Chapter 12: Prophylactic HPV vaccines: underlying mechanisms

Human papillomavirus virus-like particles (HPV VLP) can be generated by the synthesis and self-assembly in vitro of the major virus capsid protein L1. HPV L1 VLPs are morphologically and antigenically almost identical to native virions, and this technology has been exploited to produce HPV L1 VLP subunit vaccines. The vaccines elicit high titres of anti-L1 VLP antibodies that persist at levels 10 times that of natural infections for at least 48 months. At present the assumption is that the protection achieved by these vaccines against incident HPV infection and HPV-associated ano-genital pathology is mediated via serum neutralising Immunoglobulin G (IgG). However, since there have been very few vaccine failures thus far, immune correlates of protection have not been established. The available evidence is that the immunodominant neutralising antibodies generated by L1 VLPs are type-specific and are not cross-neutralising, although highly homologous HPV pairs share minor cross-neutralisation epitopes. Important issues remaining to be addressed include the duration of protection and genotype replacement.     

Chapter 16: HPV vaccines in immunocompromised women and men

HIV-positive as well as other immunocompromised women and men have increased risk of human papillomavirus (HPV)-associated anogenital and oral cancers. The effectiveness of a HPV vaccine to reduce the incidence of these tumors in immunocompromised individuals may depend on several factors, including the effects of immunocompromise on the response to vaccination, the extent of prior infection with the HPV types included in the vaccine, whether immunocompromised women and men have tumors that contain types of HPV not in the vaccines more often than the general population, and whether or not immunization occurs before immunocompromise is severe. Clinical studies are needed to determine HPV vaccine safety and effectiveness in different populations of immunocompromised women and men.     

Chapter 11: HPV vaccines: commercial research & development

We are now in the fortunate position of having two highly promising human papillomavirus (HPV) vaccines in the pipeline. Amidst the excitement of anticipating what these vaccines may be able to offer, it is worth pausing to look back at how the vaccine development story unfolded from an industrial perspective, since without the massive commitment shown by manufacturers over the last decade, without any guarantee of success, there would be no such prospect. This chapter focuses on the two HPV prophylactic vaccines, produced independently by Merck & Co., Inc. and GlaxoSmithKline (GSK), that are in advanced clinical development, and it aims to provide an insight into the key considerations for initiating the programmes in a commercial context as well as some of the research and development hurdles that needed to be surmounted to bring them to the point where efficacy has been demonstrated and the licensing process is well underway.     

Chapter 17: Second generation HPV vaccines to prevent cervical cancer

Prophylactic human papillomavirus (HPV) vaccines based on intramuscular injection of non-infectious L1 virus-like particles (VLPs) are undergoing intense clinical evaluation. As documented in preceding chapters of this monograph, clinical trials of these vaccines have demonstrated their safety and high efficacy at preventing type-specific persistent cervical HPV infection and the development of type-specific cervical intraepithelial neoplasia (CIN) cervical neoplasia. There is widespread optimism that VLP vaccines will become commercially available within the next few years. The prospects for development of alternative HPV vaccines must be considered in light of the likelihood that a safe and effective prophylactic HPV vaccine will soon be available. Three questions need to be addressed: (1) Is there sufficient need for a second generation vaccine? (2) Are there sufficiently attractive candidates for clinical trials? (3) Is there a realistic development/commercialization path?     

Chapter 27: Research needs following initial licensure of virus-like particle HPV vaccines

Human papillomavirus virus-like particle (HPV VLP) HPV vaccines currently evaluated for licensing are likely to be available soon. Licensure will be based on evidence that the vaccine is well tolerated and provides near complete type-specific protection against HPV infections and their resulting lesions in the first few years after vaccination. Several important questions will remain to be answered after licensure to guide vaccine implementation and to permit the rational evaluation of vaccination in cancer prevention programs. These include the long-term safety and efficacy of vaccination, the optimal ages for vaccination, efficacy against HPV types not included in the vaccine and against existing infections, and efficacy in males. Modulators of vaccine efficacy (e.g., HIV infection) and immune mechanisms of long-term protection also remain to be defined. The real-world effectiveness of vaccination programs will need to be assessed. Issues related to the implementation of a vaccine that targets pre-adolescents and early adolescents and to the acceptability of a cancer vaccine targeted against a sexually transmitted infection will need to be understood before vaccination programs can be successful. It is hoped that continued improvements to the current HPV vaccines will lead to the introduction in future years of second generation vaccines that simplify delivery and/or expand its coverage. Finally, the natural history of HPV types not covered in the candidate vaccines will need to be carefully studied following vaccination. Public health authorities in various countries will play a pivotal role in determining if these questions are answered in a timely manner.     

Chapter 21: Modelling the impact of HPV vaccines on cervical cancer and screening programmes

The impact of human papillomavirus (HPV)-16/18 vaccination on the incidence of infection and disease can be explored in a range of different models. Here we explore the epidemiological and economic impact of vaccination where screening is absent and where it is well established. The importance for epidemiology of assumptions about naturally-acquired immunity and heterogeneity in risk behaviours are highlighted, as are the importance for health economic outcomes of vaccine costs and the ability to modify screening strategies. To date, model results are consistent in predicting a useful role for vaccine, but further epidemiological data are required to help test the validity of models.     

Chapter 26: Innovative financing mechanisms to accelerate the introduction of HPV vaccines in developing countries

The costs of developing and producing new-generation vaccines have increased compared to many of the older, "traditional" vaccines because of new technologies and regulatory requirements. While the public sector often supports basic research costs, private manufacturers are usually responsible for the investments in product development and production scale-up. When considering investments, firms evaluate the probability of a market. Unfortunately, the developing country vaccine market is small (in revenue terms) and often unpredictable, particularly given inaccurate forecasting in the past. Low-income developing countries expect low prices. Demand (actual decisions to pay for and introduce the vaccine) is almost always lower than need (estimates of requirements to achieve optimal public health outcomes), a distinction that may be even more significant for HPV vaccines given the number of new vaccines against priority diseases that will become available over the coming 5 years. One new mechanism under consideration to address some of these challenges is Advanced Market Commitments (AMCs). By providing an assured price subsidy for developing country purchase of a future vaccine meeting predefined standards, an AMC would provide industry with greater assurances of earning a reasonable return on their investment to serve the poorest developing countries. The AMC mechanism could provide critical motivation for increased industry (private) investment that would otherwise not occur. HPV vaccines are one of six vaccines being considered for a possible AMC pilot.     

Chapter 22: Assuring the quality, safety and efficacy of HPV vaccines: the scientific basis of regulatory expectations pre- and post-licensure

The potential of human papillomavirus (HPV) vaccines will only be realized if the vaccine candidates under development prove to be safe and effective and can be consistently produced to define quality standards. Whilst the responsibility for delivering a safe and effective product rests with the vaccine producer, a vaccine requires a license to allow it to be placed on the market. Licensure is based on an evaluation of the safety and efficacy profile of a vaccine candidate by national regulatory authorities, ideally on the basis of internationally agreed, science-based specifications and procedures. For vaccines, these international specifications are developed by the World Health Organization (WHO). The scientific basis for the regulatory evaluation of the safety and efficacy of HPV vaccines is described in this paper. Once a vaccine is licensed, a second set of criteria are evaluated by a different group of experts to provide advice to national health policy decision makers as to whether the vaccine should be introduced into national immunization programmes. Factors, such as evidence of high disease burden and high cost-effectiveness are taken into account in this second decision-making process.     

Implementing HPV vaccines: public knowledge, attitudes, and the need for education

This article reviews qualitative research on public knowledge and attitudes to HPV vaccines, focusing on socio-economically challenged populations. Keyword searches were conducted on MEDLINE and ISI Web of Science for relevant peer-reviewed literature in English. A high acceptance of HPV vaccines was found despite low knowledge about HPV (types, prevalence, transmission, health risks, and cervical screening). Facilitators of HPV vaccine uptake included fear of cancer and desire to protect children's health. Barriers included low knowledge levels, perception of HPV vaccines as potential causes of sexual disinhibition, concerns about vaccine costs, social stigma, adverse effects, and parental unwillingness to permit vaccination of pre-adolescent children. Despite acceptance of HPV vaccines, implementation in low-resource settings faces social and economic difficulties. To pursue and strengthen cervical screening in these settings, public education about HPV is key.     

Prophylactic HPV vaccines: new interventions for cancer control

Human Papillomavirus (HPV) infection causes cervical cancer, a significant portion of anal, vulvar, vaginal, and oropharyngeal cancers, genital warts, and recurrent respiratory papillomatosis (RRP). HPV 16 and 18 cause 70-90% of HPV-related cancers whereas HPV 6 and 11 cause 90% of RRP and genital wart cases. Together these four types cause 30-50% of all cervical intraepithelial neoplasia such as those detected by Papinicalou screening. In June 2006, a quadrivalent HPV (6, 11, 16, 18) vaccine was licensed in the United States, and subsequently in the European Union (September 2006), both following expedited review. We describe the primary objectives of the quadrivalent HPV vaccine clinical trial program including studies in females aged 9-45 and males aged 9-26. Planned long-term efficacy and safety evaluations, as well as programs to evaluate vaccine impact on oropharyngeal cancer are also described.     

Human papillomavirus and HPV vaccines: a review

Cervical cancer, the most common cancer affecting women in developing countries, is caused by persistent infection with "high-risk" genotypes of human papillomaviruses (HPV). The most common oncogenic HPV genotypes are 16 and 18, causing approximately 70% of all cervical cancers. Types 6 and 11 do not contribute to the incidence of high-grade dysplasias (precancerous lesions) or cervical cancer, but do cause laryngeal papillomas and most genital warts. HPV is highly transmissible, with peak incidence soon after the onset of sexual activity. A quadrivalent (types 6, 11, 16 and 18) HPV vaccine has recently been licensed in several countries following the determination that it has an acceptable benefit/risk profile. In large phase III trials, the vaccine prevented 100% of moderate and severe precancerous cervical lesions associated with types 16 or 18 among women with no previous infection with these types. A bivalent (types 16 and 18) vaccine has also undergone extensive evaluation and been licensed in at least one country. Both vaccines are prepared from non-infectious, DNA-free virus-like particles produced by recombinant technology and combined with an adjuvant. With three doses administered, they induce high levels of serum antibodies in virtually all vaccinated individuals. In women who have no evidence of past or current infection with the HPV genotypes in the vaccine, both vaccines show > 90% protection against persistent HPV infection for up to 5 years after vaccination, which is the longest reported follow-up so far. Vaccinating at an age before females are exposed to HPV would have the greatest impact. Since HPV vaccines do not eliminate the risk of cervical cancer, cervical screening will still be required to minimize cancer incidence. Tiered pricing for HPV vaccines, innovative financing mechanisms and multidisciplinary partnerships will be essential in order for the vaccines to reach populations in greatest need.     

Chapter 14: HPV vaccine introduction in industrialized countries

Introduction of a vaccine requires the achievement of three initial milestones. These are licensure by a national control authority that determines the vaccine is safe and effective, development of recommendations for use by expert advisory bodies on immunization, and obtaining funding for vaccination. Once these milestones have been achieved, a successful vaccination program requires that a number of interlinked programmatic components be brought together in a coordinated fashion. These include vaccine purchase and supply, vaccination service delivery, high coverage rates, surveillance of the vaccination program, immunization finance policies and practices, and political will. Human papillomavirus (HPV) vaccination provides unique challenges in all of these areas because of the many gaps in our knowledge.     

Chapter 30: HPV vaccines and screening in the prevention of cervical cancer; conclusions from a 2006 workshop of international experts

The finding that cervical cancer only occurs in women infected with specific, "high-risk" types of the human papillomavirus (HPV) has led to the development of novel, non-cytology-based cervical cancer prevention strategies. We now have sensitive molecular methods for detecting HPV that dramatically improve our ability to detect high-grade cervical cancer precursor lesions. Perhaps more importantly, prophylactic HPV vaccines have been developed that are protective against cervical cancer precursors caused by HPV 16 and 18. In the Spring of 2006, over 100 experts in HPV, cervical cancer screening, and vaccination worked together to define how best to incorporate HPV DNA testing and the HPV vaccines into cervical cancer prevention efforts. In this summary, we summarize the opinions of this expert group on how these advances can be introduced to provide the maximum benefit to women and to reduce the global burden of cervical cancer.     

Chapter 6: Epidemiology and transmission dynamics of genital HPV infection

This chapter provides an overview of the epidemiology of human papillomavirus (HPV) infection, with a focus on the dynamics of sexual transmission. We explore concepts related to the spread of sexually transmitted infections, including population prevalence, duration of infectivity, patterns of sexual contacts, and transmissibility, including modifiers of susceptibility and infectivity. HPV prevalence and incidence are high in most studies, particularly amongst young women. There is strong evidence that transmission occurs primarily via sexual activity, most commonly vaginal and anal intercourse. Although the duration of infectivity may be short, current evidence suggests that HPV is highly transmissible. The implications of transmission dynamics for the success of future HPV vaccines are discussed.     

Market-based licensing for HPV vaccines in developing countries

Human papillomavirus (HPV) vaccines hold great promise for preventing cervical cancer, but 93 percent of mortality worldwide occurs in low- and middle-income countries, where high vaccine costs can restrict dissemination. Current models for promoting international access to health care innovations include differential pricing, advance market commitments, and voluntary and compulsory licensing. Some of these mechanisms have been effective, but much room for improvement remains. We discuss the usefulness of a new type of license that uses market forces to lower prices through generic competition in low- and middle-income countries while ensuring that pharmaceutical companies are appropriately reimbursed for their research and development.     

Manufacturing costs of HPV vaccines for developing countries

BackgroundNearly all of the 500,000 new cases of cervical cancer and 270,000 deaths occur in middle or lower income countries. Yet the two most prevalent HPV vaccines are unaffordable to most. Even prices to Gavi, the Vaccine Alliance, are unaffordable to graduating countries, once they lose Gavi subsidies. Merck and Glaxosmithkline (GSK) claim their prices to Gavi equal their manufacturing costs; but these costs remain undisclosed. We undertook this investigation to estimate those costs.MethodsSearches in published and commercial literature for information about the manufacturing of these vaccines. Interviews with experts in vaccine manufacturing.FindingsThis detailed sensitivity analysis, based on the best available evidence, finds that after a first set of batches for affluent markets, manufacturing costs of Gardasil for developing countries range between $0.48 and $0.59 a dose, a fraction of its alleged costs of $4.50. Because volume of Cervarix is low, its per unit costs are much higher, though at comparable volumes, its costs would be similar.InterpretationGiven the recovery of fixed and annual costs from sales in affluent markets, Merck’s break-even price to Gavi could be $0.50–$0.60, not $4.50. These savings could support Gavi programs to strengthen delivery and increase coverage. Outside Gavi, prices to lower- and middle-income countries, with profit, could also be lowered and made available to millions more adolescents at risk. These estimates and their policy implications deserve further discussion.