HPV vacunas y prevencion del cancer de cuello

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10.1146/annurev.med.55.091902.103520
Annu. Rev. Med. 2004. 55:319–31
doi: 10.1146/annurev.med.55.091902.103520
Copyright c© 2004 by Annual Reviews. All rights reserved
HUMAN PAPILLOMAVIRUS VACCINES AND
PREVENTION OF CERVICAL CANCER
Kathrin U. Jansen and Alan R. Shaw
Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486;
email: kathrin jansen@merck.com; alanshaw@merck.com
Key Words virus-like particle vaccines, vaccine delivery, proof-of-concept,
clinical endpoints
■ Abstract Cervical cancer and precancerous cervical lesions constitute a major
problem in women’s health. Every year 470,000 cases of cervical cancer are diagnosed
worldwide, and about half the women afflicted will die. In the United States alone,
∼14,000 cases of cervical cancer are diagnosed each year despite the availability of
screening and access to high-quality gynecological care. With the confirmation that
cervical cancer is caused by an infectious agent, human papillomavirus, the possibility
of fighting this disease with either prophylactic or therapeutic vaccination arose. This
review describes advances in vaccine development and very promising first results for
prophylactic vaccination against cervical cancer.
INTRODUCTION
Cervical cancer and precancerous cervical lesions constitute a major problem in
women’s health. Every year 470,000 cases of cervical cancer are diagnosed world-
wide, and about half the women afflicted will die. The prevalence of cervical cancer
is estimated to be 1.4 million cases worldwide (1). A substantial proportion of mod-
ern gynecological effort and expense is devoted to the detection and treatment of
cervical dysplasias and cervical cancer. In the United States alone,∼50 million
Pap tests are performed each year, and they discover∼1.2 million cases of low-
grade dysplasia (CIN1),∼300,000 cases of high-grade dysplasia (CIN2/3), and
∼14.000 cases of cervical cancer (2). The total health care cost associated with the
screening and treatment of cervical cancer in the United States is estimated to be
$6 billion per year. Despite this screening and treatment,∼5000 women die from
the disease each year in the United States. In areas of the world where most women
do not have access to regular, high-quality gynecological care and screening, cer-
vical cancer is second only to breast cancer as a cancer-related cause of death (1).
Four times as many cases of cervical cancer occur in the developing world as in
more developed countries. Although screening has dramatically reduced the inci-
dence of the disease in the developed world, it is still overall only∼75% effective.
0066-4219/04/0218-0319$14.00 319
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A VIRUS THAT CAUSES CANCER
The etiology of cervical dysplasia and cancer was unclear for a long time. Environ-
mental factors as well as smoking and alcohol consumption have received attention.
Further study focused on candidate sexually transmitted infectious agents such as
Chlamydia, Neisseria gonorrhea, and particularly Herpes simplex virus. Starting
in the early 1980s, several lines of investigation converged on the human papillo-
maviruses (HPVs) as the primary suspects to cause cervical cancer. The important
steps in this convergence were as follows:
1. Finding HPV genomes in cervical carcinomas and cloning the viruses (3).
The advent of more sophisticated detection technologies, such as polymerase
chain reaction (PCR), greatly aided the detection of HPV in cancer speci-
mens. 99.7% of all cervical cancers harbor HPV types (4).
2. Defining HPVs as a large family of closely related viruses. Over 80 HPV
types have now been identified, of which 40 infect the genital tract (5).
3. Elucidating the mechanisms of transformation. During the 1990s, several
teams of investigators demonstrated that HPV is a true “tumor virus” in
that it carries genes encoding multiple proteins that interfere with cell-cycle
control, leading to transformation and uncontrolled cell growth (6).
4. Demonstrating that infection with rabbit and bovine papillomavirus can
cause tumors in rabbits and cows (7, 8).
5. Completing epidemiological case-control studies (9–12) in humans that sup-
plied sufficient evidence to prompt the International Agency for Research
on Cancer (IARC) to declare HPV types 16 and 18 human carcinogens
in 1995. Recently, IARC published data from their pooled 11 case-control
studies suggesting that an additional 13 HPV types should be considered
carcinogens (13).
This body of information was slow to develop, and its evolution depended on
advances in cellular, molecular, and immunological diagnostic technologies that
have occurred during the past 20 years.
VIRUS GENETICS, MOLECULAR BIOLOGY,
AND LIFE CYCLE
HPVs are small, nonenveloped viruses with relatively small (∼8 kb pairs), double-
stranded circular DNA genomes (6). As members of the papovavirus family, they
share numerous characteristics with the better-known examples, SV40 and poly-
oma virus. The HPV genome codes for only eight proteins. The late L1 and L2
genes code for the virus capsid proteins, early proteins E1 and E2 are responsi-
ble for viral replication and transcription, and E4 seems to aid virus release from
infected cells (14). HPVs are DNA tumor viruses that also encode proteins that
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CERVICAL CANCER VACCINES 321
interfere with the activity of host cell-cycle–regulating proteins such as RB and
p53, among others. HPV early proteins E6 and E7 inhibit or target for destruction
cellular proteins RB and p53, and E5 has also been implicated in cellular transfor-
mation (15). There is now ample evidence that HPV has the tools to cause cancer
based on molecular mechanisms alone.
To date, over 80 genotypes of HPV have been described (5). Genotyping of
HPV is based on DNA sequences of the L1, E6, and E7 genes. A 10% difference
in sequence with respect to previously established strains is sufficient to define a
new type of virus. HPV has also been associated with several cutaneous hyper-
plastic conditions, including common warts of the hands and feet (types 1, 2, and
4), genital warts and recurrent respiratory papillomatosis (types 6 and 11), epider-
modysplasia verruciformis (types 5 and 8), and anal as well as cervical carcinomas
and adenocarcinomas (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and
73). Although many HPV types are known, only a few of them cause the vast
majority of disease. HPV types 16 and 18 are responsible for>70% of all cervical
cancer cases, followed by HPV types 31 and 45 (4), which cause an additional 10%
of cases. Two additional HPV types, HPV6 and 11, are not considered high-risk
or oncogenic types but are responsible for>90% of all anogenital warts in men
and women (16).
In general, HPV infects the basal cells of a human epithelial surface (17).
Infected basal cells divide; some progeny remain as infected basal cells while
others, also infected, move away from the basement membrane, differentiate, and
become epithelial cells. Virus replication and assembly is tightly linked to the
differentiation program of the epithelial cell. Infectious virions are produced only
in the terminally differentiated cell and are shed as virus-laden squames. This
explains why HPV cannot grow in tissue culture. Over the years, various methods—
including the nude mouse (18, 19) and SCID mouse (20) xenograft systems as well
as raft-culture systems (21)—have achieved limited propagation of infectious virus
for some HPV types, but the lack of a convenient culture system has hampered
vaccine development.
EPIDEMIOLOGY OF HUMAN PAPILLOMAVIRUS
By infecting only the cells of the basal layer and executing virus replication and
assembly only in a fully differentiated cell that is destined to die, the virus avoids
the immune system of the host.The success of this strategy is documented by the
very poor immune responses (humoral as well as cell-mediated) to HPV infection.
However, most HPV infections seem ultimately controlled and eliminated by an
immune response. The nature of this response is still under investigation. Infections
that are not controlled and persist for a long time can cause more severe pathologies
and, ultimately, cancer (22).
Infection in both women and men is clearly related to sexual activity (23, 24).
For women, the most striking risk factors for HPV infection and development
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of detectable pathology are numerous lifetime sexual partners and early onset of
sexual activity. Although women bear the brunt of dysplasias and cancer, HPV-
related carcinomas of the anal mucosa are relatively frequent in men having sex
with men (25), and the rate seems to be increasing. A third group at risk for severe
HPV infections are neonates. At birth, neonates sometimes acquire HPV types 11
and 6 from the infected birth canal of their mother. HPV can infect the mucosa of the
pharynx and cause large wart-like growths that can obstruct the airway. Recurrent
respiratory papillomatosis is rare but potentially life-threatening. Patients with this
condition undergo multiple surgical procedures each year in order to breathe and
speak (26–29).
APPROACHES TO A VACCINE AND CURRENT
CLINICAL STATUS
Multiple approaches are being tried in the quest for an effective vaccine. An ex-
cellent review of the status of the field, citing company websites and other internet
sources, was published in July 2000 (30). However, much progress has occurred
since then.
There are two major alternatives to consider when one sets out to make a vaccine
against HPV. Should one strive to prevent infection by creating a prophylactic vac-
cine, or should one focus on a therapeutic vaccine for individuals already infected?
Although vaccines in the classical sense are prophylactic, as are all currently li-
censed vaccines, multiple groups are pursuing a therapeutic vaccine. Depending
on the approach, the choice of viral antigens to use as immunogens as well as
the choice of an appropriate delivery system could be quite different. Prophylactic
vaccines are simpler in that they need only to raise an immune response sufficient
to limit infection and prevent clinical disease. A therapeutic vaccine must elicit an
immune response that can clear an already established infection. This requires a
vaccine to make the immune system do something it has failed to do during the pri-
mary infection. In other words, the therapeutic vaccine has to do better than nature.
In the case of HPV, antigens to be presented fall into two general classes: the
early proteins, which do not become part of the virion but are expressed at some
level in infected cells, and the late proteins, which make up the virus coat (6). For
a successful therapeutic vaccine, the chosen antigens should be expressed in every
infected cell and the vaccine should induce an immune response that mobilizes
the cell-mediated arm of the immune system to rid the body of virally infected
cells. Primary target antigens for a therapeutic vaccine are the oncoproteins E6
and E7 because they are expressed throughout the life cycle of HPV as well as in
cancer cells. Additional targets are the E1 and E2 proteins associated with viral
replication/transcription.
For a successful prophylactic vaccine, the obvious target antigens would be
the capsid proteins because they are the only antigens accessible for a classical
neutralizing antibody response to prevent infection. Delivery of these antigens
results in the mobilization of the humoral arm of the immune system and induces
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a strong, long-lasting, virus-neutralizing antibody response. This is not to say that
early viral antigens might not also be useful. Early work by Christensen & Kreider
demonstrated that antibodies against the L1 capsid protein neutralized HPV11
in a nude-mouse xenograft system (31). However, the prophylactic vaccine field
really took off in 1991, after Zhou et al. demonstrated that the HPV16 L1 capsid
protein, when expressed in a recombinant system, forms virus-like particles (VLPs)
resembling native virions (32). Numerous groups have now shown the successful
expression of L1 VLPs from a number of HPV types.
Unfortunately, because papillomavirus infection is species-specific, there is
no HPV disease model. Preclinical animal papillomavirus models have helped
to assess the feasibility of the various vaccine approaches. The cottontail rabbit
has a naturally occurring papillomavirus that causes large, pigmented, exophytic
skin warts. This model is widely favored for its convenience, simplicity, and re-
producibility. Both therapeutic and prophylactic cottontail rabbit papillomavirus
vaccines have been tested successfully (33, 34).
Several bovine papillomaviruses (BPVs) have been useful. The well-known
BPV1 can be used to transform mouse C127 cells grown in tissue culture. It causes
skin growths analogous to those of the rabbit. BPV4 causes papillomas of the
digestive tract in cows. These mucosal lesions are somewhat closer to the disease
targeted for a vaccine in humans. Prophylactic vaccination has been observed
to prevent BPV disease, and therapeutic vaccination has ameliorated established
warts (35, 36).
The dog, particularly the beagle, develops wart-like growths on the lips and
gums caused by canine oral papillomavirus. This is a transient condition that
blooms and resolves in a matter of weeks. In these animals, too, vaccination has
been shown to prevent infection and disease (37, 38).
For therapeutic vaccines, mouse models that use tumor cells expressing viral
antigens have also shown success (39, 40). However, mouse and other animal
models do not necessarily predict whether a particular approach will work in
nonhuman primates or humans.
ANTIGEN DELIVERY
Naked DNA
In the early 1990s, it was shown that injecting the gene for an antigen, surrounded
by the appropriate control signals, in the context of a plasmid, could raise a cel-
lular and humoral response against the antigen (41). Vaccination of rabbits with a
cottontail rabbit papillomavirus L1 DNA construct was shown to protect rabbits
from papillomavirus infection and wart formation (42). The naked DNA approach
has several advantages. It is simple, it is relatively quick to develop, and the same
methods can be applied to almost any antigen, carbohydrates being the major ex-
ception. Naked DNA was examined as a therapeutic as well as prophylactic vaccine
by several groups and showed promise in preclinical models. However, results in
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humans and nonhuman primates were disappointing; multiple very high doses of
naked DNA vaccines are required to elicit immune responses.
Vectored Gene Delivery
The relative inefficiency of naked DNA led to the next step of delivering the antigen
coding sequence in a viral vector. This allows the antigen gene to enter cells more
efficiently, and it permits targeting to particular cell types; different virus vectors
have different cell tropisms.
One of the first vaccines into the clinic was vaccinia virus expressing the trans-
forming proteins E6 and E7 of HPV types 16 and 18 (43, 44). This vaccine was
intended as a therapeutic adjunct to traditional cervical cancer therapy. Though
discontinued for cancer therapy, it is still under evaluation for its ability to ame-
liorate cervical dysplasia. Vaccinia is also being used in two Chinese development
programs delivering genes for either HPV16 or 58 L1 fused to their respective E7
genes. HPV 58 is highly prevalent in China. A highly attenuated form of vaccinia,
modified vaccinia Ankara, is being developedby Transgene S.A. as a vehicle for
the codelivery of HPV genes and the gene for interleukin-2. Addition of IL-2 to
the vaccine is intended to boost the T-cell response of the host.
Our group looked preclinically at a replication-deficient adenovirus expressing
HPV16 L1 and compared it to DNA and VLP immunization by evaluating hu-
moral as well as cell-mediated immune responses in rhesus macaques. Although
the recombinant adenovirus induced strong cell-mediated immune responses, it
induced a weaker neutralizing antibody response than VLPs did (45).
Fusion Proteins
Preclinical experiments in cattle, using fusion proteins between the minor capsid
protein L2 and the oncogene E7, suggested that vaccination with such a fusion
protein and an appropriate adjuvant could ameliorate disease. A human version of
the vaccine targeting HPV6 was licensed and tested by Glaxo SmithKline for the
treatment of genital warts. This approach demonstrated no efficacy and the vaccine
was abandoned. A second fusion-protein vaccine had a similar fate. MediGene AG
tested an HPV16 chimeric VLP in which the HPV16 L1 capsid protein was fused
to the E7 protein in 36 patients with cervical cancer. MediGene recently announced
the discontinuation of this approach because the phase I/II trial results did not fulfill
its predetermined efficacy criteria. HPV16 immune responses, however, were de-
tected in immunized patients. A third approach using a fusion protein of a Bacillus
Calmette-Guerin (BCG) heat-shock protein with E7 (Stressgen Biotechnologies
Corp.) is still being evaluated clinically against high-grade cervical dysplasia.
Virus-Like Particles
Expression of the capsid or virus-coat protein genes of certain viruses in a
heterologous system, such as yeast or insect cells, produces a VLP through
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self-directed assembly of the recombinant protein. Hepatitis B surface antigen
was the first example of a VLP that became a commercially viable vaccine. As
mentioned above, Zhou et al. (32) were the first to report that the HPV major
capsid protein L1, expressed in a recombinant system, self-assembles into a VLP.
Preclinical efficacy was demonstrated using VLPs formulated on aluminum adju-
vants. They induced a strong virus-neutralizing antibody response in nonhuman
primates (46, 47). Preclinical results were confirmed by several phase I studies that
tested the immunogenicity and safety of monovalent VLP-based vaccines. These
vaccines were generally well tolerated and generated high levels of neutralizing
antibodies (48–50).
These initial results were encouraging, but would such a vaccine actually pre-
vent HPV infection? After all, the antibody response induced by the VLP-based
vaccine is generated systemically, whereas the target cells for HPV infection are
epithelial cells of the genital tract. Therefore, the proposition that systemic an-
tibody may prevent local infection of the genital mucosa was untested. We de-
signed a double-blind, placebo-controlled proof-of-concept study to answer this
question (51). Young women (n = 2392) were assigned to receive placebo or
yeast-derived HPV16 L1 VLPs (40-µg dose) formulated on Merck aluminum
adjuvant at day 0, month 2, and month 6 by intramuscular injection. Samples
from the genital tract were obtained at enrollment, one month after the booster
immunization, and every six months thereafter. In addition, the women under-
went gynecological examinations and were referred for colposcopy according to
protocol. Biopsy tissue was evaluated for intraepithelial neoplasia and analyzed
by PCR for the presence of HPV16 DNA. DNA was prepared from the speci-
mens using routine methods. HPV16 DNA was amplified by PCR using type-
and gene-specific primers for the HPV16 L1, E6, and E7 genes. PCR products
were visualized by dot-blot hybridization using type- and gene-specific oligonu-
cleotides. The assays were validated to have a 95% probability to detect 13 copies
of HPV16 DNA per sample. The primary endpoint of the trial was persistent
HPV16 infection, defined by (a) HPV16 DNA detection in samples obtained at
two or more visits at least four months apart; (b) a cervical biopsy showing cer-
vical intraepithelial neoplasia or cancer and HPV16 DNA in the biopsy and in
a genital sample collected at the antecedent or subsequent visit; or (c) HPV16
DNA detected in a sample collected during the last visit before being lost to
follow-up.
Women were followed for a median of 17.4 months after completion of the
vaccination regimen, at which time 41 cases of persistent HPV16 infection were
accrued. All 41 cases occurred in the placebo group, none in the vaccine group. Of
these 41 cases, 31 were persistent HPV16 infection, 5 were HPV16-related CIN 1,
4 were HPV16-related CIN2, and 1 occurred in a woman who first tested positive
for HPV16 on the last visit before she was lost to follow-up. These results translate
to 100% efficacy (95% confidence interval, 90–100;p< 0.001). Since all 9 cases
of HPV16-related CIN were in the placebo group, there is great hope that an HPV
VLP-based vaccine may reduce the incidence of cervical cancer.
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Merck is currently conducting phase III clinical trials to assess the efficacy of
a quadrivalent HPV vaccine covering HPV types 16 and 18 as well as types 6
and 11. The National Cancer Institute and Glaxo SmithKline are slated to start
phase III clinical trials at the end of 2003 with a bivalent VLP-based vaccine
covering HPV types 16 and 18 (51a).
From a technical perspective, vaccination with VLPs appears promising. Nev-
ertheless, several practical issues must be addressed before these vaccines can be
licensed and deployed in clinical practice and public health programs.
PRACTICAL ISSUES
Is Prevention of Persistent Infection an Acceptable
Clinical Endpoint for a Phase III Study and Licensure?
Epidemiological studies have established that persistent infection with HPV is a
prerequisite for the development of the vast majority of high-grade dysplasia and
cervical cancer. Therefore, one would logically assume that a vaccine preventing
HPV infection would prevent cervical cancer. In the current regulatory environ-
ment, if one wishes to claim in the vaccine’s labeling that it prevents cancer, one
must actually demonstrate prevention of cancer or at least a defined precursor, not
just infection. This was the view of the U.S. Food and Drug Administration’s Exter-
nal Advisory Committee at a recent review of several HPV-vaccine projects (52).
Given the frequency of self-clearance of infection and self-resolution of early-
grade lesions, an efficacy study measuring prevention of clinical lesions rather
than infection is not an unreasonable requirement. Clinical trials generally take
place in an environment where there is an established “standard of care” for the dis-
ease to be addressed. Ethically, any deviation from this standard of care would put
trial participants at unacceptable risk. Because high-grade dysplasia (CIN2/3) is re-
garded as a direct precursor to cervical cancer and must be treated, a cervical cancer
endpoint would be unethical. An appropriate compromise is to use the appearance
of CIN2/3 lesions related to vaccine types as an endpoint in a placebo-controlled
study. Because true CIN2/3 lesions are relatively rare in current practice (53), the
phase III trial now under way will need to include tens of thousands of volunteers.
Public Health Aspects of HPV Vaccination
Assuming that the great promise seen in Merck’s proof-of-concept study is borne
out in the phase III trials, a vaccine against HPV infection and disease should
become available in several years. However, there are several questions that will
generate substantial debate.
WHEN TO VACCINATE? Current clinical studies are focused on young women in
their late teens and early twenties, oftenin university settings. Entry into university
is generally associated with increased sexual activity, and students tend to stay in
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CERVICAL CANCER VACCINES 327
one place for at least a few years, making follow-up more practical. Realistically,
however, entry into university is frequently later than onset of sexual activity. A
recent study published inCommunicable Disease Reports(54) shows the rates of
diagnosis of genital warts (first attack) in English and Welsh clinics by age and
gender. The data suggest that vaccination of adolescents aged 10–12 years would
be most desirable to control HPV infection and disease, since it is most likely that
this population is still uninfected.
Experience with vaccines in general has shown that the most efficient way to get
as many people vaccinated as possible is to vaccinate them when they are infants.
Public health programs have shown that coverage is best for pediatric programs
and less successful in adults. A further advantage is that immune responses to
vaccines are generally better in children. Because the duration of a protective
immune response after immunization with VLP-based vaccines is not yet known,
it remains to be seen whether effective infant immunization could be achieved. It
also would further crowd the already intense infant-vaccination schedule.
WHAT ABOUT MALES? Clinical studies to date have focused on females because
women suffer most from the pathology of HPV infection. Males, however, are the
vectors. With the notable exception of penile warts and some cases of penile and
anal cancer, there is little obvious pathology associated with HPV in heterosexual
males. HPV is very difficult to detect in this population. This is partly because of the
lack (until recently) of an acceptable method of sampling. Men having sex with men
do suffer from anal intraepithelial neoplasia. The anal epithelium has a transition
zone similar to that of the cervix, and this is the most frequent site of HPV disease
in this group. Since vaccines work best when given to large proportions of the pop-
ulation, vaccination trials to show some efficacy in men are also being considered.
We can learn from our experience with rubella vaccination. When effective
rubella vaccines became available in the 1970s, some public health authorities
chose to vaccinate only girls, in some cases not until their early teens. This seemed
reasonable because the main deleterious consequence of rubella infection was fetal
rubella syndrome, a major cause of devastating birth defects. Vaccinating women
before childbearing age should have been sufficient. However, experience, best
documented in Sweden, showed that sex-specific vaccination was not an effective
policy. Only when both boys and girls were vaccinated in the first years of life did
rubella and fetal rubella syndrome essentially vanish (55).
MARKETING A VACCINE FOR A SEXUALLY TRANSMITTED DISEASE Even if HPV
vaccines are shown to be safe and effective, marketing a vaccine against a sexually
transmitted disease to the general public may be problematic. The public health
and health economic benefits are likely to be considerable. Public health authori-
ties would most likely recommend a vaccine that would prevent cervical cancer, at
least for women. Parental resistance, however, can easily be imagined: “Why does
my child need to be vaccinated against this pathogen? She/he won’t be sexually
active for a long time. Let’s hold off on this until later.” The most effective strategy
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will be to maintain philosophical distance from the sexual aspects of the question
and focus on the prevention of a common cause of cancer.
IMPLEMENTING HPV VACCINATION IN THE DEVELOPING WORLD Cervical cancer
screening and access to high-quality gynecological care are limited for women
in developing countries, yet∼80% of cases occur in these parts of the world. An
effective prophylactic vaccine would have an enormous impact on women’s health,
if it could be delivered.
Three major issues must be resolved in order to take full advantage of the
promise of HPV vaccines. First, the global infrastructure must be reinforced to
accommodate the logistics of delivery of a new vaccine to a, perhaps, nonpediatric
population. This is a rather tall order, and in practice, this may become a pediatric
vaccine in developing countries even if the developed world makes a different
choice. There is no adolescent vaccination visit in most parts of the world. The
World Health Organization’s Expanded Program for Immunization delivers the
“basic six” vaccines (diphtheria, tetanus, pertussis, polio, measles and BCG) to a
large fraction of the world’s birth cohort. If effective immunity could be shown
to last into adulthood, then pediatric administration may be the easier solution for
developing countries.
Second, the capacity for producing these vaccines on a global scale must be
created. The “chicken-and-egg” aspect of this problem might not be obvious to
those outside the vaccine industry. In order to justify the capital and other ancillary
investments necessary to create manufacturing capacity approximately ten times
greater than one might normally contemplate, there must be some reasonable
assurance of a market for the product.
This is tightly linked to the third issue, funding. Today, in 2003, most of the
developing world’s vaccines are paid for by governmental or international donor
agencies. Until recently, the vaccines provided through this funding mechanism
have been “traditional” vaccines such as the basic six above. In the past few years,
there has been a growing uptake of hepatitis B vaccine and conjugated polysaccha-
ride vaccine againstHaemophilusinfluenza. This expansion has been greatly aided
by funding from the Gates Foundation and an overall reinvigorated interest in vac-
cines. To deliver an HPV vaccine for cervical cancer to the women in greatest need,
many of whom live in the very poorest countries, one can only hope that industry,
governments, and donor organizations will make similar efforts and alliances.
The Annual Review of Medicineis online at http://med.annualreviews.org
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