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HPV Vaccine

  1. Stephen Inglis

Published Online: 15 DEC 2009

DOI: 10.1002/9780470015902.a0021551

eLS

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How to Cite

Inglis, S. 2009. HPV Vaccine. eLS.

Author Information

  1. National Institute for Biological Standards and Control, South Mimms, Potters Bar, United Kingdom

Publication History

  1. Published Online: 15 DEC 2009

Introduction

  1. Top of page
  2. Introduction
  3. Vaccine Targets
  4. Vaccine Design: Conceptual and Practical Challenges
  5. Prophylactic Vaccine Candidates
  6. Licensed Vaccines
  7. References
  8. Further Reading

Serious interest in the development of human papillomavirus (HPV) vaccines began with the discovery in the mid-1970s of a strong association between certain virus types and cervical cancer (Zur Hausen et al., 1974). It had been clear for many years from epidemiological data that the disease was very likely associated with an infectious agent, but the exact cause was finally pinpointed by the discovery of papillomavirus-related deoxyribonucleic acid (DNA) consistently in tumour tissues. This sparked a period of intense research to characterize the viruses associated with tumours and to work out their natural history using the newly available techniques of molecular biology. Together with parallel research on other papillomaviruses causing disease in humans and animals, this provided the intellectual framework and the practical tools for the development of vaccines against HPV disease from approximately 1990 onwards. The next 15 years, a relatively short time in the context of vaccine development, witnessed a remarkably successful programme of commercial research and development culminating in the licensure of two HPV vaccines aimed at preventing cervical cancer and genital warts. See also Vaccination

There is also significant interest in the idea of eliminating pre-existing infection through therapeutic vaccination, based on some encouraging data in experimental models. Clinical development of therapeutic vaccines is considerably less well advanced, however, and will not be considered here.

Vaccine Targets

  1. Top of page
  2. Introduction
  3. Vaccine Targets
  4. Vaccine Design: Conceptual and Practical Challenges
  5. Prophylactic Vaccine Candidates
  6. Licensed Vaccines
  7. References
  8. Further Reading

Papillomaviruses are small (approximately 60 nm) nonenveloped viruses containing a double-stranded DNA genome wrapped in an icosahedral shell consisting of just two protein subunits, the major L1 capsid protein and the minor L2 capsid protein (Howley and Lowy, 2007). The genome encodes a small number of other proteins, E1–E7 that do not form part of the virus particle but are required for replication in infected cells. The viruses are unusual in that their replication is restricted to the epithelium (Howley and Lowy, 2007). See also Papillomaviruses

There are a very large number of different papillomaviruses affecting many species including humans. Within the HPV family there are over 100 virus types defined on the basis of sequence similarity (Howley and Lowy, 2007); divergence in the L1 gene sequence of more than 10% represents a different virus type. These different virus types are associated with different patterns and types of human disease. In broad terms they can be divided into those that affect the cutaneous epithelium, causing for example common warts, and those that affect mucosal epithelia. From a clinical and vaccine development perspective, the mucosal viruses are the most important, with the principal disease targets being cervical cancer and genital warts (Figure 1).

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Figure 1. Principal disease targets for HPV vaccination. (a) Courtesy of Professor Margaret Stanley and (b) courtesy of Professor Charles Lacey.

Cervical cancer

Cancer of the cervix is the second most important tumour in women worldwide with some 500 000 new cases diagnosed and over 250 000 deaths each year (Parkin and Bray, 2006). In developed countries the introduction of routine cervical screening for women considered at greatest risk from cervical cancer has been very successful in reducing disease incidence. Most developing tumours can be detected at an early stage before becoming invasive and can be successfully treated by a variety of techniques designed to destroy the affected tissue. Even with screening, however, there is still significant mortality from the disease (approximately 1000 deaths in the UK in 2006). In addition early stage cancer is itself an unpleasant and distressing condition, and the treatment options are not without some risks.

HPV DNA is found in virtually all cervical cancers, but the disease is particularly associated with a specific subset of virus types (Munoz et al., 2004). The pattern of association with different virus types does vary to some extent geographically, but HPV16 and HPV18 are by far the most commonly detected in cancers worldwide, accounting for just over 70% of all cervical tumours. A number of other HPV types also cause tumours to a greater or lesser extent. These viruses are described as ‘high risk’, based on their oncogenic potential (Table 1).

Table 1. Association of most common ‘high risk’ HPV types with cervical cancer worldwide (Munoz et al., 2004)
 Attributable (%)Cumulative (%)
HPV 1653.553.5
HPV 1817.270.7
HPV 456.777.4
HPV 312.980.3
HPV 332.682.9
HPV 522.385.2
HPV 582.287.4
HPV 351.488.8
HPV 591.390.2
HPV 561.291.4
HPV 511.092.4
HPV 390.793.1

Many of these high-risk HPV types fall into two genetic clusters (clade A7 – types 18, 39, 45, 59 and clade A9 – types 16, 31, 33, 35, 52, 58) (Chan et al., 1995). The extent to which this genetic relatedness may translate into immunological cross reactivity is of course a critical question for vaccine design.

Cervical cancer is the culmination of a long process, often 10–20 years that begins with chronic infection of the cells on the surface of the cervix. This leads initially to cellular abnormalities that can be detected by cytological examination of cells taken from the mucosal surface of the cervix (the cervical smear or ‘Pap’ test), or by histological analysis of biopsied tissue. This condition may persist over many years and progress from a mild- or low-grade state (cervical intraepithelial neoplasia (CIN) stage 1) to an advanced or high-grade state (CIN stage 2/3) (Figure 2). Low grade lesions are associated with both high-risk virus types and low-risk types that are rarely or never found in invasive tumours. Most of these regress naturally. Some, however, particularly those containing high-risk virus types can progress to high-grade disease. These high-grade lesions have a significant probability of progressing further to the point where the abnormal cells acquire invasive potential, spread beyond the cervical epithelium and cause malignant disease. Hence high-grade disease, if detected by cervical screening, is treated by removing or destroying the area affected. Most cases of cervical cancer originate from squamous cells of the ectocervix, but a significant and growing proportion are adenocarcinomas, derived from the mucus-producing cells of the endocervix. The early stages of this disease can also be detected by cytology (adenocarcinoma in situ, AIS). These tumours tend to be more rapidly progressing and are often associated with HPV18 and its close relatives.

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Figure 2. Histological changes associated with progression to cervical cancer. Courtesy of Professor Margaret Stanley.

Genital warts

Anogenital warts, or condyloma acuminata is a very common sexually transmitted disease, which has been increasing rapidly in recent years (Lacey et al., 2006). In the UK for example rates of diagnosis have increased between 8- and 11-fold over the last 30 years, and almost 4% of 16–44 year olds reported having been diagnosed with the disease. The disease does not result in major clinical morbidity or mortality and the lesions very rarely become malignant. It does however cause considerable psychological distress to sufferers, and is responsible for substantial healthcare costs. Several treatment options are available, but these can be painful and are not always successful. Recurrence following treatment is common with rates of between 25% and 67% reported over the following 3 months (Lacey, 2005).

The vast majority of cases are caused by two HPV types, HPV6 and HPV11. Of these HPV6 is more prevalent, accounting for approximately 75% of all cases. These two viruses are quite closely related genetically and cause identical patterns of disease. They are very seldom associated with any form of malignancy and so are considered to be ‘low-risk’ virus types.

Other human diseases caused by HPV

HPVs are also associated with other important human diseases. HPV DNA is very commonly found in cancers of the vulva, anus penis and vagina. As with cervical cancer, HPV16 is the most frequent virus type detected in these tumours, followed by HPV18, HPV31 and HPV33. There is also some evidence of an association with a subset of cancers of the oral cavity, pharynx and larynx.

Infection with HPV6 and HPV11, as well as causing genital warts and some early stage CIN, can also result in a condition known as recurrent respiratory papillomatosis (RRP). This is rare and seldom fatal but extremely unpleasant. Papillomas (warts) grow on the surface of the respiratory airways, commonly the larynx, and require surgical removal. This is often not successful, however, and recurrence is very common. The disease can appear in the first 4 years of life (Juvenile Onset RRP) and in such cases more than 100 operations may be necessary over a lifetime (Derkay, 1995).

HPVs cause a wide range of other kinds of human disease, such as warts of the cutaneous epithelium (hand, foot warts). From a vaccine development perspective, however, these have not been considered sufficiently serious to warrant attention.

Vaccine Design: Conceptual and Practical Challenges

  1. Top of page
  2. Introduction
  3. Vaccine Targets
  4. Vaccine Design: Conceptual and Practical Challenges
  5. Prophylactic Vaccine Candidates
  6. Licensed Vaccines
  7. References
  8. Further Reading

Though simple in structure, HPVs present some particularly daunting problems for vaccine development.

Generating an appropriate immune response

HPVs replicate exclusively in the epithelium. This immediately poses a challenge for vaccine design. A useful immune response against the virus, either to protect against initial infection or to eliminate one that has already been established, needs to be available at the relevant epithelial surface. The HPV types responsible for cervical cancer and genital warts are transmitted by sexual contact, and hence challenge with infectious virus may be repeated and sustained over many years. Recurrence of HPV infection is common, suggesting that natural immune responses to virus infection are often ineffective. See also Mucosal Surfaces: Immunological Protection

Furthermore the life cycle of the virus is such that once infection is established the virus particle itself is no longer available as a target for neutralization. The virus infects basal cells of the epithelium and causes these cells to divide, forming a mass of infected tissue, the papilloma or wart. At this stage, only the early virus proteins are produced, such as E6 and E7 which interact specifically with host cell proteins to stimulate cell division. The capsid proteins and complete virus particles are only produced when the infected cells go through terminal differentiation at the outer edge of the papilloma. Thus the first line of defence against virus infection, a ‘blocking’ antibody response directed against the virus capsid proteins, is likely to be of little value when the virus has obtained a first foothold.

Cell-mediated immunity (CMI) is in theory capable of detecting and destroying HPV-infected cells, through recognition by T cells of early protein sequences presented on the cell surface in conjunction with MHC (major histocompatibility complex) class 1 and II molecules. Once again, however, the T cells would need to be available and active within the epithelium. Though there is good evidence that under certain circumstances a cell mediated immune response can clear wart infections (Stern, 2005), a common feature of papillomavirus infection is persistence, suggesting that antiviral CMI responses are not optimal. See also Immunity: Humoral and Cellular

At the outset of vaccine development, therefore, it was far from clear what a successful immune response should look like and whether it would be possible to achieve it through vaccination. It was obvious, however, that a vaccine would have to stimulate a much more effective immune response than natural infection.

Disease complexity

In the case of cervical cancer, the complex and progressive nature of the disease presents a further major challenge. It generally takes many years from initial infection to development of invasive cancer, and the detection of intermediate stages along the way is not necessarily predictive of progression; the great majority of infections and cases of low or high-grade CIN do not result in cancer (Koutsky et al., 1988). A trial with development of cancer as the end-point would thus be impossible both from a practical standpoint, due to its size and duration, and also unethical, since cancer screening could not be withheld from trial participants.

The fact that cervical cancer is caused by multiple virus types also presented a substantial commercial hurdle. A vaccine compromising many components is considerably harder and more risky to develop, as well as being expensive and hence more difficult to sell.

Systems for virus reproduction and vaccine testing

One of the biggest practical obstacles to vaccine development in the early years was that human papillomaviruses cannot be grown in large scale cell culture. They only replicate in highly specialised human cells, making conventional approaches to vaccine production impossible and severely hampering vaccine research. In particular the lack of an amenable cell culture system with which to develop a virus neutralisation assay was a major difficulty. Furthermore, because the virus is exquisitely adapted to human cells, there is no direct animal model for HPV infection and disease.

Acceptability

Finally the diseases targeted by HPV vaccines are transmitted by sexual contact. This raised questions about the acceptability of such vaccines in different societal groups, which in turn could have a substantial influence on their overall impact.

Prophylactic Vaccine Candidates

  1. Top of page
  2. Introduction
  3. Vaccine Targets
  4. Vaccine Design: Conceptual and Practical Challenges
  5. Prophylactic Vaccine Candidates
  6. Licensed Vaccines
  7. References
  8. Further Reading

Vaccine development moved from concept to reality with the development of recombinant DNA-based expression systems that allowed production of large amounts of virus proteins through gene cloning. This meant that the difficulty in growing HPV could be circumvented, and that candidate vaccines could be generated for testing in model systems. Systems were quickly developed to produce each of the virus proteins in sufficient quantity to test as vaccine candidates, but from the outset attention was focused primarily on the L1 major capsid protein. See also Vaccines: Subunit

Virus-like particles

The field took a major step forward with the discovery by several groups that the L1 protein, produced in the absence of any other virus components by recombinant gene expression in heterologous cells, can ‘self-assemble’ into icosahedral structures, called virus-like particles (VLPs), that closely resemble the virus itself (Figure 3; Zhou et al., 1991; Kirnbauer et al., 1992). The importance of this discovery lay in the fact that the L1 protein needs to be presented to the immune system in the correct conformation to generate a strong neutralizing antibody response. The VLPs can be produced either directly within the expression cell itself, and subsequently purified, or can be assembled in vitro by denaturation and renaturation of purified protein. It also proved possible to form VLPs that included both L1 and the minor L2 protein.

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Figure 3. Electron micrographs of naturally occurring virus and virus-like particles produced by recombinant DNA expression.

Testing in animal models

Since there were no accessible models of HPV infection, the next best option was to test vaccination against animal papillomavirus infection. Several challenge models were available. In cattle, experimental infection with bovine papillomavirus causes warts of the alimentary tract that are amenable to study; in the presence of certain cofactors, these may progress to cancer, mimicking the situation with oncogenic HPVs. Infection of cotton-tail rabbits by cotton-tail rabbit papillomavirus (CRPV) offered a second potential model and canine oral papillomavirus (COPV) infection in dogs a third. Ultimately each of these models proved useful and provided the same answer – that it was possible to protect against disease through vaccination with VLPs (Breitburd et al., 1995; Suzich et al., 1995; Kirnbauer et al., 1996). See also Immunization of experimental animals

These studies, as well as giving considerable encouragement that vaccines might be successful, yielded the crucial insights that the L2 was not likely to be required, and that an antibody response against L1 alone might be sufficient. Passive transfer of IgG antibody from L1 VLP-immunized to unimmunized dogs was able to induce protection against COPV, and live CRPV could be neutralized by pre-incubation with antibodies generated by immunization of rabbits with CRPV-based L1 VLPs. The antibodies responsible for the protective effect were shown to be IgG, with a strong implication that they were acting by directly neutralizing the infectivity of the virus. It was also clear from these studies that the conformational integrity of the VLPs was required for the generation of high-titre protective antibodies.

Neutralisation assays

Although highly promising, these studies did not provide direct evidence for successful vaccination against human disease. This came from neutralization studies using a technically demanding laboratory model of HPV infection. The model involves infection of neonatal human foreskin fragments with HPV11 and their subsequent implantation under the subrenal capsule of a nude mouse, leading to the formation of large tumours. Pre-incubation of the HPV11 inoculum with antibodies raised experimentally against the corresponding L1 VLPs was able to block tumour formation (Smith et al., 1995).

This neutralization assay was later superseded by a more amenable system based on the use of pseudovirions (Roden et al., 1996). These are VLPs consisting of L1 and L2 proteins from the desired type containing a DNA genome engineered to contain a reporter gene). Successful infection with the pseudovirions can be detected by reporter gene expression in the target cell. Using this kind of assay, which can be adapted for use on a large scale (Pastrana et al., 2004) it has been possible to build up a much more comprehensive picture of the components of a successful immune response. It has allowed mapping of protective epitopes on the L1 protein and exploration of the extent of likely cross protection between the immune responses against different virus types. This analysis suggests that serum neutralizing immune responses are largely type specific and do not cross-neutralize, implying that multicomponent vaccines would be needed to succeed in the real world of human disease caused by multiple HPV types.

Licensed Vaccines

  1. Top of page
  2. Introduction
  3. Vaccine Targets
  4. Vaccine Design: Conceptual and Practical Challenges
  5. Prophylactic Vaccine Candidates
  6. Licensed Vaccines
  7. References
  8. Further Reading

Successful research in model systems, coupled with an attractive business case, stimulated serious interest in HPV vaccine development from the commercial sector from approximately 1995 onwards, in spite of the considerable risks that still lay ahead. Two lead candidates emerged, both of which have now been licensed by regulatory authorities. See also Vaccination of Humans

Vaccine formulations

Gardasil™, manufactured by Merck & Co., Inc., is a quadrivalent vaccine designed to prevent both cervical cancer and genital warts. It consists of four components, L1-based VLPs from HPV6, HPV11, HPV 16 and HPV18. Each VLP is produced separately by recombinant gene expression in yeast (Saccharomyces pombe), a system that is also used to produce a Hepatitis B protein vaccine. The purified VLPs are then combined in the final formulation (20 μg/40 μg/40 μg/20 μg respectively) with an aluminium-based adjuvant. The second vaccine, Cervarix™, manufactured by GlaxoSmithKline (GSK) is aimed at preventing cervical cancer only, and contains L1 VLPs from HPV16 and HPV18. In this case the VLPs are produced in insect cells (Trichoplusia ni) using baculovirus expression vectors carrying the L1 genes. The VLPs are purified from the cells, denatured using reducing agents and refolded to generate the final VLP structures for product formulation (20 μg each component). GSK's vaccine is also formulated with adjuvant, in this case a proprietary mixture of aluminium salt with 3-deacylated monophosphoryl lipid A (MPL) called AS04.

Though preclinical studies in model systems suggested that vaccines comprising VLPs alone might be successful, both licensed vaccines contain an adjuvant designed to boost the immune response. Aluminium salts have a long track record as components of human vaccines and until recently were the only adjuvants to have been approved by regulators. They are generally considered to be less effective as stimulators of cell-mediated immunity, and this was the basis for GSK's decision to include an additional component, MPL, to try to generate a better CMI response that might provide broader or longer lasting protection, even though it was not clear at that stage whether it would be advantageous or necessary. See also New Generation Vaccine Adjuvants

Clinical trial design

Designing a trial to test vaccine efficacy against genital warts is relatively straightforward since the disease is easily diagnosed. Trial design for cervical cancer was far more complex. The use of malignant cancer as a trial endpoint would be both impractical and unethical. For this reason the pivotal human studies, on which licensing of HPV vaccines was based, needed to rely on a surrogate marker of efficacy. This marker had to be practically useful, that is readily measurable in a trial of manageable size conducted in a way that did not adversely affect normal cervical screening and treatment option, and as firmly predictive of progression to cancer as possible. The chosen primary endpoint was thus development of CIN2/3, which can be monitored both by cytology and also histology, and which is highly predictive of cancer progression. The fact that CIN2/3 itself is a psychologically distressing condition and that treatment of the condition carries some risk provided a further justification for its acceptance as an appropriate endpoint.

Since the development of high-grade disease is a relatively unusual occurrence, the trials involved very large numbers of subjects to ensure any observed reduction in the endpoint could be validated statistically. For each case of CIN2/3 it was important to establish through DNA testing the HPV type that caused the lesion, in order to establish whether the vaccine worked only against the types included in the vaccine or perhaps more broadly. The trials were also designed to measure a number of secondary endpoints, such as the impact of vaccine against CIN1 and on primary infection by the virus. Each vaccine recipient was therefore tested regularly by DNA analysis for the presence of different types of HPV infection in the genital tract, and for the development of cervical abnormalities, as well as providing serum samples for measurement of immune responses against the vaccine.

The final randomized, double blinded Phase III clinical trials for Gardasil and Cervarix together involved some 40 000 women of ages between 15 and 25 (Future II Study Group, 2007a; Paavonen et al., 2007). The design of the two studies was not identical but in each case women enrolling in the trial were given three intramuscular injections over a six month period, and followed up over a period of at least four years. All trial subjects were tested serologically for evidence of prior HPV infection at the point of enrolment vaccination. Even those testing positive for virus types included in the vaccine, however, were allowed to take part in the trial, to assess whether the vaccine might be able to eliminate pre-existing infection.

Clinical trial results

The results from both trials were extremely impressive. The vaccines proved both safe and effective. In a study involving over 20 000 women over a 3-year period up to 2007, Gardasil provided almost complete protection against CIN2/3 caused by HPV16 and HPV18. The efficacy of the vaccine against genital warts was equally good. Once again the vaccine was almost 100% protective against development of the disease for at least 3 years (Garland et al., 2007). Cervarix also proved over 90% protective against high-grade cervical disease in a similarly designed trial (Paavonen et al., 2007). Remarkably both vaccines also provided a high degree of protection not only just against disease, but also against infection by the virus types included in the vaccine, which had seemed a very challenging goal at the outset of vaccine development.

The vaccines produced very strong neutralizing antibody responses, exceeding by a considerable margin those generated by natural infection and these were sustained over the length of the study. Though not completely proven, it seems very likely that these antibodies are the basis of the vaccine's efficacy. It has not yet been possible, however, to establish from the data what level of antibody correlates with the protective effect. This is a vital piece of information that will be necessary to support development of second generation vaccines containing additional virus types without the need for large scale clinical trials.

The trial results provided a number of other important pieces of information. First there appears to be some cross protection afforded by the vaccines against oncogenic virus types not included in the vaccine, though this conclusion is so far based on limited data (Schiller et al., 2008). The protection observed was incomplete, however, even against the types most closely related genetically to the vaccine types. It is likely therefore that additional virus types will be required to extend overall vaccine effectiveness against cervical cancers much beyond the 70% caused by HPV16 and HPV18. Second the vaccines have no obvious beneficial effect in women already infected with the HPV (Future II Study Group, 2007b). It is therefore important from a public health perspective that prophylactic HPV vaccines are administered before the onset of sexual activity.

Vaccine implementation and uptake

On the basis of these successful clinical trials both Gardasil and Cervarix have received licenses from medicines regulatory bodies around the world, and by the end of 2008 universal vaccination programmes had been introduced in many countries, including the USA, Australia, Germany and the UK. Most of these programmes are school-based and have been designed to provide the vaccine routinely to adolescent girls of between 11 and 13 years of age with some one off ‘catch-up’ campaigns for older girls.

The overall impact that vaccine introduction will have on cervical cancer rates over the long term is still, however, uncertain. Many factors, including the acceptability of the first vaccine to target a sexually transmitted disease (Zimet et al., 2006), may significantly limit uptake and this in turn could reduce the expected benefit from ‘herd immunity’. Though trial data indicate that protective immune responses have been sustained for at least five years, it will be many years before it is clear whether the vaccines have had a major impact on cancer outcomes. Some 30% of cervical cancers are caused by virus types not included in current vaccines, and there is some risk that the introduction of vaccination could undermine the effectiveness of existing cervical screening programmes that will need to be maintained to identify these cases. It has been further suggested that as a result of vaccine introduction, nonvaccine HPV types might over time increase in prevalence to fill an ‘ecological niche’. Finally it is not at all clear how developing countries, where the burden of disease is the greatest by far, will be able to afford and implement HPV vaccines.

These caveats aside, the development of HPV vaccines has been a tremendous achievement that required scientific work of the highest quality, an enormous commitment of effort and a great deal of risk. Its success provided a model for partnership working between the scientific communities in academia and industry, and a major boost to the whole field of future vaccine development.

References

  1. Top of page
  2. Introduction
  3. Vaccine Targets
  4. Vaccine Design: Conceptual and Practical Challenges
  5. Prophylactic Vaccine Candidates
  6. Licensed Vaccines
  7. References
  8. Further Reading
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  • Garland SM, Hernandez-Avila M, Wheeler CM et al. (2007) Females united to unilaterally reduce endo/ectocervical disease (FUTURE) I investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. New England Journal of Medicine 356(19): 19281943.
  • Howley PM and Lowy DR (2007) Papillomaviruses. In: Knipe DM and Howley PM (eds) Fields Virology, 5th ed, pp. 23002354. Philadelphia: Lippincott, Williams and Wilkins.
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  • Paavonen J, Jenkins D, Bosch FX et al. (2007) Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 370(9596): 1414.
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Further Reading

  1. Top of page
  2. Introduction
  3. Vaccine Targets
  4. Vaccine Design: Conceptual and Practical Challenges
  5. Prophylactic Vaccine Candidates
  6. Licensed Vaccines
  7. References
  8. Further Reading
  • Castellsague X, de Sanjose S, Aguado T et al. (eds) (2007) HPV and cervical cancer in the world: 2007 report. Vaccine 25 (suppl 3): C1–C230.
  • Franco EL and Drummond MF (eds) (2008) Health economics of HPV vaccination for cervical cancer prevention: historical developments and practical applications. Vaccine 26 (suppl 5): F1–F58.
  • Markowitz LE, Dunn EF and Saraiya M. (2007) Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP), vol. 56(RR02), pp. 124. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htm
  • Stern PL and Kitchener HC (eds) (2008) Vaccines for the Prevention of Cervical Cancer (Oxford Oncology Library), Paperback: 170pp. Oxford: Oxford University Press.
  • WHO/ICO (2009) Information Centre on Human Papilloma Virus (HPV) and Cervical Cancer; http://www.who.int/hpvcentre/en/