationale
of a recent court injunction that halted the Pentagon's anthrax vaccination
program.
Protocol : 4 doses of 0.5 mL each in the
deltoid muscle (there is a greater risk of local reactions when the vaccine
is given subcutaneously) : the first 3 doses should be given at intervals
of 3 weeks, followed by a 4th dose at an interval of 6 months (other protocol
: 6 doses over 18 months). Reinforcing doses of 0.5 mL i.m. should be given
annually.
Contraindications : the vaccine should
only be administered to healthy individuals from 18 to 65 years of age,
since investigations to date have been conducted exclusively in that population.
It is not known whether the anthrax vaccine can cause fetal harm, and pregnant
women should not be vaccinated.
tenderness, mild erythema or swelling lasting for ~ 2 days may occur at
the site of inoculation or even at the site of a previous injection of
the vaccine. Large-magnitude swelling occurs in 1-2% of recipients
urticaria
headache
malaise
regional lymphadenopathy
mild fever
women vaccinated against anthrax conceive and give birth to healthy children
at the same rate as unvaccinated women. Of a total of 4092 women, 3136
received at least 1 dose of the anthrax vaccine. There was a total of 513
pregnancies, with 385 following
at least 1 dose of anthrax vaccine. The pregnancy rate ratio (before
and after adjustment for marital status, race, and age) comparing vaccinated
with unvaccinated women was 0.94 (95% confidence interval [CI], 0.8-1.2;
P =.60). There were 353 live births and 25 pregnancies lost to follow-up.
The birth odds ratio after anthrax vaccination (before and after adjustment
for marital status and age) was 0.9 (95 percent CI, 0.5-1.4; P =.55). After
adjusting for age, the odds ratio for adverse birth outcome after receiving
at least 1 dose of anthrax vaccination was 0.9 (95% CI, 0.4-2.4; P =.88).
However, this study does not have adequate statistical power to rule out
a small effect of vaccination on adverse birth outcomes, given the low
incidence of adverse outcomes. A post hoc power analysis showed the study
only had a 12% power to detect a 20% increase in abnormal birth outcomes,
based on potential effects on likelihood of pregnancyref.
Men vaccinated against anthrax have sperm of comparable quality and quantity
as unvaccinated men (Catherino et al. Fertility & Sterility 2002;78(Suppl
1);O-285). We await a final report from a collaborative project between
the U.S. Naval Health Research Center (NHRC) and the Centers for Disease
Control & Prevention (CDC) regarding birth defects and anthrax vaccine
that involves chart review. That collaborative project responds to preliminary
data from a computer-based analysis that raised a tentative signal that
there may be an association with an increased rate of birth defects if
anthrax vaccine was given during pregnancy; the same analysis showed no
elevation in risk for vaccination before pregnancy. This signal is being
investigated thoroughly, to determine which of several explanations for
the signal is most likely.
[ Some UK soldiers who served in Iraq have expressed fears for their
unborn babies after claiming there have been 2 miscarriages, 3 premature
births, one still-birth, and a medical termination associated with one
Hampshire unit so far in 2004 in families in which at least one of the
parents had received the anthrax jab in each case. A total of 105 soldiers
from the Gosport based 33 Field Hospital were stationed on the Kuwaiti-Iraqi
border and then Basra at the beginning of 2003. The unit includes medics,
chefs, Royal Engineers, drivers, clerks, and quartermasters. Among the
cases is Lance Corporal Andy Saupe's son, who was born 10 weeks premature
with growth problems and limb defects. Baby Kye survived only 5 weeks before
his life support machine was switched off. L/Cpl Saupe, a 23-year-old Army
chef, had 2 anthrax injections before being deployed to the Gulf. His wife
Alex, 25, became pregnant weeks later but the foetus did not develop properly.
It follows claims that women in the first Gulf War were advised by the
Army not to conceive children for at least one year after they or their
partner received the vaccine. A number of studiesref1,
ref2,
ref3
showed a higher rate of congenital disabilities (including Goldenhar syndromeref)
of children conceived after the war by 1991 Persian Gulf War veterans (GWVs)
and born in medical treatment facilities (MTFs) than of children born to
military personnel who were not deployed to the Gulf War (NDVs) (despite
some opposed findingsref1,
ref2,
ref3),
but these were not connected to vaccination programmes : the authors concluded
they were unable to determine whether the higher rate was due to inherited,
or environmental factors or due to chanceref
]
U.S. District Judge Emmet G. Sullivan ruled on a suit filed in March 2003
by 6 service members and civilians who argued that the FDA never properly
reviewed the vaccine's ability to protect against inhalation anthrax. The
suit contended that the drug was never shown to be effective, and that
some vaccinated troops experienced extreme fatigue, joint pain and temporary
memory loss after being vaccinated. Sullivan first ordered a halt to the
mandatory vaccinations on 22 Dec 2003, saying the vaccine was being used
for an unapproved purpose. 8 days later, the FDA issued an order intended
to give the vaccine final approval for use to prevent inhaled anthrax.
Sullivan said the FDA had met his requirements and lifted the ban,
except for the 6 plaintiffs. The soldiers then asked Sullivan to reinstate
the prohibition. He agreed, rejecting the government's claim that the FDA
had considered arguments against the vaccine, on Wed 27 Oct 2004 : the
FDA's approval was invalid because it did not meet the required review
standards and the agency failed to seek the necessary public comment. There
was some public comment when the approval was first sought in 1986, but
the 2003 decision was based on research conducted later and never subjected
to public comment. The FDA argued that comments had been submitted as part
of a 2001 citizens' petition questioning proposals to begin the vaccinations,
but Sullivan found them insufficient. It was unclear whether soldiers who
already have started the series will be able to finish it. Research has
shown that the vaccine is effective after 2 or 3 shots. The vaccine has
a 2-year shelf life, so the Pentagon can store some supplies for later
use if the vaccine program is restarted. Root said the shelf life of the
vaccine likely will be extended to 3 years this winter. Because the anthrax
agent is so deadly, it has been difficult to test a vaccine that might
protect against it. The best data have come from a study in the 1950s of
workers at a factory that processed animal hides and furs, which can transmit
naturally occurring anthrax. That study found that the vaccine now used
by the military was effective in reducing the incidence of anthrax spread
by contact, but the research involved only a tiny sample of people who
might have inhaled the bacteria. Mark Zaid, an attorney for the 6 who has
also defended more than a dozen service members court-martialed for refusing
the vaccination, said one of his clients is a breast-feeding mother who
does not think the vaccine is safe for her child. Sullivan's ban on involuntary
vaccination will remain in place until the FDA reviews the anthrax vaccine
properly or until President Bush determines that the normal process must
be waived because of emergency circumstances. Anthrax vaccine was used
in a limited way in the 1991 Persian Gulf War. A more expansive effort
began in 1998. The American anthrax vaccine has been given to about 1.1
million people since 1998; the British anthrax vaccine somewhat fewer.
Difficulties in manufacturing the vaccine stopped the program in 2000 and
2001, but the vaccination effort was resumed and greatly expanded in 2002.
The Defense Department has required many troops serving in Iraq and Afghanistan
to be vaccinated, and it has punished and sometimes court-martialed those
who refused. The Pentagon expanded its anthrax and smallpox vaccination
programs in July 2004 to include troops stationed in South Korea and other
areas in Asia and Africa, despite complaints from some service members
that the anthrax vaccine made them sick. BioPort
Co. spokeswoman Kim Brennen Root said the company is continuing to
produce and ship the anthrax vaccine under its $245 million contract with
the Pentagon, which runs through 2006. The entire Australian anthrax vaccination
program for the military deployment to Afghanistan was secretly suspended
for 2 months after 38-75% of the 1500 Afghan deployment in 2002, including
elite special forces who were to engage in fierce fighting with the Taliban,
fell ill in November 2001ref1,
ref2,
ref3
anthrax spore vaccine : a live
vaccine consisting of Bacillus anthracis spores in saponified diluent,
used for vaccination of domestic farm animals against anthrax
dually active anthrax
vaccine (DAAV) created by conjugating the capsular poly-g-D-glutamic
acid (PGA) to protective antigen (PA). This converted the weakly
immunogenic PGA to a potent immunogen and synergistically enhanced the
humoral response to PA. It prevent or stop the disease by eliminating bacteria
by means of anti-capsular antibodies early in the sequence of anthrax infection,
well before severe bacteremia and toxemia take place. In addition, antibodies
to PA provide a parallel line of defense against residual toxins. DAAVs
embody the paradigm of combining both antibacterial (i.e., prophylactic)
and antitoxic (i.e., therapeutic) components into a single vaccine
anti-Borrelia
burgdorferi (sensu strictu)
vaccine : lipidated recombinant lipoprotein outer surface protein A
(OspA) adsorbed onto aluminum adjuvant
LYMErix®
(withdrawn from the market on February 26, 2002); Glaxo SmithKline Inc.:
LIQ(30 mg / 0.5 mL)IM). It is indicated for
use in persons aged 15-70 years. 3 doses of the vaccine are administered
by intramuscular injection. The initial dose is followed by a second dose
1 month later and a third dose 12 months after the first. Vaccine administration
should be timed so the second dose and the third dose are given several
weeks before the beginning of the transmission season which usually begins
in April. The duration of immunity following the three-dose vaccination
series is unknown, and the need for booster doses has not been determined.
The vaccine doesn't work in individuals (5%) that have low expression of
TLR1.
? (Pasteur Merieux Connaught)
anti-Helicobacter
pylori
vaccine : (ureA+ureB or cagA+vacA) inducing a Th2-polarized
immune response. Helicobacter pylori is in steep decline in many
parts of the world, thanks to improved sanitation and the widespread use
of antibiotics, and some biologists are beginning to wonder whether its
disappearance is really for the best. Challenge model for Helicobacter
pylori infection in human volunteers (40 mg of famotidine at bedtime
and 104-1010 cfu of H pylori in beef broth
the next morning)ref1,
ref2.
The mechanism(s) by which immunisation of mice can affect helicobacter
colonisation of mice remains a mystery, but may be related to immune mediated
environmental changes. In particular, it is proposed that severe gastritis
and T-cell mediated changes in mucin production can significantly impact
upon H. pylori colonisation : an appropriate antibody response has
not yet been accomplishedref
J8 fragment from GAS M-protein conjugated to diphtheria toxin (DT)
pneumococcal surface protein A (PspA) induces protection against
pneumococcal bacteremiaref1,
ref2.
PspA is composed of 5 domains : a signal peptide, an a-helical
domain, a proline-rich region, a choline binding domain and a C-terminal
tailref.
Antigenic variability is mapped to the highly charged a-helical
N-terminal region of PspAref.
A classification of PspA based on the amino acid sequence divergence located
just before the proline-rich region, defined as clade-defining region (CDR),
divides strains into 3 familiesref
:
family 1, composed of clades 1 and 2
family 2, composed of clades 3, 4, and 5
family 3, rarely isolated and composed of clade 6
Since cross-reactivity between families is restricted, these authors have
proposed that PspA fragments from families 1 and 2 should be included in
a vaccine formulation.
toxoids / anatoxins
(toxins which have lost their biological activity
but retain their antigenicity and their immunizing capacity) : the
use of toxoids began in 1923 at the Pasteur Institute, when Demontre and
Ramon found that diphtheria toxin treated with formalin and heat was transformed
into a nontoxic but immunogenic moiety that could be used to immunize against
diphtheria. Initially called anatoxines by Ramon, these compounds
are now known as toxoids. They protects against many
of the disease symptoms but not against the infection ! More toxoids are
often associated in vaccine formulations.
purified toxoids that have been inactivated by
chemical means (0,3% formaldehyde/formol for
48 hrs at 37 °C, glutaraldehyde, iodine, pepsin, ascorbic acid,
ketones, etc.) : LPS cannot be converted to toxoid. The mixture is maintained
at 37 °C at pH 6÷9 for several weeks
genetic means
live attenuated strains of the causative agent that produce a genetically
derived toxoid
anti-Bordetella
pertussisvaccine
: combinations of pertussis toxoid, FHA, pertactin, and the 2 types of
fimbriae. The new vaccine, known as acellular pertussis (aP) has
fewer side effects than the whole cell vaccine.). In the United States,
it is licensed for use only in children at least 15 months of age. The
acellular pertussis vaccine was protective among adolescents and adults,
and its routine use might reduce the overall disease burden and transmission
to childrenref.
3 x 0.50 mL subcutaneous injections at the level of the supra- or sub-spinal
fossa at month 3, 4 and 5 : booster after 1 year.
Acelluvax® (Biocine => Chiron,
Italy)
Celluvax® (SCL)
Coguelucheux Vaccine® (Merieux)
Cocquelucheux® or Coquelucheux®
(PMC) : adsorbed
Dur Brzuszny® (?, Poland)
Hinkuys karokoe® (National Public Health Institute)
: adsorbed
Kikhoste-Vaksine® (Statens Institut for Forkehelse)
Krztuscowi® (?, Poland)
Ksztu Siec® (?, Poland)
Pertosse® (?, Italy)
Serobacterin® (Merck) : no longer in use (1945 to
1954)
Tos Ferina® (?, Spain)
Vaxicoq® (Aventis Pasteur) : adsorbed (0.50 mL syringe-ampoule
contains Bordetella pertussis in phase 1 - 15 billion, Al(OH)3
0.001 g)
Vax-Tet®
(Finlay Vaccunas y Sueros Centro de Investigacion)
Zatevax®
(Institute of Immunology - Croatia)
3 intramuscular injections (1 mL) at months 3, 4÷5
and 6÷12. First booster at age 5÷6, following boosters every
10 yrs. Uneffective in 2÷5%. If an injury occurs between 5 and 10
years since last boosting, a novel booster is recommended if the wound
is highly contaminated and/or necrotic.
anti-Corynebacterium
diphteriae
vaccine (Ramon's vaccine) : the
schedule for immunization against diphtheria in children <7 years old
requires a 4-dose primary series of intra muscular injections (0,5÷1
mL each) of diphtheria toxoid (at 2, 4, 6, and 12 to 18 months of age)
and a booster at 4 to 6 years of age. The minimum interval between the
1st and 2nd doses and between the 2nd and 3rd doses is 4 weeks; between
the 3rd and 4th dose, the minimum is 6 months. Infants and children <7
years old are usually given diphtheria
and tetanus toxoids and pertussis vaccine (DTP); children > 15 months
may be given diphtheria
and tetanus toxoids and acellular pertussis vaccine (DTaP) for the
4th and 5th doses of the series. Diphtheria and tetanus toxoids for pediatric
use (DT) should be substituted for DTP in children for whom pertussis vaccine
is contraindicated. Infants traveling to areas where diphtheria is endemic
or epidemic should receive 3 doses of DTP or DT before travel. The first
dose should be given at 6 to 8 weeks of age and the next 2 doses after
intervals of 4 to 8 weeks. The primary schedule for persons >7 years of
age who have never been vaccinated requires 3 doses of tetanus and diphtheria
toxoids for adult use (Td) (the 2nd dose is given 4 to 8 weeks after the
first; the 3rd dose is given 6 to 12 months after the 2nd). 2 doses of
Td received after an interval of at least 4 weeks may provide some protection;
a single dose is of little benefit. Td booster doses should be given at
11 to 16 years of age and whenever 10 or more years have elapsed since
completion of a primary series or the last booster dose containing diphtheria
toxoid. For persons whose primary schedule was interrupted, the series
should be completed by using a vaccine appropriate for age. For example,
an adult who received (as a child) 2 doses of a vaccine containing diphtheria
toxoid requires only 1 more dose of Td to complete the primary series and
additional Td boosters every 10 years thereafter. It protects for 10 yrs.
As the vaccine prevents also colonization, natural boostings are rapidly
decreasing nowadays : so artificial boostings every 10 years are likely
to be introduced, expecially in the elderly. Very rare complication : postvaccinial
autoimmune encephalomyelitis
10-14 days after vaccination.
carbohydrate
antigens. Historically, conjugate vaccines have been shown to
induce boostable memory responses and longer-lasting immune responses than
polysaccharide vaccines => glycoconjugate
vaccines : the high level of success attained by Hib glycoconjugate
vaccinerefhas
been quickly followed by similar approaches to meningococcal group Cref
and Streptococcus pneumoniaeref.
Many candidate vaccines against other pathogens using the same principles
are currently at different stages of research.
anti-bacterial vaccines
anti-Haemophilus
influenzae serotype B (Hib)
polysaccharide vaccine (HbPV) : capsular polysaccharide : the fragment
of the Hib capsular polysaccharide used in some of the licensed vaccines
can be as short as 5 ribosylribitol-phosphate repeating unitsref.
Extensive use of the polysaccharides as vaccines has offered a useful way
to protect adults and older childrenref1,
ref2,
and further improvement in generating long-lasting immunity, especially
in infants, has been achieved by covalently coupling the polysaccharide
to carrier proteinsref.
=> stimulates an immune response in B lymphocytes only. 1 subcutaneous
skin injection. It protects for 1.5÷3 yrs. Used as an immunizing
agent in children between the ages of 18 months and 5 years who belong
to certain high-risk groups : uneffective before age 2 as polysaccharides
are
T-independent Ags
and the marginal zone is not fully developed yet.
AMC® (?, Cuba)
B-CAPSA® (Mead Johnson) : no longer in use (1987
to 1989)
anti-Haemophilus
influenzae serotype B (Hib)
conjugated synthetic capsular polysaccharide : the ability of
synthetic carbohydrate chemistry to mimic such fragments has been demonstrated
in several laboratories with the use of stepwise multistep preparationref1,
ref2,ref3;
the resulting synthetic antigens have served as components of candidate
vaccines that have proven efficient in generating immunity in animalsref1,
ref2.
It was evaluated in clinical trials in Cuba and showed long-term protective
antibody titers that compared favorably to licensed products prepared with
the Hib polysaccharide extracted from bacteriaref.
A phase I trial was initiated with 139 2-month-old infants who received
three vaccine doses scheduled at 2, 4, and 6 months, as recommended for
other conjugate anti-Hib vaccines. The test vaccine induced a strong and
bactericidal antibody response against Hib in infants that fell to values
ranging from 5 to 7 µg/mL at 18 months of age but remained at least
5 times that required for long-term protection. A booster dose with sPRP-TT
applied to all groups increased the antibody against Hib titers by 10-fold.
Thus, the capacity of sPRP-TT to prime an effective immune response against
Hib was demonstrated. In a second phase II trial, a total of 1141 infants
distributed in three groups received three doses of either sPRP-TT conjugate,
sPRP-TT mixed with aluminum phosphate, or the control vaccine (Vaxem-Hib®).
Of the test infants, 99.7% reached antibody titers above 1 µg/mL,
which is considered appropriate for long-lived protection against Hibref1,
ref2.
The mean IgG anti-PRP titer was 27.4 µg/mL for all infants vaccinated
with the sPRP-TT, which is consistent with previously reported clinical
trials (between 7.67 and 35 µg/mL) for anti-Hib vaccines without
adjuvantref1,
ref2
... to make it a thymus-dependent
Ag.
Used
as an immunizing agent in children between the ages of 18 months and 5
years who belong to certain high-risk groups.
Mencevax
ACWY® or ACWYVax®
(GlaxoSmithKline Inc.; cost per dose : US$ 1) : Haj pilgrims at December
are at a high risk of contracting a meningococcal infection due to overcrowding.
As a precautionary measure, Saudi Arabia has made it mandatory for foreign
pilgrims to be vaccinated before entering the country
Menomune®
(Aventis Pasteur) protects for approximately 3-5 years
B and C serotypes
VA-Mengoc-BC® (Finlay Vaccunas y Sieros Centro de
Investigation)
B serotype : the New Zealand accine is a strain-specific outer membrane
vesicle product not available in the USA as yet. Such a biologic, when
combined with the newly licensed (in the USA) protein-conjugated quadrivalent
capsular meningococcal vaccine (for types A, C, Y, and W-135), would be
a large nail in the coffin for invasive meningococcal disease
B serotype capsular polysaccharides are poorly immunogenic, conjugated
or not. Immunogenicity of polysaccharides may be improved by conjugation
with a proteic carrier (e.g. ...
group A meningococcal polysaccharide tetanus toxoid (GAMP-TT) conjugate
vaccine (source : Serum Institute
of India (SII) and SynCo
BioPartners) : high-efficiency conjugation technology using hydrazine
(cost per dose : 40 US cents)
Menactra® (Sanofi Pasteur;
licensed in USA on 14 Jan 2005) MCV4 is a tetravalent vaccine; each 0.5-mL
dose contains 4 mg each of capsular polysaccharide
from Neisseria meningitidis serogroups A, C, Y, and W-135 conjugated
to 48 mg of diphtheria toxoid. MCV4 offers protection
for 7-8 years against invasive meningococcal disease : another vaccine
that was previously available conferred immunity that lasted only 3-5 years
: both vaccines are about 85% effective, however. Only a single shot is
necessary. It typically costs patients about $100 (£55; €81),
but because it is being recommended by the Centers for Disease Control
and Prevention and the American Academy of Pediatrics, its cost is likely
to be covered by most health insurance plansref.
In February 2005, the Advisory Committee on Immunization Practices (ACIP)
recommended routine vaccination for 3 groups of young peopleref
:
children between 11 and 12 years old at routine doctor checkups
15 year olds or those students entering high school, because they’re becoming
more socially active and exposed to more germs
new students at college who will be living in student accommodation, because
disease spreads easily among people at close quarters for other persons
at increased risk (Military recruits, travelers to areas in which meningococcal
disease is hyperendemic or epidemic, microbiologists who are routinely
exposed to isolates of N. meningitidis, patients with anatomic or
functional asplenia, and patients with terminal complement deficiency)
5 persons aged 17-18 years in New York, Ohio, New Jersey and Pennsylvania
(2) experienced Guillain-Barre
Syndrome (GBS)
14-31 days after MCV4 vaccination, occurred during 10 Jun - 25 Jul 2005,
after > 2.5 million doses of vaccine have been distributed. Data from the
Vaccine
Safety Datalink (VSD), a collaborative project between CDC and 8 managed
care organizations in the USAref,
and the Health Care Utilization Project on GBS incidence in persons aged
11-19 years indicate a background annual incidence of 1-2 cases per 100
000 person-years (CDC; Healthcare Utilization Project Nationwide Inpatient
Sample; Agency for Healthcare Research and Quality, unpublished data, 1989-2001).
This finding suggests that the rate of GBS based on the number of cases
reported within 6 weeks of administration of MCV4 is similar to what might
have been expected to occur by chance alone. However, the timing of the
onset of neurologic symptoms (i.e., within 2-5 weeks of vaccination) is
of concern. In addition, the extent of underreporting of GBS to VAERS is
unknown; therefore, additional cases might be unreportedref1,
ref2.
Pre-licensure studies conducted by Sanofi Pasteur of approximately 7000
recipients of MCV4 revealed no GBS casesref.
CDC has conducted a rapid survey by using available VSD and other health
care organization databases. No cases of GBS have been detected among nearly
110 000 MCV4 recipients represented in these databases. Data from 2 VSD
sites indicated that 86-97 percent of vaccine recipients had 6 weeks of
follow-up via automated data collection. These data do not rule out an
association between MCV4 and GBS. During 1999-2005, a total of 30 million
doses of 3 different meningococcal C conjugate vaccines (MenC), with either
diphtheria CRM (nontoxic variant of diphtheria toxin) or tetanus toxoid
as carrier proteins, have been used in the United Kingdom (UK) for persons
aged less than 18 years. 5 cases of GBS were reported in the UK after administration
of MenC vaccines (UK Department of Health, unpublished data, 2005). This
reported number of cases is lower than would have been expected to occur
by chance in a population this age. To date, evidence is insufficient to
conclude that MCV4 causes GBS. An ongoing known risk for serious meningococcal
disease exists. Therefore, CDC is recommending continuation of current
vaccination strategies. Whether receipt of MCV4 vaccine might increase
the risk for recurrence of GBS is unknown; avoiding vaccinating persons
who are not at high risk for meningococcal disease and who are known to
have experienced GBS previously is prudent. FDA and CDC are alerting health-care
providers to this preliminary information and are actively investigating
the situation because of its potentially serious nature. The manufacturer
has sent letters to health-care providers and is updating the package insert
to reflect that GBS has been reported in association with the vaccine.
CDC recommends that adolescents and their caregivers be informed of this
ongoing investigation as part of the consent process for vaccination with
Menactra. FDA and CDC are requesting that providers or other persons with
knowledge of possible cases of GBS (or other clinically significant adverse
events) occurring after vaccination with MCV4 report them to VAERS. Reports
of GBS should be submitted to VAERSref
or by telephone at 800-822-7967. CDC further requests that health-care
providers report other cases of GBS that occur among persons aged 11-19
years to state health departments in accordance with state or local disease-reporting
guidelines. CDC suggests that state health departments consider enhancing
surveillance for GBS in adolescents to assist in answering these critical
questions. Cases of meningococcal disease should be reported to state health
departments and, if available, information on vaccination status should
be provided; isolates should be saved and sent to state health departments
for serogroup identificationref.
It is curious that only one of the 5 cases described above had a seemingly
"clean" medical history with no prior episodes or illnesses or possible
exposures that might predispose for GBS (one of the cases had a history
of 2 prior episodes of GBS following receipt of other vaccines in early
childhood, another had a mother with a history of GBS, another had a sore
throat which may have been due to an infectious etiology 6 days after receipt
of the vaccine, and another was on multiple psychotropic agents).
1 subcutaneous injection (100 mg in babies,
50 mg in adults; booster at month 7 in newborns).
Boosters every 3-5 years. The vaccine is administered to persons over 2
years of age at risk in event of an epidemic of meningococcal disease caused
by these serotypes and routinely only to military recruits.
Web resources : Meningitis
Vaccine Project (MVP) by WHO and PATH
anti-Salmonella
typhiintramuscular
vaccine : purified Vi polysaccharide from the
strain
Ty2, used for immunization against typhoid fever in persons at risk
for exposure due to travel or household contact
23 serotypes (1, 2, 3, 4, 5, 8, 9, 12, 14, 17, 19, 20, 22, 23, 26, 34,
43, 51, 54, 56, 57, 68, and 70, which are responsible for about 90% of
pneumococcal disease in the USA) (23PS)
1 subcutaneous injection (0.5 mL) protects
from week 2÷3 after injection up to 5-6 yrs. Polysaccharides are
T-independent
Ags
and so they do not induce neither memory B-cell nor class switch. Anyway
this pathway allows vaccination being effective also in individuals affected
by CMI deficiencies,
but not in babies before age 2, when marginal zone is not fully developed
yet. Used for immunization of persons over 2 years of age having chronic
cardiac, pulmonary, hepatic, or renal disease, AIDS,
Hodgkin's
disease,
diabetes
mellitus,
SCA,
or anatomic or functional asplenia,
and persons in nursing homes or other institutions where there is high
risk of pneumococcal disease or with age > 65. Immunogenicity of
polysaccharides may be improved by conjugation with a proteic carrier :
PCV7 : capsular antigen saccharides from S. pneumoniae serotypes
4, 6B, 9V, 14, 18C, 19F and 23F (heptavalent) conjugated to diphtheria
CRM197 protein (Prevnar®;
Wyeth Lederle) ; administered at ages 2 months, 4 months and 6 months,
with a final dose between the ages of 12 months and 15 months; SUS(2 mg
/ 0.5 mL, 4 mg / 0.5 mL, 2 mg
/ 0.5 mL, 2 mg / 0.5 mL, 2 mg
/ 0.5 mL, 2 mg / 0.5 mL, 2 mg
/ 0.5 mL)IM, 20 mg / 0.5 mL)IM. It helps prevent
routine fevers, headaches, and earaches in young children—as well as rarer,
invasive infections with bacterial pneumonia or meningitis—caused by the
7 most widespread varieties of 90 types of pneumococcus bacteria. Kids
and adults routinely carry all 90 strains in their noses and throats, even
when they are not sick. Prevnar vaccinations have been recommended for
all American babies since mid-2000. Between 1999 and 2001, "invasive" pneumococcal
infections, the most serious category, dropped 68% in babies under age
2. Prevnar also lowered pneumococcal infection rates in older people who
had never received the vaccine : over the same 2 years, invasive pneumococcal
infections in the USAdropped 29% in adults aged 20 to 39 and 17% in people
over 65 thanks to the fact that vaccinated babies no longer carry the 7
most prominent strains in their noses and throats, so they can't infect
parents or grandparents. Between 1999 and 2001, another study in the Pittsburgh
area found the percentage of pneumococcal acute
otitis media (AOM)
caused by strains that Prevnar doesn't protect against more than doubled,
from 16 to 37%. This shift in prevalence from one kind of infection to
another is due to a "replacement" effect because Prevnar effectively replaces
infections by the 7 targeted strains of pneumococci with similar infections
by the other 83 strains. Prevnar vaccination also enables a slight increase
in middle ear infections caused by 2 unrelated bacteria. These infections
spread more easily because the vaccine wipes out their 7 former competitors.
If vaccines would target something that's in all pneumococci, then you
won't have this problem.
a novel nonavalent conjugated vaccine reduces invasive pneumococcal disease
by more than 65% in children with HIV and 83% in HIV-free children. It
slashes overall mortality by 5% among all children, and by 6% among those
with HIV. The vaccine also significantly reduces the incidence of invasive
pneumococcal disease caused by antibiotic-resistant strains by up to 67%.
anti-human
pathogenic fungi
vaccine : laminarin (Lam), a well-characterized but poorly immunogenic
b-glucan
preparation from the brown alga
Laminaria
digitata, with the diphtheria toxoid CRM197, a carrier
protein used in some glyco-conjugate bacterial vaccines. This Lam-CRM conjugate
proved to be immunogenic and protective as immunoprophylactic vaccine against
both systemic and mucosal (vaginal) infections by Candida
albicans.
Protection probably was mediated by anti-b-glucan
antibodies as demonstrated by passive transfer of protection to naive
mice by the whole immune serum, the immune vaginal fluid, and the affinity-purified
anti-b-glucan IgG fractions, as well as by administration
of a b-glucan-directed IgG2b mAb. Passive protection
was prevented by adsorption of antibodies on Candida cells or b-glucan
particles before transfer. Anti-b-glucan antibodies
bound to C. albicans hyphae and inhibited their growth in vitro
in
the absence of immune-effector cells. Remarkably, Lam-CRM-vaccinated mice
also were protected from a lethal challenge with conidia of Aspergillus
fumigatus,
and their serum also bound to and markedly inhibited the growth of A.
fumigatus hyphae. Thus, this novel conjugate vaccine can efficiently
immunize and protect against 2 major fungal pathogens by mechanisms that
may include direct antifungal properties of anti-b-glucan
antibodiesref
preventive
cancer
vaccines should be ideally directed against dysplasia antigens
rather than tumor antigens : many of the potentially insurmountable problems
that diminish the effects of therapeutic cancer vaccines,
would not need to be considered in the setting of cancer prevention (see
also immunooncology).
Shared tumor antigens can be produced as synthetic or recombinant proteins
and are, therefore, ideally suited for prophylactic vaccination of individuals
who do not have a tumour, but are at high risk of developing a tumour.
Having vaccines that could prevent the progression of these esions to cancer
would make the cancer screening efforts much more useful than they are
now and set the stage for a more general use of prophylactic cancer vaccines
in the near future.
vaccines against tumour causing infectious microorganisms
young women with hereditary
risk of breast
carcinomas
and ovarian carcinoma
due to mutations in the gene encoding BRCA1
or BRCA2
: in the most extreme case of cross-reactivity, autoimmune destruction
of normal breast or ovarian tissue should have no more serious consequences
than their surgical removal
colorectal
carcinomas
: colon-tumour antigen mucin 1 is not expressed by normal colon, but is
expressed by adenomatous polyps in the tumour-associated O-underglycosylated
form
anti-ricin
vaccines : a harmless fragment of the ricin molecule, RTA 1-33/44-198,
given to mice either as a liquid dropped directly onto the skin or as a
patch impregnated with the chemical protects mice from a respiratory challenge
with ricin toxin in 100% and 709% of cases, respectively. Patches will
be more practical than skin drops for treating humans as the correct dose
can easily be delivered. Vaccination using ricin toxoid or its A chain
(RTA) is protective in animals but both vaccines have two potential toxicities,
ribosome inactivating protein (RIP) and vascular
leak syndrome (VLS).
3 recombinant RTA constructs from which both toxicities were eliminated
by site-specific mutations have been described : one mutant, V76M/Y80A
(RiVax), has now been further characterized for immunogenicity and
toxicity in animals. RiVax is safe at doses of at least 8 mg in mice, 800-fold
higher than the protective dose, and induces neutralizing antibodies in
both mice and rabbitsref.
RiVax is a recombinant RTA with 2 amino acid substitutions that disrupt
its ribotoxic site (Y80A) and its VLS-inducing site (V76M). This mutant
recombinant RTA was expressed and produced in Escherichia coli and
purified. When RiVax was injected i.m. into mice it protected them against
a ricin challenge of 10 LD50s. Preclinical studies in both mice and rabbits
demonstrated that RiVax was safe. Based on these results, a pilot clinical
trial was conducteed in humans under an IND application submitted to the
FDA. In this study, 3 groups of 5 normal volunteers were injected 3 times
at monthly intervals with 10, 33, or 100 µg of RiVax. The vaccine
was safe and elicited ricin-neutralizing Abs in 20% of individuals in the
low-dose group, 80% in the intermediate-dose group, and 100% (5 of 5) in
the high-dose group. These results justify further development of the vaccineref
Dermatophagoides
pteronyssinusis
a major trigger of allergy and atopic asthma world-wide, and thus, a good
vaccine candidate for allergy prevention.
i.m. injection of a gene construct (pCMVD) containing an Der p 5
results in the induction of Der p 5-specific IgG antibodies, but not IgE
antibody. The effect of transduced allergen gene on the expression of specific
IgE response in mice after i.p. challenge with recombinant Der p 5 (rDer
p 5). Both vector (mock) control- and pCMVD-treated mice were i.p. sensitized
with rDer p 5 at 3 weeks after injection of gene construct. Results showed
that there is a 90% reduction in the level of specific IgE in pCMVD-treated
mice when compared with mock-treated mice. Furthermore, the suppression
of specific IgE response can be adoptively transferred with CD8+
T cells from pCMVD-treated mice and such inhibition is in an antigen-specific
manner, since the level of specific IgE to an irrelevant allergen, Der
p 1, remained unchanged in comparison to that of the mock-treated group.
In addition, Der p 5-specific CD8+ T cells could produce high
levels of IFN-g which probably inhibit allergen-specific
IgE responsesref.
since Der p 1 is a cysteine protease, the catalytic effects of Der
p 1 vaccination may be unpredictable. One approach to reduce this risk
is to vaccinate with DNA encoding enzymatically inactive forms of Der p
1 : Der p 1 DNA without its native pre-pro sequences potently induces Der
p 1-specific antibodies, as long as its pre-sequence is substituted by
another leader sequence. Without any pre-pro sequence, the same DNA fragment
is well expressed but fails to induce significant level of anti-Der p 1
antibodies, without further boosting by proteinref.
I.m.
immunisation with full length Der p 1 cDNA induces significant humoral
response to the left domain (approximately corresponding to amino acids
1-116) but not to the right domain (approximately corresponding to amino
acids 117-222) of Der p 1 allergen. DNA constructs pDer p 1 (1-222) and
pDer p 1 (114-222) complexed with chitosan and delivered orally
followed by an i.m. injection of pDer p 1 (1-222) 13 weeks later successfully
primes Th1-skewed immune responses against both domains of Der
p 1ref.
anti-venom vaccines :
anti-Bothrops
asper
vaccine : the region comprising amino acid residues 115-129 of myotoxin
II, a Lys49 phospholipase A2 from the venom of Bothrops asper, was
previously shown to constitute a heparin binding site, and to be associated
with its toxic activities. The corresponding synthetic peptide, KKYRYYLKPLCKK,
was coupled to diphtheria toxoid as a carrier, and utilized as an immunogen
in mice, to explore the possible protection from the myotoxic activity
induced by myotoxin II in vivo. Mice receiving peptide-carrier injections
produced antibodies to peptide 115-129, which cross-reacted to myotoxin
II, as determined by enzyme-immunoassay. In contrast, no antibodies against
peptide 115-129 were detected in mice immunized with myotoxin II, despite
the strong antibody response to the whole antigen. Thus, region 115-129
of myotoxin II is not an immunodominant B-cell epitope in the mouse. After
immunization with conjugated peptide or myotoxin II, mice were challenged
with myotoxin II, and the extent of myonecrosis was estimated by determining
their plasma creatine kinase activity, in comparison to non-immunized mice.
After the challenge, both the group immunized with myotoxin II, and the
group immunized with peptide 115-129, had a significant reduction of myonecrosis.
These results demonstrate that region 115-129 of myotoxin II constitutes
a neutralizing epitope, and provide further evidence for the relevance
of this region in its myotoxic effect in vivoref
anti-Bothrops
colombiensis
(Central and South American snake) : a new technique is described for the
preparation of Bothrops venom and their different fractions toxoid.
This method preserves a high degree of immunogenicity but eliminates lethal
effects. All the animals vaccinated with Bothrops crude venom toxoid
survived when they were injected with crude venomref.
anti-Crotalus
durissus cumanensis
vaccine : a new technique is described for the preparation of Crotalus
venom toxoid. This method preserves the immunogenicity but eliminates the
toxic effects. All the animals vaccinated with Crotalus venom toxoid survived
when they were injected with raw venomref
anti-Naja atra
vaccine : potency of 60 antitoxic unit was reached after 2 immunizations
in 2-week intervals of rabbits and horses with 10-25 mg venom which was
detoxified by 0.125% glutaraldehyde. Now this procedure has become a routine
antivenine-producing method by which snake bivalent neurotropic antivenine
is produced. The stability test showed that Taiwan cobra toxoid kept at
37 degrees C for 40 days, the antigenicity increased by 24% and toxicity
decreased by 10% as compared to the toxoid maintained at 4°Cref
anti-Naja
nigricollis
vaccine : a free peptide capable of eliciting antibodies that neutralize
toxin a, a protein that binds specifically to
the acetylcholine nicotinic receptor, has been synthetised. Of the 5 tested
fragments that encompassed the whole toxin sequence, only fragment 24-41
stimulated T cells from BALB/c mice primed with the whole toxin and conversely,
only T cells from mice primed with fragment 24-41 could be stimulated by
both the toxin and priming peptide. No other peptides had such properties,
indicating that only fragment 24-41 possessed T determinant(s) in BALB/c
mice (H-2d haplotype). In agreement with the current view that B cell proliferation
requires specific T cell stimulation, only fragment 24-41 elicited an antibody
response. However, the antipeptide antisera failed to bind to the native
toxin and thereby to neutralize it. Instead, it recognized an unfolded
form of the toxin. The peptide 24-41 was then made cyclic. A circular dichroism
analysis revealed that, in organic solvent, this peptide had a tendency
to adopt a beta-sheet structure, as in the folded toxin, whereas the linear
peptide adopted an helical structure. The cyclic peptide not only remained
T stimulating but elicited antisera that recognized and neutralized the
native toxin. Furthermore, the antisera cross-reacted with several toxin
variants. Our data show, therefore, that it is possible to give an appropriate
B cell specificity directly to a T cell-stimulating peptide, an approach
that may be of value for the design of synthetic vaccinesref.
Action of formaldehyde on the a toxinref
anti-Trimeresurus
flavoviridis
vaccine : in order to clarify the effect of Habu Toxoid, serum sampling
was performed with from July 1990 to February 1991, on 503 vaccinated subjects
living in Amami Islands by staff of Naze health center. Sera were analyzed
by Enzyme Linked Immunosorbent Assay (ELISA) for levels of serum antitoxin
to venom, both anti-Hemorrhagic Factor 1 (anti-HR1) and anti-Hemorrhagic
Factor 2 (anti-HR2). Information on vaccinated subjects-age, sex, occupation,
vaccination date, frequency, period and interval of vaccinations, years
after final vaccination and past history of Habu bites-was obtained and
analyzed with relation to serum antitoxin levels. The following results
were obtained: 1) Serum antitoxin levels, both anti-HR1 and anti-HR2, of
the Habu bitten group (N = 47) were significantly higher than that of the
unbitten group (N = 456). This finding suggests that crude Habu venom injected
by bites elevated the levels. Regardless of past history of Habu bites,
levels of antibody to HR2 was significantly lower than that to HR1. 2)
Among the unbitten group, detection of antitoxin was related to subjects'
attributes. Production of antitoxin was related to being male, high frequency
of vaccinations, long period of vaccinations and short period after final
vaccination. 3) Among the unbitten group, anti-HR2 was found in high levels
with the following factors: high frequency of vaccinations and short period
after final vaccination. However among the well-vaccinated group (N = 153),
differences in antitoxin levels by vaccination frequency were not recognizedref.
Immunization of human beingsref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8,
ref9,
ref10,
ref11,
ref12,
ref13,
ref14,
ref15,
ref16,
ref17,
ref18
immunocontraceptive
vaccines :
male immunocontraceptive
vaccines
autoantibodies to external domains of the sperm plasma membrane
: the body must make enough antibody to cripple all of the hundreds of
millions of sperm in each ejaculate
affect the movement of normal motile spermatozoa. Serum antibodies increase
amplitude of lateral head displacement (ALH) and decreased velocity of
progression (VSL) whereas sperm eluted antibodies decrease ALH and increase
VSL.
investigational sperm vaccine against 4 proteins associated with the acrosomal
reaction (safe and immunogenic in female baboons)
7 out of 9 (78%) male Macaca radiata monkeys injected every 3 weeks
with human epididymal
protease inhibitor (Eppin) / serine protease inhibitor-like, with Kunitz
and WAP domains 1 (SPINLW1) (an androgen-regulated, sperm-binding protein
containing protease-inhibitory motifs, is expressed specifically in the
testis and epididymis) manufactured copious antibodies against the Eppin
protein, and all of these monkeys proved infertile when mated with females.
66% of a group injected with a placebo vaccine went on to father offspring.
Only 5 out of 7 (71%) monkeys recovered their fertility once the injections
were stopped. One problem is that antibodies against sperm proteins can
affect other cells in the testes and cause orchitis. In the new study it
is thought that the antibody is latching on to sperm further down the male
reproductive tract, leaving the testes unharmedref.
testis specific protein fP13 is a 97-kDa protein homologous to the
FSP2 and CABYR
proteins described by Flinkinger. The pVAX-fSP13 vector is to be used as
DNA vaccine using the fox as an experimental model. To ensure the functionality
of the pVAX1-fSP13 vector, researchers have transfected MDCK cells using
lipofectamine, and using RT-PCR and western-blot we have observed the subsequent
expression of the fSP13 protein. In their assays they use foxes as canine
model to study the humoral and cellular immune responses after immunisation
by intra-muscular route with pVAX1-fSP13. Further work using alternative
immunisation routes should be tested to measure the effect on canine reproduction.
LHRH-based
vaccines in humans, although theoretically possible, are unlikely,
because profound behavioural modification can occur as a consequence of
inhibiting the production of testosteronein
males. However, a avery active area of research is the use of LHRH-based
vaccines in the control of hormone-dependent cancers, including breast
and prostate cancers. Because the sequence of LHRH is conserved in all
mammals, LHRH-based immunocontraceptives are candidates for use in the
companion animal livestock and livestock arenas. Here the concerns of behavioral
modification are not of such overriding importance and the use of immunocontraception
as an alternative to surgical castration has attracted a great deal of
attention.
female immunocontraceptive vaccines :
a phase I clinical trial of the immunogenicity and safety of a vaccine
against the C-terminal region of the b
subunit of human chorionic gonadotropin (hCG-B)
demonstrated a dose-related immune response. The antigen was a synthetic
peptide of the C 109-145 region of hCG-B, conjugated to diphtheria toxoid,
and administered in a water-soluble synthetic adjuvant in a saline-oil
emulsion. This vaccine had been previously tested for toxicity in laboratory
animals and for immunogenicity, safety and contraceptive effectiveness
in baboons. 30 previously sterilized women were given 2 injections 6 weeks
apart, ranging from 50 to 1000 mg of the antigen.
Each woman tested free of HLA B27 antigen and reacted negative to the diphtheria
toxoid skin test. Based on calculated contraceptive antibody binding level
of 0.52 nmol/l, all subjects mounted an effective antibody response for
at least 6 months. 2 subjects in the group given 1000 mg
who were followed for 9 and 10 months maintained this level of antibody.
12 women showed an anamnestic response to diphtheria toxoid, while 8 did
not. The only adverse reactions were mild, transient pain at the injection
site. Several women who received unstable adjuvant experienced more severe
myalgia. Menstrual changes appeared in 5 subjects: early menopause in 1,
spotting in 3 and menorrhagia in 1 woman. Only transient positive findings
were seen in some sera screened for autoantibodies. This preliminary trial
indicates that anti-hCG vaccine is a hopeful reversible contraceptiveref.
to examine the immunogenicity of the plasmid DNA encoding human
sperm associated antigen 9 (hSPAG9), the cDNA corresponding to hSPAG9
was cloned in mammalian expression vector pcDNA 3.1 down stream of cytomegalovirus
promoter. Immunization of female BALB/cJ mice with pcDNA-hSPAG9 plasmid
DNA in saline by intramuscular (i.m.), by adsorbing onto gold microcarriers
(delivered by gene gun) and by recombinant hSPAG9 (r-hSPAG9) protein generated
antibody response against Escherichia coli expressed r-hSPAG9 protein
and native SPAG9 in human sperm. Although mice immunized with r-hSPAG9
protein exhibited highest antibodies titres (P<0.001), the difference
in the antibody titres seen by the 2 modes of plasmid DNA delivery were
not significant (P>0.05). A dominant IgG1 isotype response was
observed in mice immunized with pcDNA-hSPAG9 plasmid DNA delivered by gene
gun as compared to a mixed IgG1-IgG2a isotype response
in mice immunized with r-hSPAG9 protein and pcDNA-hSPAG9 plasmid DNA delivered
by i.m. Further, antibodies generated by pcDNA-hSPAG9 plasmid DNA localized
acrosomal compartment of human sperm and inhibited sperm adherence to or
penetration in zona-free hamster egg penetration test. These studies for
the first time, demonstrate the feasibility of generating an immune response
to sperm specific hSPAG9 protein by DNA vaccine and that antibodies thus
generated recognize native SPAG9 in human spermref.
with a seasonally polyestrus breeding structure, the unwanted domestic
cat population has proven difficult to control. Various lethal methods
have been used in an attempt to lower this population of cats. Recently,
humane attempts to control "pest species," such as the feral cat, have
focused on immunocontraception. Female cats were immunized once (n = 3
cats per group). SpayVac® (source : ImmunoVaccine
Technologies (IVT)) is a vaccine that uses antibodies raised against
porcine (ZP) antigens to prevent fertilization of the ovum. SpayVac®,
delivered in a single dose, has been evaluated in fallow deer and several
species of seals with >90% reduction in fertility and no adverse reactions.
A study evaluated the effectiveness of SpayVac in reducing fertility in
domestic kittens. 30 female kittens were treated with SpayVac containing
either Freund's complete adjuvant (FCA) or alum, or with a control vehicle.
Kittens were monitored for side effects, estrus cycling at maturity, and
fecundity. Anti-porcine ZP antibodies were quantified by ELISA. Immunohistochemical
assays measured the species specificity of the antibodies produced and
IgG binding in vivo. Despite high anti-porcine ZP antibody titers,
neither formulation of SpayVac® prevented estrus cycling
at maturity or reduced fecundity. IHC assays indicated that antibodies
produced by cats treated with SpayVac® recognized porcine
ZP, but not feline ZPref.
A panel of native zona pellucida (ZP) antigens isolated from 5 mammalian
species was screened for immunocontraceptive activity in the cat (Felis
catus). Native soluble-isolated ZP (SIZP) was prepared from the ovaries
of cows (bZP), cats (fZP), ferrets (feZP), dogs (cZP), and mink (mZP).
Vaccines were constructed using SIZP from each of the above species encapsulated
in liposomes suspended in saline and emulsified with Freund's complete
adjuvant. Serum was collected for determination of antibody titers against
SIZP and for binding of antibodies to feline ovaries. All cats responded
to immunization by producing anti-SIZP antibodies. The most immunogenic
SIZP in cats was from mink, followed by feZP, cZP, and fZP in descending
order. Antibodies had low reactivity for fZP, and no reactivity against
feline ovaries was detected by immunohistochemistry. A breeding trial was
commenced 20 weeks after immunization. All cats became pregnant, averaging
4.1 +/- 0.7 viable kittens per litter. Porcine SIZP is not an effective
antigen for immunocontraception of cats. SIZP from 5 other mammalian species
were immunogenic in the cat, but ZP antibodies failed to bind to fZP
in situ, and fertility was not impededref
heterologous Ags
(heterotypic vaccine / heterovaccine) : a vaccine that confers
protective immunity against a pathogen not present in the vaccine, because
it contains cross-reacting antigens which they share in common with that
pathogen
heterophilic Ags
Some examples :
anti-Corynebacterium
diphteriae
vaccine : non-toxic protein CRM197
from a genovar induces cross-reactive Abs against diphteria toxin.
Better antigens can be created by directed molecular evolution :
nature would never select for many of the products that directed evolution
allows you to create as they wouldn't help the cell. The initial step in
DNA
shufflingref
(Genetic ReAssortment by MisMatch Resolution (GRAMMR) DNA shuffling) is
to isolate several slightly different genes that code for the same product.
Enzymes chop the genes into random fragments, and a primer-less PCR recombines
fragments from various genes. Finally, recombined fragments are reassembled
into unique, full-length chimeric genes. Maxygen
products created with this technology include :
chimeric dengue antigens that produce antibodies working against all 4
strains of dengue virus
: this could have important advantages as low levels of antibodies can
actually enhance the ability of the virus to cause hemorrhagic fever.
chimeric HBsAg that led to as much as 12-fold greater antibody response
than the most potent wild-type vaccine.
mouse DCs are efficiently infected with influenza virus but do not release
infectious progeny virus. Ex vivo-infected DCs secrete IL-12
and induce a potent Th1-like
immune response when injected into mice (virus-specific antibody response
is primarily of the IgG2a isotype)ref
preservatives and tissue fixatives, which are supposed
to halt any further chemical reactions and putrefaction (decomposition
or multiplication) of the live or attenuated (or killed) biological constituents
of the vaccine.
nanoscopic vaccine delivery system based on the biodegradable and natural
polymer gelatin, to deliver therapeutic protein antigens along with
adjuvants into dendritic cells (DCs). In this study, gelatin nanoparticles
were tested for qualitative and quantitative uptake in murine DCs in vitro.
A second aim of this study was to prove that the carrier system is able
to deliver tetramethylrhodamine conjugated dextran (TMR-dextran), as a
model drug into the DCs. The TMR-dextran was incorporated during the preparation
of the gelatin nanoparticles. DCs were generated from murine bone marrow
cells by an established ex vivo technique. Flow cytometry showed that 88%
of the cells positive for the specific murine DC marker CD11c took up TMR-dextran
loaded gelatin nanoparticles, whereas only 4% of the soluble form of TMR-dextran
was taken up. Double color confocal laser scanning microscopy (CLSM) showed
that gelatin nanoparticles were phagocytosed by DCs and the triple color
CLSM showed that the TMR-dextran was localized mainly in lysosomes as expected,
but partly also outside the lysosomes, presumably in the cytoplasm. An
in vitro release study of TMR-dextran from gelatin nanoparticles demonstrated
that there was hardly any release in phosphate buffered saline (PBS), but
by trypsin-assisted degradation of gelatin nanoparticles resulted in the
release of about 80% of the TMR-dextran from the particlesref.
Lirubel® (Dow Pittman Moore) : no longer in use (2/65-6/78)
M-R II® (MSD)
M-R-Vax® (Merck) : no longer in use (7/71 to ?)
M-R Vax II® (Merck)
Morubel® (Biocine => Chiron, Italy)
Mo-Ru Viraten® (Swiss Serum and Vaccine Institute)
Rudi-Rouvax® (Aventis Pasteur)
Zamruvax® (Institute of Immunology)
measles,mumps
and rubella (MMR) vaccine : its use was
once linked to autismref1
[retracted],
ref2
and bowel disease, but no real evidences has been found. Given at age 12
months, and a booster at 3 to 5 years. The Institute of Medicine (IOM)
of the US National Academies after reviewing recent studies concluded on
May 2004 that there is no link between autism and vaccines containing the
mercury-based preservative thimerosal
: their report also rules out a link between autism and the MMR vaccineref.
Anyway a genetic susceptibility might make some individuals more vulnerable
to toxic effects of the ethylmercury-containing vaccine preservative, thimerosal,
given alone or in 4 common vaccines given to children : autoimmune disease-sensitive
SJL/J mice showed growth delay; reduced locomotion; exaggerated response
to novelty; and densely packed, hyperchromic hippocampal neurons with altered
glutamate receptors and transporters (resembling autism). Strains resistant
to autoimmunity, C57BL/6J and BALB/cJ, were not susceptibleref.
The researchers based their experimental design on the observation that
some children with autism have a family history of autoimmune disease.
Imovax ROR® (Institut Merieux)
LM-3 RIT® or RIT-LM-3® (Dong
Shin Pharmaceuticals)
M-M-RVax (Chiron, Germany only)
M-M-R
II® (Merck & Co) : PWSO (1000 U / 0.5 mL, 5000
U / 0.5 mL, 1000 U / 0.5 mL) SC
Measles, Mumps, Rubella® (Dow Chemical)
MMR (generic) (Dow Chemical) : no longer in use (1974 to 1975)
MMR® (MSD)
MMR II® (MSD)
Morupar® (Biocine => Chiron, Italy, Asia, Latin America)
was recalled on March 2006 and withdrawn because of an increased rate of
post-immunization adverse effects
Children who are allergic to eggs are at no greater risk of a severe allergic
reaction to the MMR vaccine, which is cultured in chick embryo cells. The
real culprit in allergic reactions to MMR could be gelatin. Overall, any
severe adverse effect is almost certain to occur within half an hour of
the vaccination. Investigations into these prior events
have concluded that the deaths following administration of the measles
vaccine were related to toxic shock syndrome resulting from the use of
non-sterile syringes and the use of the reconstituted vaccine out of the
time range specified for administration, resulting in contamination of
the administered vaccine. The measles vaccine comes in a lyophilized form
(freeze-dried) that is reconstituted with diluent on the day of use.
Standard practice is to have vials of diluent distributed and stored with
the vaccine vials so that appropriate diluent and amounts are used routinely
for vaccination activities. Current recommendations are to discard any
unused vaccine from reconstituted vials at the end of a vaccination session.
In the case of the deaths reported in November 2001 in Algeria, the event
was traced to the use of solvent rather than diluent for the reconstitution
of the vaccine at the local health facility where the events occurred.
In the May 2002 case of Cuba, the preliminary report on the investigation
identified "Gram-positive aerobic bacilli" in remaining vaccine vials in
the affected health facility, suggesting there were breaches in sterilization
practices at the local area. In the 2004 event in Brazil, it appears as
though the severe adverse events were widespread, occurring in multiple
states within Brazil (one newswire mentions 15 states and the other mentions
7 states and the Federal District) : 5 children suffered from anaphylactic
shock, with breathing difficulties and falling blood pressure, and 115
others presented with allergic symptoms to the measles vaccine manufactured
by Chiron, Italy, used on Saturday Aug 22 on the 1st day of the national
vaccination campaign against the disease. If the event is not localized,
it suggests a problem with the product that was distributed to multiple
locations, rather than a localized event such as breaks in safe vaccination
procedures or use of incorrect diluent for reconstitution of the vaccine.
The description of the adverse events as anaphylactic shock and other allergic
related reactions suggests the presence of a highly allergenic contaminant
in one of the 2 products used for the vaccination process, either the vaccine
itself or the diluent used to reconstitute the vaccine. One of the questions
that come to mind is the providence of the diluent used to reconstitute
the vaccine, as we have not heard of similar events in other countries
that may be using the same vaccine. Was the diluent produced locally (in
Brazil) or was it imported together with the lyophilized vaccine?
Web resources :
diphteria,
tetanus
and pneumococcal vaccine
: 4 doses at ages 6, 10, and 14 weeks, and 9 months elicits high concentrations
of functional antibodies against all but one pneumococcal serotype included
the vaccine. Moreover, "most serum samples contained antibodies with measurable
opsonophagocytic activity," ranging from 43% to 98%, after three doses,
they report. The functional activity of anti-pneumococcal antibodies after
the fourth dose was significantly higher than after the third dose, as
demonstrated by the opsonophagocytic titer. After the fourth dose, the
opsonophagocytic activity was measurable in 75% to 100% of samples, depending
on serotype.
diphteria,
tetanus
toxoid and pertussis (DTwP
or DPT) vaccine. 5 doses at 2, 4, 6, 12-18 months and 4-6 years of
age it is a very stable compound that withstands temperature
and humidity fluctuations.
ADCM® (?, Russia)
Adifteper® (Ism)
AFDC® (?, Russia)
AKDS® (?, USSR)
AKOC® (?, Russia)
Alditerpera® (Sevac) : adsorbed
Anatoxal Di Te Per® or Di Te Per Anatoxal®
(Swiss
Serum and Vaccine Institute)
Diferti Trippel® (?, Sweden)
Dif-Per-Tet-All® (Biocine)
DIFTAVAX® (Sclavo, Inc.)
DSDPT® (Dong Shin Pharmaceutical Co.) : adsorbed
DT Coq® (Aventis Pasteur)
DTP® or DTwP® (Aventis Pasteur,
Wyeth Lederle, Glaxo SmithKline)
DTC® (for diphteria, tetanus and coquellode; ?)
Dual Antigen® (Serum Institute of India) : pediatric
Dual Antigen SII® (Serum Institute of India) : adsorbed
Funed-CEME® (Belo Horizonte, FunED)
Kilkhosta Trippel® (?, Sweden)
Krztuscowi, Blonicy, Tezcowi® (?, Poland)
rhorephn, kokjihowa, ctoroohrha® (?, Russia)
Sii Triple Antigen® (Serum Institute of India)
Stelkramp® (?, Sweden)
Tri-Immunol® (Lederle Laboratory) : 3/48 to present
Trinivac® (Merck) : no longer in use (1952 to 1964)
Adacel™ (Sanofi Pasteur) is a tetanus toxoid (T), reduced diphtheria
toxoid (d) and acellular pertussis vaccine (ap), adsorbed (Tdap)
in adolescents and adults aged 11-64 years. It contains the same
components as DTaP vaccine indicated for infants and children, but the
diphtheria toxoid and one of the pertussis components are in reduced quantities.
Approved by FDA on 10 Jun 2005. The antibody responses of the adolescents
and adults who received a single dose of this vaccine were at least as
good as those observed in the infants following 3 doses of the pediatric
vaccine. For diphtheria and tetanus, the antibody responses following this
vaccine were comparable to those following immunization with a USA-licensed
Td vaccine. In clinical trials, the safety of this vaccine was compared
to a USA-licensed Td vaccine. Among adolescent recipients of this vaccine,
injection site pain and low-grade fever were observed more frequently than
among those who received Td vaccine. Rates of adverse reactions were similar
in adults receiving this vaccine or receiving Td vaccineref
Boostrix®
(GlaxoSmithKline) is a tetanus toxoid (T), reduced diphtheria toxoid (d)
and acellular pertussis vaccine (ap), adsorbed (Tdap). Although
booster vaccines for adolescents 10-18 years of age containing T
and d are currently licensed and marketed for use in this age group, none
contains a pertussis component. Boostrix has the same components as Infanrix,
a DTaP vaccine for infants and young children, but with lower amounts of
both diphtheria and pertussis components. Boostrix is indicated for use
as a single booster dose to adolescents 10-18 years of age. The efficacy
of the vaccine was measured by looking at the immune response to the vaccine,
as measured by antibody concentrations. The response to the T and d components
was at least as good as the response to a licensed Td vaccine. Boostrix
also induced an antibody response to the pertussis component of the vaccine.
The response to the pertussis component was compared to the response induced
by a 3-dose series of Infanrix given to infants in a previous study. The
response of adolescents to Boostrix was considered adequate. It is not
known how long immunity to pertussis will last. Adolescents who received
Boostrix experienced pain, redness, and swelling at the injection site.
The frequency of redness and swelling after Boostrix was similar to what
is expected following the administration of a Td vaccine. However, pain
reactions at the injection site were more frequent with those who received
Boostrix. Other side effects included headaches, fever and fatigue for
a short period of time after the injection. Vaccination in adolescence
should prolong immunity, but an additional booster will probably be needed
later in life. The current vaccine is effective and does protect for a
certain amount of time, up to the age of 7
EEEV, WEEV,
VEEV, West Nile virus, and tetanus (VEWT-WN) vaccine : the 2 or 3 vaccination
routine is good protection against a preventable disease for horses.
Induction of CTL responses Vaccines based on killed or inactivated pathogens, recombinant or purified
proteins, are generally effective in inducing Th lymphocytes
and Ab responses, but are generally ineffective at induction of CTL responses.
The apparent reason for this limitation is likely to hinge on the basic
biology of Ag processing : CTL are efficiently induced when Ag is endogenously
synthesized and presented in the context of nascent MHC class I molecules.
Th1
polarized responses can be induced by particular adjuvants (expecially
TLR
ligands), but the only possibility for induce CTL with foreign Ags is to
induce cross-presentation
by administering synthetic epitopes that can extracellularly bind surface
MHC class I molecules.
Contraindications :
moderate-to-severe acute illness (with or without fever)
fever
moderate otitis media (with or without fever)
immunosuppression in the recipient (family history, symptomatic or asymptomatic)
or in a household contact, for live
vaccines
moderate to severe vomiting and/or diarrhea (with or without fever) for
all vaccines, not only oral vaccines (e.g. OPV)
anaphylactic (life-threatening) reaction to a previous dose of any vaccine
fever within 48 hours, encephalopathy within 7 days after a dose for DTP/DTaP
hypersensitivity to 2-phenoxyethanol or alum in HAV vaccine, baker's yeast
in HBV vaccine, gelatin in MMR and varicella, neomycin in IPV, MMR, and
varicella, streptomycin in IPV, DTP/DTaP within 3 days of previous dose
of DTP or DTaP
underlying neurological disorder (including seizure disorders, cerebral
palsy, and developmental delay) for DTP/DTaP
recent or simultaneous IVIg or IMIg administration for MMR and varicella
Adverse side effects / adverse
events following immunization (AEFI) The term side effects encompasses all the changes in homeostasis that
don't contribute to progression of immunity against the intended target.
They depend on :
dose
route of administration (ROA)
properties of the preparation itself
genetic factors of the vaccinated.
The immunogenicity of vaccines does not always correlate with their reactogenicity.
Pathogenesis :
pharmacological effect due to ligands contained in the vaccine (e.g.
LPS)
immunomodulation due to TLR
ligands or contaminant cytokines
autoimmunity
: routine childhood vaccinations do not increase the risk of developing
diabetes
mellitus.
As thimerosal was removed from childhood vaccines, the number of neurodevelopmental
disordes has decreased in the USAref.
vaccination
of the immunocompromised
hostref
: after immunosuppression (e.g. in tranplanted patients) memory lymphocytes
are lost and new immunization schedules are required to restore immunity
non-leukaemic cancers
: children with solid tumours and lymphoma received 1 or 2 doses of trivalent
split virus influenza vaccine, according
to current UK guidelines, in autumn 2001 and/or 2002. Children were currently
receiving chemotherapy or were within 6 months of completing chemotherapy.
Pre and post vaccination sera were assessed for antibodies to the prevalent
influenza strains by haemagglutination inhibition (HI). 66 children were
assessed prior to 69 episodes of vaccination. In 30% episodes, children
were susceptible to all three circulating influenza viruses (65% to H1N1,
42% to H3N2 and 90% to B) and only one patient showed
protective titres (HI32) against all three strains. Seroresponse rates
(4-fold rise in HI) for H1N1, H3N2
and B were 52%, 33% and 51% in 65 episodes. Following immunisation protective
titres to all 3 viruses were seen in 25 episodes (38%) and protective responses
to 1 or 2 viruses were seen in a further 12 (19%) episodes. There was no
significant difference in response rates among children on treatment and
off treatment and by intensity of chemotherapy. Children with solid tumours
and lymphoma are highly susceptible to influenza infection. Influenza vaccine
was well tolerated in this patient group and children showed a significant
response to immunisation. These findings support the recommendation for
annual influenza vaccination in these childrenref.
leukemia/lymphomas
: cancer patients receiving chemotherapy are prone to develop infections
that might postpone treatment and lead to complications. In general, adults
with cancer are at least at the same risk of infection with vaccine-preventable
diseases as are healthy populations. Because of their compromised immune
function, many patients who have undergone cancer treatment are specifically
at increased risk of morbidity and mortality associated with measles and
varicella infections. Asplenic patients with lymphoma are at increased
risk of fulminant bacterial infections. Influenza infection is associated
with significant morbidity in cancer patients. Although the protection
conferred by immunization is lower in immunosuppressed patients with cancer,
immunization with inactivated vaccines is indicated. Live vaccines should
not be used except in very rare instancesref.
chronic lymphoproliferative disorders (CLPD) and multiple myeloma (MM)
: none of 34 patients had untoward reactions to the vaccine used. Seroconversion
and seroprotection were up to the standard established by the European
Agency for the Evaluation of Medicinal Products. Only one patient developed
influenza during follow-upref
after 1 vaccination, 25 patients (72%) and 34 controls (87%) were serologically
protected against 2-3 influenza strains. A higher proportion of patients
with solid tumors (81%) than lymphoma (38%) achieved protection. Age, months
on chemotherapy, and curative versus palliative treatment did not influence
responses to vaccination. In this study the chemotherapy regimens used
were mild or moderately immunosuppressiveref
in children receiving chemotherapy for malignancyref
:
children with solid tumours and lymphoma are highly susceptible to influenza
infection. Influenza vaccine (performed both on and after chemotherapy)
was well tolerated in this patient group and children showed a significant
response to immunisationref
9 of 12 children with malignant diseases without antibodies to A/Victoria/75
before immunization developed them after the first dose of vaccine. Adverse
reactions after vaccination were minimalref
during the National Influenza Immunization Program in 1976, 147 children
with neoplastic diseases received Wyeth split-product bivalent influenza
vaccine: A/New Jersey/8/76 (HSW1N1), A/Victoria/3/75
(H3N2). 13 normal siblings served as controls. 71
patients received 2 doses of the vaccine 4 weeks apart. After the second
injection of A/NJ/8/76, there was a difference between the response of
the patients on chemotherapy and those off therapy >= 30 days--38% vs.
76%, P < 0.01 for 4-fold rise and 26% vs. 57%, P < 0.05 for the attainment
of protective (>= 32) hemagglutination inhibition (HI) titers. These differences
were observed in both leukemia-lymphoma and solid tumor patients. There
was a difference in HI titers to A/Vic/75 between patients on and off chemotherapy
after a single injection, 34% vs. 71%, P < 0.001 for a 4-fold rise.
After the second immunization, only 52% on, and 86% off therapy (P <
0.05) had a four-fold rise in titers. 32%of the patients on treatment who
achieved "protective" titers did so only after the second immunization.
Immunoglobulin levels and neutropenia did not correlate with the inability
to obtain a 4-fold rise in titers. Patients on chemotherapy cannot be effectively
vaccinated by a new antigen, and that single yearly boosters may be insufficient
for recall of old antigens. Patients off chemotherapy >= to 30 days respond
as normal controlsref
among children receiving immunosuppressive therapy for cancer, possible
early loss of specific immunity acquired from prior vaccination or disease,
and likely diminished responsiveness to initial or booster vaccination
must be considered. In addition, the safety of vaccine administration requires
separate study in this population. Published evidence demonstrates preservation
of vaccine-induced antibody titers against tetanus, diphtheria, poliomyelitis
and (in children treated for lymphoma) pneumococcus. In contrast, prior
immunity to varicella, influenza, and hepatitis B (when naturally acquired),
and measles (acquired by vaccination) is compromised during and/or after
antineoplastic therapy. Studies of immunologic protection acquired by prior
vaccination against hepatitis B, varicella, and H influenzae have
not been published. The safety of administering toxoids and inactivated
vaccines in this population is well documented. In contrast, morbidity
must be expected if live attenuated vaccines (oral polio vaccine, attenuated
measles vaccine or attenuated varicella vaccine) are administered to children
receiving anti-cancer therapy. The risks of using live vaccines should
be measured against demonstrable benefits in any vaccine program. The response
to initial or booster immunizations against tetanus and diphtheria are
similar to those in healthy children. For all other immunizations reviewed,
responsiveness is diminished during periods of chemotherapy, more strikingly
in children treated for leukemia than for solid tumors. Antibody responses
to these vaccines range from slightly blunted (in the case of H influenzae
B) to marginal (influenza) or completely useless (pneumococcus and hepatitis
B in children treated for leukemia)ref
haematological malignanciesref
: 2 doses of influenza vaccine do not improve the antibody responseref
children with B-cell acute lymphoblastic
leukemia (B-ALL)
developed significant antibody titers to A/Panama /2007/ 99 antigen 4 weeks
after the second immunization. Seroconversion rates after 2 doses of vaccine
were 57.1 to 84.6% and seroresponse rates were between 24 and 60% in children
with ALL. Compared to children with asthma in remission, who were regarded
as immunocompetent individuals, the ALL children had less seroconversion
and lower seroresponse rates to A/New Caledonia/20/99 (H1N1).
The seroconversion and seroresponse rates to B/Yamanashi/166/98 and A/
Panama/2007/99(H3N2) antigens were comparable in
asthmatic and leukemic children. On the other hand, the antibody response
in children with ALL who received reinduction chemotherapy suggests that
the therapy did not impair seroresponse ratesref.
Although post-immunization geometric mean titers were lower in children
with ALL receiving maintenance chemotherapy compared to healthy children
for the H1N1 antigen (P<0.001), the H3N2
antigen (P=0.03), and for the influenza B antigen (P=0.003),
at least 60% of children with ALL had at least a 4-fold rise in HAI titers
to each of the influenza antigens. Children receiving maintenance chemotherapy
for ALL should receive yearly influenza vaccineref.
Among 42 susceptible children receiving continuing chemotherapy immunised
with 2 doses of influenza vaccine, 66% made some protective response to
the vaccine and 55% showed protective antibody titres to all three viral
strains following vaccination. Older age was associated with increased
response to the H1N1 and H3N2
vaccine components, but total white cell count or neutrophil count at immunisation,
type of cancer, or length of time on treatment for acute lymphoblastic
leukaemia did not affect responseref.
Studies were performed in 25 patients previously vaccinated against influenza
(Group A) and in 20 children who had never been immunized before (Group
B). In Autumn, 1996, they were vaccinated with subunit trivalent influenza
vaccine containing 15 mg of hemagglutinin of
A/Singapore/6/86, A/Wuhan/359/95 and B/Beijing(184/93. Anti-HA and anti-NA
antibody titers were determined before immunization and 3 weeks and 6 months
after vaccination by the hemagglutinin inhibition test and the neuraminidase
inhibition test. In Group A mean fold increase of HA antibodies ranged
from 17.2 to 26.7 three weeks after vaccination and from 22.1 to 38.2 6
months after vaccination, while in Group B it ranged from 15.7 to 22.6
and from 30.3 to 39.3, respectively. In the case of neuraminidase, mean
fold increases for Group A varied from 9.2 to 13.2 3 weeks after immunization
and from 15.6 to 21.1 6 months after vaccination, whereas for Group B they
varied from 5.5 to 8.3 and from 14.4 to 23.4, respectively. 6 months after
vaccination the proportion of subjects with HA antibodies > or = 1:40,
as well as those with at least 4-fold increase of HI antibody titers, ranged
from 68 to 100% in Group A and from 90 to 100% in Group B. No vaccinated
child was infected with the influenza virus; the vaccine was well-tolerated
and did not cause any adverse reactionsref.
In 44 children receiving maintenance treatment or after treatment, the
GMT increased > 4 times for hemagglutinins H1N1 and
H3N2. A somewhat lower increase was observed in case
of hemagglutinin HB. The proportion of subjects protected after vaccination
was 35% for hemagglutinin H1N1, 76% for H3N2
and 100% for HB. The response rate was 33% for hemagglutinin H1N1,
47% for H3N2 and 45% for HB. In the control group
the proportion of subjects protected and the response rate were very lowref.
In 49 children immunized with a purified subvirion trivalent influenza
vaccine, 6 months after vaccination GMT for hemagglutinin 1 (H1)
was much higher than previous values. GMT for hemagglutinin 3 (H3) and
hemagglutinin B (HB) was lower than three weeks after vaccination, but
much higher than the original values. In the control group GMT for H1 was
on a low level all the time and for H3 and HB it was lower when
compared with the original values. The proportion of vaccines to antibodies
> or = 40 ranged between 45% and 88%. 6 months after vaccination GMT for
neuraminidase 1 (N1) increased when compared with the second
sampling; for neuraminidase 2 (N2) and neuraminidase B (NB)
it was slightly lower. In the control group GMT for all antigens was on
a low level all the time. The results point to a significant seroconversion
for both components after vaccination when compared with the control groupref.
The immunosuppressive effects of long-term combination chemotherapy in
children with acute leukemia in remissionref.
Antibody responses of two doses of a bivalent influenza vaccine containing
A/Victoria/75 (A/Vic/75) and A/New Jersey/76 (A/NJ/76) viral antigens were
studied in 22 children receiving maintenance chemotherapy for acute lymphoblastic
leukemia (ALL), 16 children no longer receiving therapy for ALL, and 50
sibling controls. Before immunization, the three groups showed no difference
in titer of antibody to either antigen. After the first immunization, children
off therapy showed significantly higher titers to A/NJ/76 than did either
sibling controls of children receiving therapy (P < 0.01). After the
second immunization, children off therapy showed significantly higher antibody
titers to both antigens than did children receiving therapy or controls
(P less than 0.01 for both A/NJ/76 and A/Vic/75). Antibody titers of children
receiving therapy were not significantly different from those of controls.
A year later, there were no significant differences in antibody titers
among the groups. Thus, children with ALL who are receiving chemotherapy
respond normally to 2 doses of influenza vaccine, whereas children off
therapy manifest abnormally high titers of antibody to both influenza virus
antigensref.
Children with acute lymphocytic leukemia and other malignancies between
three and 17 years of age were immunized with bivalent influenza vaccine
containing A/New Jersey/76 and A/Victoria/75. Folowing a 2-dose immunization
schedule, only 37% (25468) on cancer chemotherapy seroconverted to a hemagglutination
inhibition titer greater than or equal to 20 for A/NJ/76; the seroconversion
rate in those not on chemotherapy was 92% (68/74, P < 0.001). The immune
response to the A/Vic/75 antigen was also related to a history of recent
chemotherapy. There was no correlation between the immune response and
the peripheral WBC count except at counts <= 1,000. The optimum time
to immunize children with malignancies is when they have been off chemotherapy
for 1 month and have peripheral WBC counts > 1,000ref.
NHL : PET scan hypermetabolism induced by influenza vaccination in a patientref
patients with lymphoma, who tend to have hypogammaglobulinemia, responded
less well to bivalent inactivated influenza vaccine containing A/Port Chalmers/1/73
(H3N2) and B/Hong Kong/5/72 antigens than did patients
with solid tumours. Among the latter the failure to show a 4-fold or greater
increase in antibody titre correlated with a poorer 18-month survivalref
B-cell chronic lymphocytic leukemia
(B-CLL)
: immune response to influenza vaccination was poor. Response rates (>
4-fold titre increase) were 5% for influenza A and 15% for B after the
single vaccination and 15% for A and 30% for B after the booster vaccination.
Protection rates were 0% for influenza A and 25% for B after the single
vaccination; they were 5% (H1N1) and 10% (H3N2)
for influenza A and 30% for B after the booster. The MFI+/-S.D. (range)
after the booster vaccination was 0.26+/-0.33 (0-1.00), 0.17+/-0.34 (0-1.00)
and 0.35+/-0.34 (0-1.20) for H1N1, H3N2and
influenza B, respectively. Thus, single and booster vaccinations with influenza
virus vaccine do not appear to be of great value to patients with B-cell
CLLref.
The Vaxigrip vaccine was administered containing the antigens A/Ghizhou/54/89,
A/Singapore/6/86, and B/Yamagata/16/88. The side-effects observed were
minimal and well tolerated. Antibody production with titres > 1:20 on day
15 was observed at least for one antigen in 35 patients (81%). In 23 of
them (63%) this response was retained on days 30 and 60. Patients with
IgG levels (< 700 mg/dl) responded less well as compared to those having
normal IgG levels (> 700 mg/dl)ref.
No difference in the response to vaccination against influenza virus types
A and B protein could be detected in patients treated with ranitidineref.
A correlation between immunological response to vaccination and both absolute
numbers of CD4+/CD45RA+naive T cells and
CD5- B cells was foundref.
Hodgkin's lymphoma
: during and after chemotherapy, both pre- and postimmunization levels
of antibody to Streptococcus pneumoniae, Hemophilus influenzae
type b, and tetanus toxoid antigens were significantly lower in patients
than in controls. Impairments in the antibody response were most severe
in intensively treated patients and improved as the interval between treatment
and immunization increased. The primary, but not the secondary, antibody
responses to the hemagglutinins of the influenza virus A/Victoria/75 and
A/New Jersey/76 also were impaired in treated patientsref
although geometric mean titres of the haematological lymphoproliferative
or myeloproliferative disorders patients showed lower initial antibody
levels, smaller increments, and lower final titres, after vaccination 83%
of this group achieved satisfactory antibody levels to the A/Pt Chalmers
strain, and 57% to the B/Hong Kong strain. The lowest antibody levels and
smallest responses occurred in patients with NHL, Hodgkin's disease, and
multiple myeloma. 4 of 7 patients who showed low antibody levels, and no
response to the first injection, responded to a second doseref
mean antibody titer elevations were lower for both antigens in all disease
groups, being significant (p < 0.05) for A/Victoria in patients with
NHL, acute leukemia and lymphoproliferative diseases, and for A/New Jersey
in patients with HLs and NHLs. In comparison to controls, significant depression
of antibody response to both antigens was seen in patients on combination
chemotherapy (p < 0.0005), to a lesser extent in patients on daily single
alkylating agent chemotherapy (p < 0.05), while untreated patients did
not differ significantly. Lymphopenia and depressed immunoglobulin levels
were associated with a higher failure rate in eliciting "protective" greater
than or equal to fourfold antibody titer increases. The findings suggest
that patients with hematologic malignancies who are receiving chemotherapy
at the time of vaccination are unlikely to attain seroconversion to protective
antibody levels with influenza vaccineref
Side effects :
atypical lymphoid infiltrations arose within the influenza inoculation
sites of two adult female patients. One patient developed a low-grade cutaneous
marginal zone B-cell lymphoma (MZL) that was responsive to local excision
and radiation therapy despite spread to a distant cutaneous site. The second
patient's clinical course was characterized by a locally aggressive, histologically
reactive inflammatory reaction responsive only to radiation therapy after
multiple failed attempts at surgical resectionref
after vaccination with a 23-valent polysaccharide vaccine against pneumococci,
most patients and controls achieved protective serum levels of antibodies
against the different serotypes, with the exception that fewer patients
were protected against serotype 4. The responses in controls were, however,
generally stronger to all serotypes. Tumor type did not influence this
vaccination responseref.
multiple myeloma (MM)
: resistance to S. pneumoniae and response to Pneumovax II was poor
: prevaccination, 45 patients (93%) had suboptimal antibody titres and
in 26/43 patients (61%) titres remained low post vaccinationref
Hodgkin's lymphoma
: before treatment antibody responses to pneumococcal vaccine was normal
regardless of the stage of disease unless treatment began within 10 days
of immunization. Levels of antibody decreased during therapy in proportion
to the intensity of treatment but remained higher than levels in comparably
treated patients who were not immunized at diagnosis. Patients should receive
pneumococcal vaccine at diagnosis at least 10 days before initiation of
treatment. Patients who are treated before immunization may be immunized
several months after treatment, although the response of heavily treated
individuals to vaccination may be marginal. More studies are needed to
determine whether reimmunization of patients initially immunize at diagnosis
is safe and effectiveref
multiple myeloma (MM)
resistance to Hib and response to vaccination was comparable with the healthy
adult UK populationref.
No increased incidence of leukemia in children vaccinated with polysaccharide-diptheria
toxoid conjugate and oligosaccharide-CRM197 conjugate Haemophilus
influenzae type b conjugate vaccine formulationsref
B-cell chronic lymphocytic leukemia
(B-CLL)
: patients have decreased capacity to mount relevant antibody responses
upon immunization, and development of hypogammaglobulinemia is part of
the natural history of the disease. H2 receptor blockade by
ranitidine improves the in vivo antibody production in B-CLL patients
following vaccination. Anti-polysaccharide antibodies in B-CLL patients,
vaccinated with a tetanus-toxoid conjugated vaccine against Haemophilus
influenzae type-B (Hib), reached long-term protective levels in > 90%
of B-CLL patients randomized to ranitidine treatment, as compared to 43%
of the untreated patients (P = 0.024). Plasma histamine levels were 2-fold
to 20-fold higher in 23 out of 31 B-CLL patients, compared to normal controls,
and these levels showed a significant positive correlation to disease duration.
These findings indicate the possibility of improving in vivo antibody
production against a highly relevant pathogen in B-CLL patients by H2
receptor blockade, and the combined finding of an immune-stimulatory effect
of ranitidine and increased plasma histamine levels, strongly suggests
the involvement of histamine in the pathogenesis of B-CLL immunodeficiencyref
all anti-diphtheria toxoid (D), tetanus toxoid (T), and Haemophilus
influenzae type b (Hib) antibody levels decreased during ALL treatment,
and protective levels after treatment were noted for 17% against D, 33%
against T, and 100% against Hib. No high-risk patient had full D or T protection
after treatment. After vaccination all the standard- and intermediate-risk
patients achieved full protection against D, T, and Hib. The high-risk
group showed insufficient immune response (full protection after vaccination:
D 56%, T 22%, Hib 78%). No difference was found between vaccination at
1 month or 6 months after treatment. The poor antibody production in the
high-risk group correlated to low numbers of antibody-secreting cells.
Nonprotective antibody levels against D, T, and Hib after childhood ALL
are more common than previously thought. Insufficient immune response was
restricted to the high-risk group and was related to a low number of memory
B cells in this study. Immunizations should be included in follow-up after
childhood ALL, and the policy should be adapted to treatment intensityref
in bone
marrow transplantationref1,
ref2:
Vaccination of stem cell transplant recipients: recommendations of the
Infectious Diseases Working Party of the EBMTref.
The conditioning regimen used in marrow graft recipients ablates normal
and abnormal immunohematopoietic elements and prepares the marrow microenvironment
for the donor marrow to develop. The repopulation of the immune system
is dependent on appropriate nesting, proliferation, maturation and differentiation
of donor cellsref.
Ultimately, the recipients lose immune memory of exposure to infectious
agents and vaccines accumulated throughout their lives. The loss of protective
immunity to agents such as tetanus, poliovirus, and measles has been consistently
demonstrated in patients submitted to allogeneic and autologous bone marrow
transplantation (BMT), and consequently a reimmunization program is necessary
to ensure immunityref1,
ref2,
ref3,
ref4.
Several surveys regarding reimmunization after BMT have demonstrated that
vaccination protocols vary greatly among BMT centers, with insufficient
data to establish solid recommendationsref1,
ref2,
ref3,
ref4.
The European Group for Blood and Marrow Transplantation, the Centers for
Disease Control and Prevention, the Infectious Disease Society of America,
and the American Society of Blood and Marrow Transplantation have recommended
that the following vaccines be included in reimmunization protocols for
autologous, syngeneic and allogeneic BMT recipients: diphtheria toxoid,
tetanus toxoid, pertussis vaccine (children <7 years old), Haemophilus
influenzae type b (Hib) conjugate, 23-valent pneumococcal polysaccharide,
inactivated influenza vaccine, inactivated polio vaccine and live-attenuated
measles-mumps-rubella vaccineref.
Antibody responses to vaccinations given within the first two years after
transplant are similar between autologous peripheral blood stem cell and
bone marrow transplant recipientsref.
vaccines currently recommended in reimmunization protocols :
vaccines
time after BMT
no. of doses
vaccine type
tetanus and diphtheria
after 4 months (evidence recommends an early start)
3 doses
toxoid
Hemophilus influenzae
after 4 months (evidence recommends an early start)
2 doses
conjugate polysaccharide
polio
after 4 months (evidence recommends an early start)
3 doses
inactivated virus
pneumocococcal
after 12 months
1 dose?
polysaccharide
hepatitis B
after 4 months (evidence recommends an early start)
3 doses
recombinant
influenza
yearly
1 dose/year
inactivated virus
MMR
after 2 years
1 dose
attenuated virus
diphtheria toxoid : immunity
to diphtheria wanes over time. Lum et al.refshowed
that while 100% of the BMT patients with immune donors had antibodies to
diphtheria within the first 100 days after transplantation, about 30% of
them lost immunity thereafter. Increasing susceptibility (up to 40%) was
noticed in those with chronic graft-versus-host disease (GVHD). Other investigators
evaluating long-term diphtheria immunity showed that only 54.5% of the
patients still had antibodies to diphtheria with barely protective antitoxin
levels one year after BMTref.
There is evidence that multiple doses are more effective than a single
dose in allogeneic recipients without chronic GVHD vaccinated 2 to 6 years
after BMTref.
Chronic GVHD seems to interfere with the response to vaccination 4 months
after BMTref.
Although diphtheria vaccination starting one year after transplantation
has been mostly recommended, no definitive data are available concerning
the best time to start vaccination.
tetanus toxoid : there is contrasting
information concerning the persistence of tetanus immunity one year after
BMT. Some investigators have observed sustained immunity in long-term allogeneic
BMT survivors irrespective of toxoid administration pre- or post-transplantationref.
On the other hand, Ljungman et al.ref
observed that only 50% of the patients who were immune prior to transplantation
sustained tetanus immunity for one year. More recently, Parkkali et al.ref
also observed an increasing reduction in the mean concentration of anti-tetanus
antibodies in this population. In the cited study, the patients were randomized
to start early (6 months) or late (18 months) tetanus reimmunization. Before
vaccination, 90% of the patients in the early group were immune to tetanus
in contrast to 70% in the late group. Both schedules were equally immunogenic.
However, in the late group, the recipient's antibody response after the
first and second vaccine doses was correlated with donor's antibody levels,
suggesting that donor immunity affects recipient response to tetanus toxoid.
Acute GVHD does not seem to interfere with the response to tetanus vaccinationref.
Some studies on chronic GVHD did not show an effect on the response to
vaccinationref,
while others suggested that chronic GVHD may interfere with the intensity
of the response (below four-fold rises) or with the duration of tetanus
immunity after vaccinationref1,
ref2.
Although most BMT centers start tetanus immunization one year after transplantation,
currently available information does not justify postponing tetanus immunization
for > 6 months after BMTref.
The correlation of donor antibody levels with the response to tetanus vaccination
indicates that prospective studies randomly vaccinating the donors before
marrow harvesting should be conducted in this setting to better evaluate
the need for donor vaccination in reimmunization programs.
pneumococcal polysaccharide
: BMT recipients are particularly at risk to develop life-threatening pneumococcal
infections due to functional hyposplenism as a result of pre-transplant
total body irradiation and chronic GVHD. The currently available pneumococcal
vaccines are the 14- and 23-valent polysaccharide vaccines and the 7-valent
conjugate vaccine. The polysaccharide vaccines contain only pure polysaccharides
and require mature function of the immune system for a maximal response.
The vaccines are therefore poorly immunogenic in transplant populations.
Moreover, the polysaccharide vaccine does not cover 20% of the commonly
pathogenic strains and immunized patients remain susceptible to themref.
Evaluating a 14-valent pneumococcal vaccine in allogeneic BMT patients,
Winston et al.ref
observed that pre- and post-vaccination levels were significantly lower
in BMT recipients compared to normal control subjects. Multiple regression
analysis showed that vaccination within the early post-transplant period
and corticosteroid therapy of GVHD were the two factors influencing the
antibody response. Other investigators have also observed decreasing pneumococcal
antibody levels over the first year after BMT and a poor antibody response
to a 23-valent pneumococcal vaccineref1,
ref2,
ref3,ref4.
Little information is available regarding the impact of GVHD on the response
to the pneumococcal vaccine since even non-GVHD patients are poor responders.
Immunization of the donors before marrow harvesting did not influence the
level of specific antibodies one year or more after transplantationref1,
ref2.
The data from most of the pneumococcal vaccine studies suggest that the
key factor affecting response is possibly time to vaccination and consequently
vaccination should be recommended after the second year of transplantation
or even laterref1,
ref2.
However, impaired serum opsonic activity is expected during the first year
after transplantation when life-threatening pneumococcal infections pose
a greater risk. Thus, the currently available vaccine is not of substantial
additional help in preventing pneumococcal infection during the first year
post-transplant. Long-term survivors without chronic GVHD are at lower
risk for pneumococcal infection and probably only a few of them would benefit
from vaccination. Among chronic GVHD patients, the use of corticosteroids
affects their response to vaccination, rendering this strategy at least
questionable. The benefit of the new 7-valent pneumococcal conjugate vaccine
has been recently investigated in allogeneic hematopoietic cell transplantation.
Donors were randomized to receive or not one dose of the conjugate vaccine
7 to 10 days before transplantation. The recipients received three doses
of the vaccine at 3, 6 and 12 months after BMT. Protective immunity was
achieved earlier in patients whose donors had been vaccinated, but after
the three doses of the vaccine, protective immunity was similar in the
2 groupsref.
More studies are needed to better evaluate the effectiveness of the conjugate
vaccine in BMT recipients. Due to the limited coverage of pneumococcal
pathogenic strains by the 7-valent conjugate vaccine, prolonged prophylactic
oral penicillin should be associated with the vaccination to prevent pneumococcal
infection after BMT. Opsonophagocytic activity against Streptococcus
pneumoniae type 19F in allogeneic BMT recipients before and after vaccination
with pneumococcal polysaccharide vaccineref.
Haemophilus influenzae
type b conjugate : polysaccharide vaccines were not sufficiently immunogenic
to the immature immune system of children and the preliminary results of
Hib vaccination were disappointing. A new generation of polysaccharide-protein
conjugated vaccines was developed and proved to be more immunogenic in
children and also in BMT patients. The polysaccharide antigen is conjugated
to a protein such as tetanus or diphtheria toxoid or both. Data from Hib
vaccination studies in BMT patients have demonstrated that at least two
doses of the conjugated vaccine are necessary to ensure protective antibody
levelsref1,
ref2.
Comparing multiple Hib vaccination schedules after BMT, Vance et al.ref
observed that protective levels were achieved after the third or second
dose of Hib vaccine in patients starting immunization at 3 or 6 months
after BMT, respectively. Parkkali et al.ref,
using a single dose of diphtheria conjugated Hib vaccine in 45 BMT recipients
randomized to start vaccination at 6 or 18 months, observed that both schedules
were equally immunogenic. Since the greatest risk for infection by encapsulated
bacteria occurs during the first 2 years after BMT, early-start schedules
should be preferred in this setting. Donor and recipient immunization with
Hib vaccine before BMT proved to be more effective than recipient vaccination
after BMT as demonstrated by a higher antibody concentration in patients
as early as 3 months post-transplantationref.
Other investigators showed that between 4 and 18 months after BMT the response
to Hib vaccination did not correlate with GVHD, use of immunosuppressive
drugs or time to vaccinationref.
The results of these studies indicate that at least 2 doses of Hib-conjugated
vaccine can be administered safely and effectively as early as 4 months
after BMT. The impact of donor immunization before marrow harvesting on
the appearance of protective antibody levels soon after BMT must be confirmed
in larger, prospective, randomized trials before being widely recommended.
poliovirus vaccine : immunity to polio is progressively lost after BMT.
Immunocompromised patients and their household contacts should not receive
live-attenuated
oral poliovirus vaccine. Thus, inactivated
poliovirus vaccine (IPV) is recommended after transplantation. Ljungman
et al.ref
demonstrated that 50% of the patients lost immunity to all 3 poliovirus
types 1 year after BMT. Patients who received 3 IPV doses 12, 13 and 14
months after BMT had significantly higher specific antibody titers 1 year
later in comparison to patients who received only one dose. GVHD did not
interfere with the response to vaccination when the 3-dose regimen was
adopted. Other investigators have observed similar findingsref.
More recently, Parkkali et al.ref
compared the response to poliovirus vaccination in 45 patients randomized
to receive IPV at 6, 8 and 14 months (early group) after BMT or at 18,
20 and 26 months (late group). Both schedules were similarly immunogenic.
Acute GVHD accelerated the decrease of poliovirus antibody titers before
vaccination but did not interfere with the response to IPV. Chronic GVHD
did not influence the duration of polio immunity or the response to vaccination.
These data suggest that poliovirus immunization also does not need to be
postponed for more than 6 months after BMT.
measles vaccine : immunity
to measles decreases continuously after BMTref1,
ref2.
Although severe measles is expected to occur in immunocompromised patients,
there are only 2 reports in the literature of measles following transplantationref1,
ref2.
Probabilities of measles immunity of about 47, 27 and 20% have been reported
3, 5 and 7 years after BMT, respectivelyref.
Among non-vaccinated BMT recipients, Machado et al.ref
observed that 36.6% were susceptible to measles between the first and second
year after BMT and this rate increased to 57.7% after the second year.
Type of BMT (allo or auto), acute or chronic GVHD and the use of immunosuppressive
drugs did not influence the persistence of immunity in that series. The
live-attenuated trivalent measles-mumps-rubella vaccine has been administered
safely and effectively after the second year of transplantation. Its use
has been recommended only in patients not receiving immunosuppressive drugsref1,
ref2,
ref3,
ref4.
However, the duration of measles immunity after vaccination and the need
for booster doses deserve further investigation in this population. Among
vaccinated patients, Machado et al.ref
observed that 70% had lost measles immunity 3 years after vaccination,
suggesting that serological surveillance to check for immunity should be
performed in long-term survivors. Moreover, the value and the frequency
of booster doses of the vaccine should be better investigated in patients
who lost measles immunity. It is important to stress that although most
of the recommendations for BMT recipient vaccination are independent of
where in the world the patient lives, there are local variations in the
scenario of infections that must be taken into account and adjustments
in official guidelines are strongly recommendedref.
For example, in 1997, hundreds of BMT recipients were exposed to measles
when > 20,000 cases of measles were diagnosed during an outbreak in the
city of São Paulo, Brazil. 8 patients acquired measles and early
measles vaccination was the strategy used to avoid the appearance of new
measles cases among the patients who had lost specific immunityref.
To evaluate the safety and effectiveness of this strategy, live-attenuated
measles-mumps-rubella vaccine was administered one year after BMT to all
patients, even those receiving immunosuppressive drugs. No moderate or
severe side effect was noted and all susceptible patients responded to
vaccination. The probability of sustained immunity was 60.2% 2 years after
early vaccination (Machado CM, Sumita LM, Rocha IF, Pannuti CS & Souza
VAUF (2002). Early measles vaccination in BMT recipients. The 12th International
Symposium on Infections in the Immunocompromised Host. Bergen, Norway,
June 23-26, 2002). Thus, this strategy can be safely used during outbreaks
in countries that have not achieved measles elimination. Safety of early
immunization against measles/mumps/rubella after bone marrow transplantationref.
Long-term immunity to measles, mumps and rubella after MMR vaccination
among children with bone marrow transplantsref.
During follow-up after allogeneic stem cell transplantation (SCT), patients
frequently lose their immunity to infectious agents such as measles. The
aim of the study was to analyze the influence of different factors on measles
immunity. In total, 395 patients with a disease-free survival of at least
1 year were included. Measles vaccination was given at 2 years after SCT
to children and young adults without chronic GVHD or ongoing immunosuppression.
In all, 264 patients had matched sibling donors and 131 either mismatched
family or unrelated donors. Totally, 318 patients received bone marrow
and 77 peripheral blood stem cells. Overall, 375 patients had undergone
myeloablative and 20 nonmyeloablative conditioning. Out of 395 patients,
133 (34%) were seronegative to measles. In multivariate models, younger
age or being vaccinated to measles, rather than previous measles disease,
before transplantation were risk factors both for becoming seronegative
and to have doubtfully protective immunity to measles. Acute GVHD grade
II-IV was a risk factor for seronegativity and blood stem cells a risk
factor for doubtfully protective immunity. Children and young adults previously
immunized to measles have a high risk for becoming vulnerable to a measles
infection. Since measles is again circulating in many countries and measles
is a serious infection after SCT, vaccination should be consideredref.
measles immunity
years after vaccination (P = 0.049 comparing immune status according
to
time after vaccination (chi-square test).)
total
< 3 years
> 3 years
susceptible
6 (27.3)
7 (70)
13
immune
16 (72.7)
3 (30)
19
total
22 (100)
10 (100)
32
influenza vaccine : few data are available
concerning influenza vaccination after bone marrow transplantation. Engelhard
et al.ref
vaccinated 48 patients with 2 doses of influenza vaccine administered 2
to 82 months after BMT. Vaccination before the 6th month was totally ineffective
and the second dose did not add substantial benefit in terms of specific
response and its indication is therefore questionable. Preliminary results
of a study evaluating the use of GM-CSF (2.5 µg/kg) as an immunomodulating
factor to enhance the response to influenza vaccination showed a limited
benefit, mostly in those vaccinated before the first year after BMT. Since
side effects were not negligible, its use deserves further investigationref.
other vaccines and perspectives
varicella
vaccine : no data are available concerning the safety and effectiveness
of live-attenuated varicella vaccine before the first year of transplantation,
when the risk of varicella- zoster virus (VZV) reactivation is higher.
Sauerberi et al.ref
did not observe any case of chickenpox or herpes zoster for up to 2 years
after vaccination in 15 patients who received one dose of VZV vaccine 12
to 23 months after BMT. These data are difficult to interpret since the
occurrence of zoster is expected around the sixth month after transplantation
and the risk of a second episode is less than 5% in this population. Thus,
few patients would be really "at risk" after the first year of transplantation
and the benefit of late vaccination would be minimal. Redman et al.ref
heat-inactivated the live-attenuated vaccine and observed diminished clinical
severity of zoster in patients who received three doses of the inactivated
vaccine 1, 2 and 3 months after BMT. These data suggested that the process
of inactivation did not eliminate the immunogenicity of the vaccine, which
apparently conferred some protection. Based on this observation, Hata et
al.ref
recently demonstrated that 4 doses of the inactivated varicella vaccine
given before hematopoietic cell transplantation and during the first 90
days thereafter (1 dose at +30, +60 and +90) reduced the risk of zoster
in autologous BMT recipients. The protection was correlated with the reconstitution
of CD4 T cell immunity against VZV. The safety and effectiveness of the
attenuated varicella vaccine administered to recipients during the first
6 months after autologous and allogeneic BMT remain to be demonstrated
in controlled trials.
other licensed vaccines have been recommended on an individual basis.
hepatitis B vaccine has been recommended after
the first year of BMT in countries where the infection is common and children
are routinely immunized against hepatitis B. In the setting of BMT, hepatitis
B vaccine has been evaluated in different circumstances: to immunize susceptible
patients after transplantation and also to adoptively transfer hepatitis
B immunity through vaccination of the donors before marrow harvesting.
Surprisingly, few data are available concerning the effectiveness of hepatitis
B vaccine in BMT recipients and the duration of immunity after vaccination.
Nagler et al.ref
observed seroconversion rates of about 70% within 40 days of transplantation
in autologous BMT recipients receiving a single dose of hepatitis B vaccine
immediately before or after transplantation. Transient seroconversion was
seen in about 35% of the patients. Ilan et al.ref
demonstrated transfer of hepatitis B immunity in the first 45 days of transplantation
from donors vaccinated before marrow harvesting. Adopting the classical
vaccination schedule proposed for immunocompetent hosts, Machado et al.
(Machado CM, Rocha IF, Diomede B et al. (1996). Effectiveness of hepatitis
B vaccination and persistence of immunity after BMT (Abstract). The Ninth
International Symposium on Infections in the Immunocompromised Host. Assisi,
Italy, June 23-26, 1996) observed 100% seroconversion in 50 patients vaccinated
after the first year of BMT. However, one year after vaccination nearly
60% of the patients had lost hepatitis B immunity. Sustained immunity was
more likely to occur in children and in subjects without chronic GVHD.
Interestingly, time to vaccination did not influence the response to vaccination
or the duration of immunity, suggesting that no benefit is added by postponing
hepatitis B vaccination after the first year of BMT. Maintenance of immune
memory to the hepatitis B envelope protein following adoptive transfer
of immunity in bone marrow transplant recipientsref.
The EBMT recommends rHBV starting 6-12 months after HCT. Immunization is
optional in the CDC guidelines. Nevertheless, rHBV is required for re-entry
to school and certain workplaces. To determine the immunogenicity of rHBV
following HCT, the pre and post vaccine titers of 292 allogeneic transplant
recipients who were immunized with rHBV were analyzed. Immunization was
initiated in patients off immunosuppression who achieved specific minimal
milestones of immune competence. Overall, 64% of patients seroconverted.
In multivariate analyses, response was adversely affected by age >18
years (p<0.01) and history of prior chronic GVHD (p<0.0001) but not
by donor type, use of T cell depletion, adoptive immunotherapy, or rituximab.
By comparison, 89% of rHBV non-responders mounted a 3 fold rise in polio
titers following 3 doses of inactivated poliovirus. These data demonstrate
that the rate of seroconversion following rHBV is lower in allogeneic HCT
recipients compared with age matched normal controls. The data emphasize
the need to document pre and post vaccine titers to ensure response and
suggest that immunization guidelines based on time interval from HCT, irrespective
of immune competence, may not ensure adequate protection against certain
vaccine preventable diseasesref.
there are no data on the use of inactivated
hepatitis A vaccine in transplant recipients. Considering the efficacy
of the vaccine in healthy subjects and the recommendation of vaccination
to travelers to endemic areasref,
studies evaluating the safety and effectiveness of hepatitis A vaccine
would be of great importance in this population. Children submitted to
BMT and recipients traveling to such areas would benefit from hepatitis
A vaccination.
"herd immunity" states that when enough people in a community are
immunized, all are protected. For the MMR vaccine, that proportion is 95%.
Anyway, there are many documented instances showing just the opposite,
i.e. fully vaccinated populations do contract diseases (measles, Hib meningitis,
...)
epidemiological studies : if 100 people are vaccinated and 5 contract
the disease, the vaccine is declared to be 95% effective. But if only 10
of the 100 were actually exposed to the disease, then the vaccine was really
only 50% effective. Since no one is willing to directly expose an entire
population to disease--even a fully vaccinated one--vaccine effectiveness
rates may not indicate a vaccine's true effectiveness.
age : an 8 pound 2 month old child receives the same dosage as a
40 pound 5 year old : infants with immature, undeveloped immune systems
may receive 5 or more times the dosage (relative to body weight) as older
children !
the number of "units" within doses has been found upon random testing
to range from 1/2 to 3 times what the label indicates; manufacturing quality
controls appear to tolerate a rather large margin of error. "Hot Lots"
(vaccine lots with disproportionately high death and disability rates)
have been identified repeatedly by the NVIC, but the FDA has never recalled
a vaccine lot due to adverse reactions : some would call this infanticide.
race, culture, diet, geographic location of recipients
this was perhaps never more dramatically disproved than an instance a few
years ago in Australia's Northern Territory, where stepped-up immunization
campaigns resulted in an incredible 50% infant mortality rate in the native
aborigines. The aborigine's vitamin C deficient "junk food" diet
(imposed on them by white society) was a critical factor (vaccination depletes
vitamin C reserves; children in shock or collapse often recovered in a
matter of minutes when given vitamin C injections).
the risk of contracting polio from the vaccine correlates with injections
of antibiotics : a single injection within one month of vaccination
raised the risk of polio 8 times, 2 to 9 injections raised the risk 27-fold,
and 10 or more injections raised the risk 182 times.
Copyright © 2001-2005 Daniele Focosi.
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