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The impact of immunization on cancer control: the example of HPV vaccination 

The impact of immunization on cancer control: the example of HPV vaccination
Chapter:
The impact of immunization on cancer control: the example of HPV vaccination
Author(s):

Ann Burchell

and Eduardo Franco1

DOI:
10.1093/med/9780199550173.003.0006
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date: 21 August 2019

Many types of cancer are aetiologically linked to infections with specific microbial agents. Taken together, such infections are responsible for about 18 per cent of all cancers worldwide and up to 25 per cent of cancers in developing nations [1]. Such a high attributable fraction is second only to that of tobacco smoking in cancer control. The realization that some cancers are caused by infectious agents means that vaccination can be considered as a primary prevention measure. Vaccination has substantial public health potential. No other preventive measure has such dramatic appeal, in terms of a successful track record in public health. Only vaccination has the ability to eliminate disease. Vaccination for cancer prevention has moved beyond theory and become a reality for two neoplastic diseases: liver cancer and cervical cancer. This chapter reviews briefly the role of infections as causal agents in cancer, describes anti-hepatitis B virus (HBV) immunization as the first cancer vaccine paradigm, and finally focuses on the latest paradigm of prophylactic vaccination against human papillomavirus (HPV) infection as the new front in cancer prevention.

Microbial aetiology of cancer and the example of HBV vaccination

Although many viruses, bacteria, and protozoan and metazoan parasites have been mentioned in the biomedical literature as potentially carcinogenic, conclusive epidemiologic and molecular evidence to date has been unequivocally demonstrated for only a few agents, relating to many forms of cancer. Simply finding pathologic or molecular evidence that an agent is present in the human host or that the latter was previously exposed to this agent is not sufficient to establish causation. The World Health Organization's International Agency for Research on Cancer (IARC) has developed valuable guidelines that can be used in deciding for policy purposes whether a biological, chemical, or physical agent (or an industrial process) can be deemed as causally related to cancer in humans. These guidelines are applied during expert review of the published evidence concerning a putative association. The conclusions of this process are published as part of IARC's monograph series on evaluation of carcinogenicity and can be accessed online in that agency's website (http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php, accessed September 5, 2008).

Since its inception, the IARC monograph programme has evaluated several microbial agents. The list is summarized in Table 6.1. As shown, several infectious agents have been established as carcinogenic or probably carcinogenic to humans. For others, the evidence is less conclusive but points to a possible carcinogenic role, whereas for some other agents the evidence is inconclusive. Among those for which the evidence is compelling are hepatitis B and C viruses (HBV and HCV; liver cancer), certain genotypes of human papillomavirus (HPV; cervical, anogenital, and oral cancers), Epstein-Barr virus (EBV; certain types of lymphomas and nasopharyngeal carcinoma), human T cell lymphotropic virus I (some forms of leukaemias), human immunodeficiency virus (HIV; AIDS-associated malignancies), human herpes virus 8 (HHV-8; Kaposi's sarcoma), Helicobacter pylori (stomach cancer and mucosa-associated lymphoid tissue lymphomas), Schistosoma haematobium (bladder cancer), and some forms of liver flukes (e.g. genus Opistorchis; liver cholangiocarcinoma). Altogether, it has been estimated that these agents cause 17.8 per cent of incident cancers worldwide (12.1 per cent, 5.6 per cent, and 0.1 per cent for viral, bacterial and parasitic infections, respectively) including as much as 5.2 per cent for HPV alone [1].

Table 6.1 Microbial agents evaluated by the International Agency for Research on Cancer's monograph series with respect to the accumulated scientific evidence that they may cause cancer in humans

Monograph volume and year

Infectious agent

Evaluation

Group

59, 1994 [2]

Hepatitis B virus (HBV) (chronic infection)

Carcinogenic

1

Hepatitis C virus (HCV) (chronic infection)

Carcinogenic

1

Hepatitis D virus (HDV)

Not classifiable

3

61, 1994 [106]

Schistosoma haematobium

Carcinogenic

1

Opistorchis viverrini

Carcinogenic

1

Clonorchis sinensis

Probably carcinogenic

2A

Schistosoma japonicum

Possibly carcinogenic

2B

S. mansoni

Not classifiable

3

O. felineus

Not classifiable

3

Helicobacter pylori

Carcinogenic

1

64, 1995 [8]

Human papillomavirus (HPV) types 16 and 18

Carcinogenic

1

HPVs types 31 and 33

Probably carcinogenic

2A

HPVs, other types (except 6/11)

Possibly carcinogenic

2B

67, 1996 [107]

Human immunodeficiency virus (HIV) type 1

Carcinogenic

1

Human T lymphotropic virus (HTLV) type I

Carcinogenic

1

HTLV-II

Not classifiable

3

HIV-2

Possibly carcinogenic

2B

70, 1997 [108]

Epstein-Barr virus (EBV)

Carcinogenic

1

Human herpesvirus (HHV) type 8

Probably carcinogenic

2A

90, 2007 [16]

HPVs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66

Carcinogenic

1

HPVs 6, 11

Possibly carcinogenic

2B

HPV genus Beta

Possibly carcinogenic

2B

Groups 1, 2A, 2B, and 3 are the overall assessment, summarized as shown.

As shown in Table 6.1, the accumulated evidence for a causal role for chronic HBV infection in hepatocellular carcinoma was the first target among biological exposures assessed by the IARC monograph programme [2]. It is estimated that 54.4 per cent of global liver cancers are attributable to HBV, for a total of 340,000 cases in 2002 [1]. An HBV vaccine became commercially available in 1981 and was found to be highly efficacious in preventing chronic HBV carriage [3]. Further refinements to the vaccine preparation were made over the years, which also contributed to a reduction in production costs, thus making HBV vaccination affordable enough for inclusion in public health programmes. Long-term follow-up data from several countries has shown that symptomatic HBV infection is rare following vaccination, and that immunity persists for at least a decade [4].

British Columbia, Canada, was one of the first regions in North America to introduce universal HBV vaccination. In 1992, a school-based programme was initiated, offering HBV vaccine to all Grade 6 students (children aged 11 years). Following this introduction of adolescent vaccination, the annual incidence rate of acute hepatitis among those aged 12 to 20 years declined from 1.7 per 100,000 in 1992 to zero per 100,000 in 2001, suggesting elimination of HBV transmission within the targeted age group [5]. Similar impacts on rates of acute hepatitis B have been observed in other jurisdictions [4]. Furthermore, there is now evidence that HBV vaccination has the desired effect of preventing liver cancer. For example, a mass newborn vaccination programme was implemented in Taiwan in 1984, with later catch-up programmes for older children and adults [6]. Annual incidence rates of childhood (aged 6–14 years) hepatocellular carcinoma subsequently declined from 0.70 per 100,000 in 1981 to 1986 to 0.57 in 1986 to 1990, and further to 0.36 in 1990 to 1994. Mortality rates from childhood hepatocellular carcinoma also declined in the same period. The full impact of the Taiwanese programme will be verifiable once these vaccinated cohorts reach the peak age of onset of liver cancer.

The lessons learned from the implementation of HBV vaccination are extremely valuable as the first example of a successful prophylactic cancer vaccine. The rationale for adopting an HBV vaccine in clinical practice is simple; hepatitis B is an important disease in itself and is responsible for considerable morbidity and economic costs, even without factoring in the benefits in reduced risk of liver cancer later in life. However, affordability was an important issue; at $100 per course of immunization initially the vaccine was out of reach for most developing countries. Even in Western countries, cost considerations led to policies recommending immunization only of high-risk individuals and health workers, which unfortunately restricted the impact of vaccination to preventing only 5 per cent of the cases of liver cancer [7]. Subsequently, strong leadership by various agencies and the WHO permitted rapid technology transfer to multiple manufacturers, including those in developing countries. The end result was a remarkable reduction in vaccine production costs to about $1 per paediatric dose, which led to demonstration projects of mass immunization in several high-risk countries [7].

The experience with HBV vaccination has become particularly important also because we have now the opportunity to include a second cancer in the list of neoplastic diseases that can be prevented by immunization. Recently, two prophylactic vaccines against HPV infection have become available. HPV infection is recognized today as the necessary causal factor of all cervical cancer (squamous cell and adenocarcinomas) cases in the world, and the cause of a substantial proportion of many other anogenital neoplasms [8,9]. HPV has also been implicated in the genesis of head and neck cancer. The evidence for the oncogenic potential of HPV did not come easily, but resulted from a culmination of more than 25 years of vigorous multi-disciplinary research by molecular biologists, virologists, immunologists, clinicians, and epidemiologists. This realization paved the way for new exciting approaches for preventing cervical cancer, which is the second most common malignancy of women worldwide [10]. In the remaining of this chapter we summarize the scientific progress that led to the recognition of HPV as a cause of cervical and other cancers, the subsequent development of HPV vaccines, and how the implementation of these vaccines will result in a paradigm shift in the prevention and screening of HPV-related cancers.

The epidemiology of cervical cancer and HPV infection

Epidemiology of cervical cancer

Worldwide, cervical cancer is the second most common malignant neoplasm of women, accounting for nearly 10 per cent of all cancers (non-melanoma skin cancers excluded). It is estimated that 493,000 new cases of invasive cervical cancer were diagnosed in 2002, 83 per cent of which were in developing countries [10]. Cervical cancer can be characterized as a disease of poorer nations, with a disproportionate number of cases and the greatest proportion of deaths occurring in such regions. The highest risk areas for cervical cancer are in sub-Saharan Africa, Melanesia, the Caribbean, and Latin America, with average annual incidence rates above 30 per 100,000 women (rates standardized according to the world population of 1960) (Figure 6.1). Not surprisingly, in view of the substandard healthcare conditions, these areas also bear a disproportionately high mortality burden due to cervical cancer. Every year, an estimated 273,000 deaths from cervical cancer occur worldwide, with over three-fourths of them in developing countries [10].

Fig. 6.1 Average annual incidence and mortality rates for cervical cancer by region, 2002. Standardization according to the age structure of world population of 1960.

Fig. 6.1
Average annual incidence and mortality rates for cervical cancer by region, 2002. Standardization according to the age structure of world population of 1960.

Source: Globocan 2002 (Ferlay et al. [10]).

One of the main reasons for the global heterogeneity in cervical cancer incidence and mortality is the implementation of Pap cytology screening in high-income countries over the past 50 years. In developed countries where universal organized or opportunistic screening was adopted, there was a 50 to 80 per cent reduction in cervical cancer rates [11]. Cervical cancer rates are now substantially lower in Western Europe and North America at less than 10 new cases annually per 100,000 women [12].

In developed countries, 66 per cent of women diagnosed with cervical cancer survive longer than five years whereas the 5-year survival rate in developing countries is less than 50 per cent [13]. The impact of this relatively low survival experience is increased by the fact that in high-fertility developing countries, cervical cancer generally affects women in the early post-menopausal years who often are the primary or sole caregiver for many school-age and teenage sons and daughters. The pre-mature loss of these mothers has a tremendous negative impact on the social structure of the local communities.

Epidemiology of HPV infection

The more than 100 HPV genotypes (types, for short) that have been catalogued so far are classified according to their DNA homology, which closely reflects tissue tropism (mucosal or cutaneous) and oncogenic potential [14]. About 40 types infect the epithelial lining of the anogenital tract and surfaces, as well as of other mucosal areas of the body, such as the upper aero-digestive tract. Among these mucosal HPVs, some 13 to 18 types have been identified as of probable or definite high-oncogenic risk (HR-HPV) on the basis of the frequency of association with cervical and other anogenital cancers and their pre-cancerous lesions. Over the years, the list of HR-HPVs has increased as a reflection of the continuous improvement in assay performance and the accumulated clinical literature on the distribution of HPV types in lesions from many parts of the world [15]. A recent conservative assessment by the IARC's Carcinogenicity Monograph Series referred to types 16, 18, 31, 33, 35, 39, 45, 51, 52, 55, 56, 58, 66 as HR-HPVs [16].

Infections with most mucosal HPV types that are not deemed as HR-HPVs are of no clinical consequence and cause no symptoms or visible lesions; such types are considered of low-oncogenic risk (LR-HPV). Two LR-HPVs, however, HPVs 6 and 11, can cause benign lesions of the anogenital areas known as condylomata acuminata (genital warts), as well as a large proportion of low-grade squamous intraepithelial lesions (LSIL) of the cervix. Such LR-HPV infections are responsible for substantial morbidity and incur high costs associated with the treatment of the clinically relevant lesions. Perinatal transmission of HPV is also possible and can cause in rare instances recurrent respiratory papillomatosis in infants and young children [15].

Genital HPV infection is the most common sexually transmitted infection (STI) among women [17]. The prevalence of HPV infection varies greatly by age and by geography [18,19]. Among asymptomatic women in the general population or attending routine cervical cancer screening, prevalence rates are in the 2 per cent to 44 per cent range [15]. In a meta-analysis using data from 78 published studies, among women with normal cytology the age-adjusted global prevalence of any HPV type infection was 10.4 per cent, with considerable variation by age and region [19]. Prevalence was highest for young women and decreased in the middle age groups, followed by a second peak in prevalence in the older age groups. The two most common HPV types were HPV-16 (prevalence 2.5 percent) and HPV-18 (0.9 per cent).

HPV DNA has also been clearly identified in the male genitalia, anal mucosa, and oral cavity, but compared to women, fewer prevalence data exist. Depending on the population studied, sampling method and anatomic site, male genital HPV prevalence ranges from 0 to 73 per cent [20,21]. HR-HPV appears to occur in a higher proportion of male than in female infections [20]. Penile HPV prevalence increases with the number of sex partners and with the number of sex worker partners [21]. Men who have sex with men have been observed to have a particularly high prevalence of HPV [22].

Follow-up studies have documented high rates of HPV acquisition among young women; several studies have reported cumulative incidences of 40 per cent or greater after three years of follow-up [15]. High incidence among men has also been observed [21], although far fewer longitudinal studies have been conducted among males. Data supporting sexual intercourse as the primary route of genital HPV transmission include high incidence following sexual debut, documented transmission of genital warts between sex partners, concordance in sex partners for type-specific and HPV-16 variant-specific HPV DNA, the rarity of genital HPV infection in women who have not had vaginal intercourse, the strong and consistent associations between lifetime numbers of sex partners and HPV prevalence, and increased risk of HPV acquisition with new sex partners [23]. Many earlier studies did not observe a protective effect of condoms [24], but, in more recent studies specifically designed to address this question, consistent condom use does appear to reduce the risk of HPV infection [25,26].

Natural history of HPV infection and progression to cervical cancer

Following HPV acquisition, the natural history consists of either HPV clearance or development of a persistent HR-HPV infection and cervical neoplastic development. HPV infection triggers a slow process of disruption of the normal maturation of the transformation zone epithelium of the uterine cervix near its squamo-columnar junction [27]. This process of abnormal changes is initially limited to the cervical epithelium. These pre-invasive lesions, known in the old classifications as dysplasia or, more recently, as squamous intraepithelial lesions (SIL), can be discovered through cytological examination using the Papanicolaou technique (‘Pap’ screening test) and confirmed by colposcopic examination and biopsy as cervical intraepithelial neoplasia (CIN). They are invariably asymptomatic and if left untreated, they may eventually extend to the full thickness of the cervical epithelium (cervical carcinoma in situ (CIS)), and traverse the lining formed by the basement membrane to become invasive. This process may take a decade or longer but will eventually occur in a substantial proportion of CIS patients.

Although HPV infection is the central cause of cervical cancer, only a small percentage of women who are infected go on to develop cervical cancer or its precursors. Most HPV infections detected via molecular hybridization techniques are transient, and are no longer detectable within one to two years [15]. Even among women with persistent infection, HPV alone is not a sufficient cause and much work has been devoted to determining why certain HPV-positive women develop cervical cancer while others do not. The multi-factorial model of cervical cancer aetiology suggests an interplay of various cofactors. Smoking, high parity, long term use of oral contraceptives, co-infections and immunosuppression have been found to increase the risk of cervical cancer. Other factors such as genetic polymorphisms in the Human Leukocyte Antigen (HLA) system, polymorphisms in some oncogenes, nutrition, insulin-like growth factors (IGFs), and viral factors have also been identified as contributing to the overall cervical cancer risk [28].

Identification of the causal role of HPV in cervical carcinogenesis

Early on, cervical cancer was hypothesized to be related to sexual activity even before the advent of analytical epidemiologic studies. The simple premise was the widely held view that nuns did not develop this neoplasm whereas sex trade workers had an increased risk. Epidemiologic studies clearly identified specific sexual behaviours as key risk factors, such as age at first sexual intercourse and number of sexual partners [23]. During much of the 1960s and 70s, the consistency of epidemiologic findings pointing to a sexually-transmitted infection model propelled research efforts to identify the putative causal microbial agent or agents. Many sexually-transmitted agents were considered, and the herpes simplex virus (HSV-2), syphilis, gonorrhoea, and Chlamydia trachomatis were suspected. The evidence available at the time indicated that genital infection with HSV-2 was the most likely culprit. Although HSV was proven carcinogenic in vitro and in vivo, the evidentiary link to cervical cancer was mostly indirect [29].

In the 1980s the attention gradually turned to a new candidate, HPV, with the emergence of a consistent evidence base from molecular biology. Harald zur Hausen was the primary leader behind the long-standing hypothesis that proliferation of HPV in the cervical epithelium leads to disruption of cell maturation that develops as CIN, the pre-cancerous lesion; he was awarded the Nobel Prize in 2008 for this work. His initial insightful observations and experiments were made as early as in the late 1970s (reviewed in [30]). He and others subsequently conducted groundbreaking research that led to an understanding of how the early viral oncogenes E6 and E7 interfere with key regulators of the cell cycle, thus immortalizing cervical cells and preventing them from undergoing senescence and being lost by the normal exfoliation that regenerates the epithelium. The demonstration of this series of molecular events was essential for the scientific community to accept that HPV infection was the likely cause of cervical cancer, as shown in Figure 6.2.

Fig. 6.2 Causation of cervical cancer by human papilloma virus.

Fig. 6.2
Causation of cervical cancer by human papilloma virus.

Source: From The Nobel Foundation, 2008 in relation to the award of the Nobel Prize to H. zur Hausen (http://nobelprize.org/nobel_prizes/medicine/laureates/2008/press.html), with permission of the Nobel Foundation.

This acceptance did not come easily. There was much scepticism concerning the role of HPV infection. Reasons included observations that HPV infection was quite ubiquitous and, as such, it could not plausibly be a cause of disease. Contributing to the controversy were the weak to moderate associations that were observed in early molecular epidemiologic studies, unlike those one would expect from a key intermediate endpoint in cervical carcinogenesis (Figure 6.3). Later it was learned that measurement error in detecting cervical HPV DNA (thus leading to misclassification of the exposure) in these initial case-control studies had considerably underestimated the relative risk for the effect of HPV infection on cervical cancer (reviewed in [31]). As the experience with HPV DNA testing methodology led to the adoption of modern assays, such as polymerase chain reaction, the magnitude of the relative risks increased dramatically to near triple-digit point estimates (Figure 6.3).

Fig. 6.3 Relative risks for associations between HPV and cervical cancer in case-control studies of first generation.

Fig. 6.3
Relative risks for associations between HPV and cervical cancer in case-control studies of first generation.

Abbreviations: NAH: non-amplified DNA hybridization; PCR: polymerase chain reaction; RR: relative risk; CI: confidence interval. Adoption of improved HPV DNA detection techniques such as PCR and better experience with laboratory procedures aiming at controlling contamination and other sources of measurement error led to a gradual increase in the RR estimates in successive studies.

Sources: Reeves et al. 1989 [109]; Donnan et al. 1989 [110]; Peng et al. [111]; Muñoz et al. 1992 [32]; Shen et al.1993 [112]; Eluf-Neto et al. 1994 [113]; & Asato et al. 1994 [114].

It was a series of large and well-conducted case-control studies by the IARC using modern laboratory techniques that demonstrated that infection with certain HPV types is unequivocally one the one strongest cancer risk factor ever found (Figure 6.4) [32,33]. For example, the relative risk between tobacco and lung cancer is estimated between 7 and 15 [34], whereas the relative risk between HPV-16 and squamous-cell cervical cancer is 435 [32]. These studies also produced precise HPV type-specific estimates of relative risks, allowing for identification of specific types for prevention strategies [32,35].

Fig. 6.4 Relative risks for the association between specific HPV types and invasive cervical cancer as estimated using the pooled data from the IARC case-control studies. These studies had improved HPV detection methods relative to the first generation of studies. In consequence, RR estimates are substantially higher than those in Figure 6.3.

Fig. 6.4
Relative risks for the association between specific HPV types and invasive cervical cancer as estimated using the pooled data from the IARC case-control studies. These studies had improved HPV detection methods relative to the first generation of studies. In consequence, RR estimates are substantially higher than those in Figure 6.3.

Source of data: Muñoz et al. (2003).[33], reproduced with permission from HPV Today, issue no. 4, February 2004.

In 1995, the IARC expert panel classified HPV 16 and 18 as ‘Group 1, Human Carcinogens’ in its Monograph series on carcinogenicity evaluation (Table 6.1) [8]. Following the 1995 IARC monograph was the recognition that HPV infection was not only the unequivocal central cause of cervical cancer but that it should also be viewed as a necessary cause [9]. No other cancer prevention paradigms (e.g. smoking-lung cancer, HBV-liver cancer) have this distinction [36]. Support for this assertion comes from the strong epidemiological evidence (Figures 6.3 and 6.4) and the detection of HPV DNA in up to 99.7 per cent of cervical cancers from all geographic areas [9,32,37,38]. As the evidence from new molecular epidemiologic studies came to light after 1995, the IARC decided to reconvene its HPV expert panel which resulted in an additional 11 HPV types to be classified as Group-1 carcinogens (Table 6.1) [16].

The empirical epidemiologic evidence concerning the carcinogenicity of different HPV types seen in the IARC studies [32] was consistent with what molecular virologists had predicted via phylogenetic relatedness analyses [39] and bioassays of oncogenic activity [40]. On the basis of the prevalence of the different HPV types in cervical cancers from different parts of the world it could be concluded that HPVs 16 and 18 were unequivocally the ones with the highest combined attributable proportion. HPV-16 is the most prevalent type causing approximately 54 per cent of cervical cancers worldwide, followed by HPV-18 which is associated with approximately 17 per cent of cervical cancers. As shown in Figure 6.5, in combination, HPV types 16 and 18 cause about 70 per cent of all cervical cancers [35]. Other HR types such as HPV-45, -31, and -33, albeit next in ranking, are responsible for less than 7 per cent of all cervical cancers, individually [41]. The ranking of the HR-HPV types shown in Figure 6.5 served as rationale for the development of the two initial prophylactic vaccines against HPV infection.

Fig. 6.5 Proportion of the global burden of invasive cervical cancers attributable to the incremental combination of different HPV types in a hypothetical prophylactic HPV vaccine of increasing valency.

Fig. 6.5
Proportion of the global burden of invasive cervical cancers attributable to the incremental combination of different HPV types in a hypothetical prophylactic HPV vaccine of increasing valency.

HPV 16 is the most common type, being detected in 53.5 per cent of all cervical cancers. The second most common type is HPV 18, at 17.2 per cent. Altogether, about 71 per cent of all cervical cancers are due to either HPV 16 or HPV 18, which forms the theoretical expectation for the preventive benefit from immunization with a bivalent HPV vaccine containing these two types.

Source: Adapted with permission from Munoz et al. (2004). Int J Cancer. Aug 20. 111(2):278–85.

HPV vaccination

The human immune system is composed of an innate, non-specific component and an adaptive component. Adaptive immunity is conferred by a series of highly-specialized cells that process and prevent or eliminate specific pathogenic challenges. It may occur after either natural infection or vaccination, such that immunity is ‘acquired’. Exposure to a particular pathogen or its antigen produces a primary immunological response involving B and T lymphocytes. This is followed by the development of immune memory cells, which can remember the pathogenic antigen and can launch a rapid protective response upon re-exposure.

A vaccine is a substance that contains antigen from a particular pathogen and is administered for the prevention or treatment of an infectious disease. Vaccine preparations may consist of live, attenuated, or killed micro-organisms or their antigenic proteins. Prophylactic vaccines aim to prevent infection by inducing neutralizing antibody response. Therapeutic vaccines aim to prevent proliferation of infected cells via cell-mediated immunity, thereby inducing regression. An ideal vaccine will provide at least the same degree and duration of protection as natural infection, without the accompanying clinical illness, with minimal side effects; and whose administration is simple, safe, acceptable, and cost-effective [4].

Development of HPV vaccine technology

As early as the 1980s, many laboratories worldwide were studying the immune response against HPV infection using linear epitopes, i.e. peptides derived from the nucleotide sequence of selected HPV genes that could be candidates for inducing a protective, neutralizing immune response. Today's successful prophylactic vaccines against HPV (see as follows) finally became a reality with the development of a technology that produces HPV virus-like particles (VLP) via expression of the major HPV capsid gene L1 in eukaryotic cell systems (yeast or insect cells). The expressed capsid protein self-assembles as pentamers and 72 of the latter spontaneously join to form a structure that resembles an intact HPV virion. The VLP does not contain the viral DNA and thus it is not infectious. However, the ordered arrangement of epitopes in the VLP makes this formulation highly immunogenic. The VLP technology has its roots in research by Robert Garcea in Colorado on polyomaviruses, which are closely related to HPVs [42,43]. Later, Zhou and colleagues in Brisbane, Australia, conducting work inspired and co-authored by Ian Frazer were the first to show in 1991 that the L1 (major) and L2 (minor) capsid genes of HPV 16, when expressed in a eukaryotic cell system, coded for the proteins that spontaneously self-assemble as VLPs [44]. Subsequently, the VLP technique was perfected and it was demonstrated that VLPs were highly immunogenic, inducing high titres of neutralizing antibodies. L1 alone can self-assemble into VLPs but L2 cannot; therefore, the first HPV vaccine candidates, including the current commercially available ones, consist of L1-based VLPs [45]. The historical account concerning the development of this research has been recently summarized by Frazer in a commentary [46].

The 1995 IARC monograph labelling HPV-16 and -18 as ‘Group 1, Human Carcinogens’ [8] gave pharmaceutical companies the needed body of evidence to allow them to take the financial risks in developing and field-testing candidate HPV vaccines. Variations of the L1-based VLP technology were subsequently adopted as formulations by Merck & Co., Inc. and GlaxoSmithKline Biologicals as candidate prophylactic vaccines against HPV in the mid-1990s. Following another decade of research and development, two highly efficacious vaccines that prevent HPV infection and cervical pre-cancers became available. These are Gardasil® (Merck & Co., Inc., NJ, USA) and Cervarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium).

Table 6.2 describes the main characteristics of the two commercially available HPV vaccines. Cervarix® is a bivalent vaccine that targets the two HPV types (16 and 18) that are attributed to 70 per cent of cervical cancers worldwide. Gardasil® is a quadrivalent vaccine that targets types 16 and 18 as well as two additional types, 6 and 11, which are responsible for 90 per cent of genital warts. Both vaccines utilize recombinant technology to produce L1 VLPs but are based on different expression systems. The vaccines differ in their quantity of VLPs and their adjuvant systems. AlSO4, the adjuvant used in Cervarix is supposed to yield an enhanced immunologic response with production of neutralizing antibodies [47]. The rationale behind the two vaccines also differs [48]. For the bivalent vaccine, the rationale was to focus on the oncogenic types 16 and 18 and produce a strong, sustained immune response. For the quadrivalent vaccine, the rationale was also to provide immunity to the two most important oncogenic types, and further to prevent infection with the two non-oncogenic types that cause most genital warts and recurrent respiratory papillomatosis.

Table 6.2 Characteristics of currently-available prophylactic human papillomavirus (HPV) vaccines

Characteristic

Cervarix®

Gardasil®

HPV types included

16, 18 (bivalent)

6, 11, 16, 18 (quadrivalent)

Dose of L1 protein

20/20 µg

20/40/40/20 µg

Expression system

Insect cells (baculovirus)

Yeast

Adjuvant

AlSO4 (proprietary)

Aluminum hydroxy phosphate sulfate

Injection schedule

0, 1, 6 months

(0.5 ml, intramuscular)

0, 2, 6 months

(0.5 ml, intramuscular)

Follow-up data available

5.5 years (Phase II)

15 months (Phase III)

5 years (Phase II)

3 years (Phase III)

Clinical trial evidence for vaccine efficacy

Phase II and III randomized controlled trial results are available for both the bivalent and quadrivalent vaccines [49–54]. Because of the inherent differences in study designs and methods used by the two vaccine teams, it is a daunting task to summarize efficacy results for both virological and lesion endpoints. The following section and Table 6.3 provide a brief summary of interim results as of mid-2008. At this writing, all trials are still ongoing and final analyses have not yet been conducted. Recent in-depth reviews of the vaccine formulations, study methods, and trial findings have been published elsewhere [28,47,55–57]. In short, both vaccines have been proven to be highly efficacious.

Table 6.3 Overview of vaccine efficacy results in human papillomavirus (HPV) vaccine Phase II and III trials

Endpoint

Cervarix®

Gardasil®

Vaccine efficacy

Analysis

Reference

Vaccine efficacy

Analysis

Reference

Vaccine efficacy for various endpoints among susceptible women (i.e. with no evidence of current or past infection at study entry)

4 month persistent cervicovaginal infection or disease associated with HPV 6/11/16/18

Not reported

90% (71–97)

89% (73–96)

ATP

MITT

[51]

[51]

6 month persistent cervical infection with HPV 16/18

96% (75–100)

94% (78–99)

80% (70–87)

ATP

ITT

MITT

[50]

[50]

[52]

Not reported

CIN1+ caused by HPV16/18

89% (59–98)

MITT

[52]

100% (<0–100)

100% (32–100)

ATP

MITT

[51] [55]*

[51] [55]*

CIN2/3+ caused by HPV 16/18

90% (53–99)

MITT

[52]

98% (86–100)

95% (85–99)

ATP

MITT

[54]

Vaccine efficacy regardless of infection status at study entry or during course of vaccination

CIN2/3+ caused by HPV 16/18

Not reported

44% (26–58)

ITT

[54]

Vaccine efficacy shown as the percentage reduction in the number of cases among vaccinated individuals, with 95% confidence interval given in brackets.

CIN, cervical intraepithelial neoplasia. ATP, according-to-protocol analysis. ITT, intention-to-treat analysis. MITT, modified intention-to-treat analysis.

*95% confidential interval reported by Schiller et al. [55] using Phase II data [51].

The preventive impact of a vaccine is quantitatively expressed as ‘vaccine efficacy’, which is the percentage reduction in the number of cases among vaccinated individuals relative to placebo. An overview of vaccine efficacy results is provided in Table 6.3. The initial phase II trials were aimed at studying efficacy among healthy young women with no evidence of current or past infection with the HPV types included in the vaccine formulation. Exclusionary criteria for enrolment, randomization, and/or efficacy analysis included report of seven or more (bivalent) or five or more (quadrivalent) sex partners in lifetime, abnormal cytology (bivalent), presence of antibodies to the targeted HPV types, and presence of HPV-DNA of the targeted HPV types (quadrivalent) or any HR-HPV types (bivalent) at or before study entry [57]. High (over 80 per cent) vaccine efficacies against incident HPV infection, persistent infection, abnormal cytology and disease were observed in both according-to-protocol (ATP) and (modified) intention-to-treat (ITT) analyses [49–51,57].

A Phase II efficacy trial of Gardasil® among young men was underway at the time of writing, but results are not yet available. This trial will assess vaccine efficacy, safety, and immunogenicity in young men using the endpoints of HPV infection, and genital warts [55]. Among participating men who have sex with men, a further endpoint of anal dysplasias will be evaluated [55].

Phase III trials among women have been considerably larger in size (>18,000) than the Phase II trials, and thus were better suited to investigate disease endpoints for vaccine efficacy [52,54]. Participants ranged from 15 to 26 years of age and reported four or fewer sex partners in their lifetime at enrolment. Unlike the phase II trials, women in phase III trials were not necessarily excluded if they had current HPV infection or evidence of past infection, indicated by detection of antibodies for the targeted HPV types. This inclusion allows for the assessment of vaccine efficacy as it might be expected in the general population, and according to a variety of characteristics related to infection status, serostatus and disease state [47].

Interim results from these phase III trials have been reported [52,54] and follow-up of participants for at least four years is going on. In the according-to-protocol (ATP) analyses, vaccine efficacy was greater than 90 per cent against persistent infection, abnormal cytology, and disease related to the targeted HPV types (Table 6.3). ATP analyses were generally limited to women who were DNA-negative and sero-negative to the vaccine-targeted types at study entry, who received all three vaccine doses, who had no protocol violations, and who remained DNA-negative during the full course of vaccination (bivalent) or until one month after the last injection (quadrivalent).

Modified ITT analyses of the phase III trials included women who received at least one dose but excluded women who were HPV DNA positive for a targeted type at enrolment. This modification to the ITT approach was done to investigate the effect of vaccine in a susceptible population. These analyses provided somewhat lower estimates of vaccine efficacy than the per-protocol analyses, likely due in part to the inclusion of women who did not receive all three injections. Nevertheless, most still indicated high efficacy (Table 6.3) [52,54]. Results from these modified ITT analyses reflect what might be achieved in a universal vaccination programme that opted to vaccinate girls prior to initiation of sexual activity, and thus prior to HPV exposure.

ITT analyses from the Phase III studies would be expected to have the lowest estimates of vaccine efficacy, since these included women regardless of their infection status at enrolment. These estimates give a sense of what might be expected upon administration of vaccine to the sexually-active general population irrespective of whether or not there has been exposure to HPV, which is not the intended policy for HPV vaccination guidelines. Results of such an analysis are available from the phase III trial for Gardasil® (Table 6.3) [54]. Twenty-seven per cent of study participants were HPV DNA-positive and/or sero-positive for the vaccine-related types at study entry. When these women were included in the analysis, vaccine efficacy was 44 per cent (95 per cent CI 26-58) against CIN2 or higher-grade lesions (CIN2+) caused by HPV 16/18 and 17 per cent (95 per cent CI 1-31) against CIN2+ caused by any HPV type [54]. These lower efficacy results are not surprising given that neither the bivalent nor quadrivalent vaccines showed evidence of efficacy against clearance or disease progression in women who were already infected with HPV 16 or 18 at enrolment [47]. That is, no therapeutic effect was observed. Nonetheless, even among women who were already infected with between one and three HPV types targeted in the quadrivalent vaccine, there was still protection against infection with the remaining type(s) [58].

The safety profiles of both vaccines have been shown to be similar to other non-infectious protein subunit vaccines such as tetanus or hepatitis B vaccine [47,55,56]. Immediate local adverse events were commonly pain, erythema, and swelling at the injection site. Systemic symptoms such as fever, myalgias, headaches, and gastrointestinal irritability were reported but did not significantly differ between study groups. The proportions of serious or pregnancy-related adverse events were also equivalent between study groups.

Both the bivalent and quadrivalent vaccines are highly immunogenic [47,55]. Seroconversion rates are 100 per cent one month after administration of all three doses, with peak geometric mean antibody titres (GMT) typically 100-fold higher than those resulting from natural infection. Over time, GMTs decline to a plateau at least 10-fold higher than that seen in natural infection, with no indication of a decline five years post-vaccination. Furthermore, there is evidence of a B cell memory response, which would be required for long-term immunity [47,55]. Immunogenicity as well as safety has also been documented among women outside the age range of the phase II and III clinical trials (i.e. girls aged 9–14 and women aged 27–55 years) [47]. The quadrivalent vaccine is similarly immunogenic and safe among boys aged 9 to 16 years [55].

The currently-available HPV vaccines were specifically designed to target a limited number of HPV types (bivalent: 16, 18; quadrivalent: 6, 11, 16, 18). Nevertheless, there is a biological basis for cross-protection against other types, and preliminary clinical evidence for cross-protection against types 31 and 45 is emerging [47,55,59]. Confirmatory evidence for the extent of cross-protective efficacy and its duration is eagerly awaited. The fact remains that an ideal HPV vaccine would be able to induce strong immunity against a broad spectrum of types.

Given the evidence for efficacy, safety, and immunogenicity that emerged from the phase II and III clinical trials and bridging studies, the two HPV vaccines have been licensed for use in over 80 countries in the world, including a US FDA license (Gardasil®) and European Medicines Agency (EMEA) licenses [48].

Implementation of HPV vaccination

The licensure of HPV vaccines prompted a broad discussion regarding the most appropriate public health policy for whether and how to implement these vaccines in many countries throughout the world [60,61]. The key issues are cost, target age for vaccination, and concerns regarding vaccination for a sexually-transmitted infection [48]. Currently, the cost of HPV vaccine far exceeds the financing abilities of developing countries and most middle-income countries, many of which have the highest rates of cervical cancer globally. Immediately following approval, the costs in the United States were around $300 to $500 for the three doses needed, but different purchasing agreements and competition from the second vaccine have led to costs of around $150 or perhaps lower; agreements in different countries are often confidential. International agencies (e.g. the Global Alliance of Vaccines and Immunization, the Pan American Health Organization Revolving Fund, UNICEF) will play an important role in easing the introduction and implementation of vaccines to developing countries [48,60,62]. Centralized procurement via these international mechanisms could result in far more affordable prices. Moreover, as seen with HBV, the cost of vaccination will gradually decline during the next decade, presumably to levels that will permit cost-effective deployment to developing countries.

The most appropriate age for vaccination must be balanced between what is expected to have the most health impact and what is most feasible given existing public health infrastructure. Currently, there is agreement that vaccination should occur prior to sexual initiation, or soon afterwards, i.e. pre-adolescent and adolescent girls [60]. This strategy is feasible in some developed countries that already have successful school-based vaccination programmes for this age group (e.g. HBV vaccine), but in other countries an adolescent programme would be a considerable challenge [60]. Conversely, infant vaccination programmes are universal and could have far greater impact for HPV and cervical cancer prevention, should immunity induced by these vaccines prove to be long-lasting [48].

Because HPV is a sexually transmitted virus, a unique set of concerns arise, particularly among conservative cultures in which sexuality among young people and/or the unmarried is taboo [48]. Some fear that HPV vaccines would increase sexual activity among youth, perhaps hastening sexual initiation, as it would send a message that society encourages or at least tolerates adolescent sex. These arguments against HPV vaccination are analogous to similar concerns that have been raised regarding sex education programmes or condom distribution among adolescents; however, there is strong evidence that such programmes result in safer sex behaviours or even delayed engagement in sexual activity [63]. This highlights the importance of incorporating broader sexual health counselling in adolescent-based HPV vaccination programmes, which could similarly address concerns that vaccination would adversely affect condom promotion and other safer sex messages [4]. Another argument against vaccination has been that a girl who would only have sex with one partner, her husband, would not be at risk of HPV infection and cervical cancer. Yet rates of acquisition are high in women's first sexual relationships [23]. Furthermore, in many parts of the world men report more partners than women, both before and after marriage, meaning that having sex with only one's husband does not eliminate the risk of HPV exposure [64]. A vaccine strategy targeted only towards women who have multiple partners (or other high-risk groups such as patients attending STD clinics) is likely to fail, given the lessons learned from attempts to implement hepatitis B vaccine in this fashion [4] and the fact that HPV vaccination is only maximally effective before HPV exposure. This past experience led to the conclusion that universal vaccination of young adolescent girls must be the goal of any HPV vaccine implementation strategy [48].

Long before efficacy data became available from clinical trials, public health researchers began to project the public health and economic impact of HPV vaccines under various implementation strategies [65]. As these vaccines became reality, research activity in this arena expanded exponentially [66–71]. Encouragingly, findings have been largely consistent across models. Models project that HPV vaccines would have a substantial impact on reducing HPV infections and cervical cancer, particularly in developing countries with no screening programmes. Vaccine implementation could be extremely cost-effective in scenarios in which the per-woman cost of vaccination is under $25, and/or when existing cervical screening strategies are modified (see next section). These mathematical models depend on a set of assumptions regarding the epidemiological parameters for HPV infection, progression to cervical pre-cancers and cancer, and long-term vaccine-induced immunity. Although many of these parameters have good estimates for various populations, uncertainties remain. One of the most influential parameters is the duration of protection that is provided by the vaccines, which is currently unknown. Observing the extent and duration of vaccine-acquired as well as naturally-acquired HPV immunity is a research priority.

Although vaccine efficacy among males is not yet known, the use of Gardasil among adolescent boys has been approved in the European Union, Australia, and elsewhere [55] for reasons of gender equity, although publicly funded vaccination is only available for girls. The benefit of vaccinating boys is a debated issue, which will only intensify should male vaccination prove to be efficacious. Prevention of HPV-related outcomes among males would be to their direct health benefit; nevertheless, HPV-related cancers are far rarer among men than they are in women. Male vaccination may also benefit women through herd immunity, in that it could break the chain of heterosexual HPV transmission in a population. Assuming 100 per cent protection in preventing HPV infection by the target types, models have only shown a cost-effective benefit of vaccinating boys when vaccine coverage among girls is low. Therefore, some argue that targeting resources to achieve high vaccine coverage in girls may prove to be more productive [55].

Cervical cancer screening and the projected impact of vaccination

Pap test screening as the mainstay of cervical cancer control

Following its introduction in or before the 1960s in many countries, the Papanicolaou cytology technique (Pap test) is undoubtedly the cancer screening test with the best record of accomplishments in contemporary medical practice [11]. Pap test screening targets the detection of pre- invasive cervical neoplastic lesions, thereby allowing close monitoring of equivocal or low-grade abnormalities on repeat tests or immediate referral for colposcopy, biopsy, and treatment of high grade or more severe lesions. This strategy permits preventing cervical cancer by arresting neoplastic development within the cervical epithelium before it becomes invasive.

Organized or opportunistic Pap screening has been the primary reason for the substantial reductions in cervical cancer morbidity and mortality in high-income countries. However, the economic burden imposed by cervical cancer screening is substantial. In most Western countries, for each new case of invasive cancer found by Pap cytology there are approximately 50 to 200 other cases of abnormal smears consistent with equivocal atypias or precursor lesions, which require triage and clinical management. Overall, these secondary screening activities impose a great financial burden on the health care system of countries that maintain cervical cancer screening programmes.

Most developing countries have yet to derive the same benefit from Pap test screening that developed countries have experienced, either because programmes have not been implemented at all or were instituted without the entire chain of components of quality assurance and follow-up procedures that are necessary for screening to be effective. As a result, incidence of cervical cancer has continued to increase in many Latin American, African, and Asian countries, possibly due also to the liberal changes in sexual mores that began in the 1960s that led to more widespread HPV transmission. Furthermore, the reductions in cervical cancer morbidity seen in many western countries have begun to stabilize which brings a sense of diminishing returns.

In spite of its success in developed countries, Pap cytology has important limitations related to the inherently subjective interpretation of morphologic alterations in cervical samples, sampling variation, and fatigue that results from the repetitive nature of reading smears. In consequence, the sensitivity of Pap cytology to detect high-grade CIN or invasive cervical cancer is relatively low at 51 per cent, whereas its specificity is considered high, at 98 per cent [72]. Therefore, the Pap test's high false negative rate is its most critical limitation. The advent of liquid-based cytology techniques has contributed to mitigate the problem of efficiency in processing cervical samples but the limitations of cytology remain the same [73]. This low sensitivity for an individual testing opportunity has to be compensated by the requirement to have women entering the eligible screening age-range with an initially negative smear to repeat their tests at least twice over the next 2 to 3 years before they can be safely followed as part of a routine screening schedule. This effectively brings a programme's sensitivity to acceptable levels but safeguards must be in place to ensure compliance, coverage, and quality; costly undertakings that have worked well only in western industrialized countries.

Cervical cancer screening post-vaccination

Despite the enthusiasm regarding the prospect from HPV vaccination, cervical cancer screening must continue after vaccination for a number of reasons. First, both vaccines are effective as pre-exposure prophylaxis for disease caused by HPV-16 and -18; however, women currently infected with these viruses may not derive any benefit [74]. Moreover, the target types included in the two vaccines are causally linked to about 70 per cent of all cervical cancers (Figure 6.5) [35]; therefore, even in a scenario of 100 per cent vaccine effectiveness and 100 per cent vaccine coverage, screening would still be necessary to detect lesions caused by other HR-HPV types. Although some degree of cross-protection against infection with phylogenetically-related HPVs (e.g. HPVs 45 and 31) has been observed [47], there is also a possibility of an increase in prevalence of other HPV types in vaccinated populations, as a result of the vacated ecologic niches following the progressive elimination of HPVs 16 and 18 (a yet unproven phenomenon known as type replacement). There is also the possibility that the type-specific immunity conferred by vaccination may wane over periods extending beyond five years.

Despite these caveats, a vaccinated woman may experience much lower risks of developing pre-cancerous lesions over a period that may extend for a decade or longer. Subsequent intensive screening via annual or biennial Pap cytology may waste resources while providing only marginal additional benefit beyond that conferred by immunization during a woman's main reproductive years. Implementation of HPV vaccination will impose a substantial burden on the health budgets of most countries. Proper planning of cervical cancer screening, an intervention that represents today a key healthcare expenditure, may help offset the costs that will stem from vaccination.

Expected impact of vaccination on screening practices

As the successive cohorts of vaccinated young women reach screening age there may be a gradual reduction in cervical lesion prevalence. Decreases in colposcopy referral rates to about 40 per cent to 60 per cent or less of the existing case loads in most Western countries are plausible, judging from attributable proportion estimates [75] and preliminary findings from vaccination trials [76]. Such reductions are likely to translate into initial savings to the health care system or to individuals. It is expected that the vaccine-induced decrease in cervical lesion prevalence may lead to a degradation of Pap cytology performance (because of a decreased expectation of abnormalities on a day's smear workload) and a decline in the positive predictive value of Pap cytology (due to reduced lesion prevalence) [77,78].

In the longer term, a statistically noticeable reduction of the burden of cervical cancer via HPV vaccination is unlikely to be observed for at least 10 to 15 years even if vaccine coverage is high because of the dual facts that vaccination below age 20 will not affect high grade CIN rates appreciably for 5 to 10 years and another 5 to 15 years will be necessary for this to be translated into reductions in cancer incidence. A paradoxical situation may arise if vaccine uptake is higher or happens exclusively among women who will eventually be adherent with screening recommendations. If adolescents and young women who are more likely to be vaccinated are also the ones destined to be screened regularly, the reduction in incidence of cervical abnormalities will happen nearly exclusively among such women. The fact they will benefit from screening makes them less likely to develop cervical cancer even if they had not been vaccinated, because any pre-cancerous lesions may eventually be found and treated. On the other hand, young women who were not vaccinated because of inability to pay may also be less likely to be screened and their undetected lesions will progress until invasion occurs, when the associated symptoms will then lead them to seek medical attention, which will then reveal cervical cancer [77]. This undesirable scenario of compounded social inequity is unlikely to occur in countries that already enjoy the benefits of an organized screening programme that reaches all women. Such high-income countries are also likely to adopt an organized and universal vaccination programme that benefits all segments of society.

New screening options following HPV vaccination: HPV DNA testing

HPV DNA testing in cervical cancer screening largely circumvents the limitations of Pap test screening, and has other advantages in a post-vaccination world [79]. HPV testing has much higher sensitivity than cytology but only slightly lower specificity in women 30 years or older [80–83]. Furthermore, HPV DNA testing is reproducible for large-scale implementation and eliminates the subjective interpretation of cytology. Adoption of this method could potentially lengthen the screening intervals and have fewer quality control requirements, which would result in more affordable and sustainable screening, particularly in developing countries. Randomized controlled trials of HPV testing in primary cervical cancer screening are currently ongoing and many have already provided results in support of this method's superior performance in detecting cervical cancer precursors with a greater margin of safety than Pap cytology (reviewed in [78]).

HPV DNA-based cervical cancer screening would also serve the purpose of a surveillance mechanism post-vaccine implementation, thus allowing an efficient and low-cost strategy to monitor long-term protection among vaccinated women while providing the benefit of continued screening. As HPV typing becomes incorporated in future HPV assays there will be an improved opportunity to manage HPV positive cases and to gain insights into the long-term effectiveness of vaccination [77].

Simply making cytology screening less frequent may not be a viable strategy to achieve a cost-effective combination of vaccination and screening. The anticipated reduction in the prevalence of pre-cancerous lesions requires rethinking the optimal screening approach. This decline in prevalence will necessarily result in a lower positive predictive value of both Pap and HPV screen tests. However, the accuracy of Pap tests is expected to be more adversely affected because it is prone to the vagaries of subjective interpretation, particularly in conditions of low lesion prevalence [78]. Conversely, HPV testing has the screening performance characteristics that would make it an ideal primary cervical cancer screening test in such conditions. Pap cytology should be reserved for triage settings, i.e. in assisting management of HPV positive cases. Among HPV-positive patients, the prevalence of pre-cancerous lesions will be high, leading to enhanced accuracy of the Pap test [78]. The advantages of the proposed approach have been described elsewhere [77,78] and are being evaluated in Finland [84], Northern Italy [85], and in British Columbia, Canada.

Expected impact on other HPV-associated cancers

HPV has been implicated in the development of malignancies of other anogenital sites besides the cervix including vagina, vulva, penis, and anus [20]. Unlike cervical cancer, in which 100 per cent of cancers are caused by HPV, cancers of other anogenital sites show lower risk attributions for HPV. It is estimated that 90 per cent of anal cancers, and 40 per cent of vaginal, vulvar, and penile cancers are attributable to HPV [1]. It is also thought that HPV may cause a substantial proportion of other anogenital malignancies and those of the upper aero-digestive tract [20].

Vaginal and vulvar cancers

Cancer of the vagina is extremely rare with an average incidence rate of approximately 1 new case per 100,000 women per year worldwide [86]. HPV seems to play a central role in the causal pathway. HPV-DNA is detected in 64 per cent to 91 per cent of vaginal cancers and 82 per cent to 100 per cent of their precursor lesions (vaginal intraepithelial lesions of grade 3) and HPV-16 appears to be the most prevalent type [87]. The model of vaginal cancer pathogenesis is very similar to that of cervical cancer and indicates the central role of HPV as the central sexually-transmitted agent [20]. Women with primary vaginal carcinoma are more likely to have been previously diagnosed with an anogenital tumour, particularly of the cervix [88].

Invasive squamous cell carcinoma of the vulva is relatively rare at slightly less than 5 per cent of all female genital tract malignancies but its incidence has increased over the past 30 years, especially in young women [89]. Approximately 60 per cent of vulvar cancers contain HPV DNA, particularly of HPV-16 [16,90]. However, there seem to be two distinct, age-dependent risk factor profiles for vulvar cancer [20]. Those affecting older women tend to be keratinizing squamous cell carcinomas and are rarely associated with HPV (less than 10 per cent). Vulvar cancers that have an early age of onset tend to be warty or basaloid carcinomas and constitute an HPV-related subgroup of tumours (60 per cent to 90 per cent are positive for HPV) [87]. These HPV-positive tumours seem to have become more frequent in recent decades and tend to have the same risk profile as other HPV-related anogenital cancers, i.e. association with high-risk sexual behaviours [20].

Findings on the efficacy of vaccination in preventing vaginal and vulvar pre-cancerous lesions with the quadrivalent vaccine [Gardasil®] are available [91]. Evidence suggests that the quadrivalent vaccine is highly effective against vulvar and vaginal intraepithelial neoplasia over a mean follow-up of 3 years. In the according-to-protocol analysis, vaccine efficacy was 100 per cent (95 per cent CI 72-100); this analysis was restricted to susceptible women who were HPV 16/18 DNA-negative and sero-negative to HPV 16/18 at study entry, who remained DNA-negative throughout the vaccination period, received all three doses, and did not violate the protocol [91]. The intention-to-treat (ITT) analyses estimated vaccine efficacy of 71 per cent (95 per cent CI 37-88) for lesions associated with HPV 16/18, and 49 per cent (95 percent CI 18-69) against lesions regardless of HPV type detected. These encouraging results suggest that the umbrella of protection conferred by HPV vaccination may be wide enough to potentially prevent all female lower genital tract cancers associated with the vaccine-targeted HPV types.

Penile cancer

Most penile cancers are squamous cell carcinomas and are a very rare disease in developed countries in Europe and North America, where incidence rates vary between 0.3 to 1 case per 100,000 men-years. Incidence is higher in parts of Africa (Uganda), Asia, and South America (Brazil and Colombia) at up to 4 cases per 100,000 men-years [92]. The exact etiologic mechanisms that lead to the development of penile cancer are largely unknown although the assumed attributable risk for HPV is 40 per cent [1]. Similarly to vulvar cancer, basaloid or warty penile carcinomas are most likely to contain HPV DNA (up to 100 per cent), whereas the more common keratinizing carcinomas have a lower HPV prevalence (30 per cent to 40 per cent) [93]. HPV-16 is also the most prevalent type in HPV-related penile cancer [94].

Clinical evidence for the efficacy of HPV vaccines in preventing penile cancer is not anticipated to become available from clinical trials among men due to the rarity of this cancer. Unlike pre-invasive lesions of the vulva and vagina, which serve as acceptable endpoints for judging vaccine efficacy, identification of penile intraepithelial neoplasia is yet to be widely used in practice, and thus no surrogate endpoints for vaccine efficacy are available for penile cancer. Any population-based impact will be documentable only during post-vaccination surveillance. Even in populations that opt to vaccinate only females, rates of penile cancer may decline as a secondary outcome of reduced HPV infection among women and less opportunity for transmission to male partners. It has been known that men are more likely to develop pre-cancerous lesions of the penis that are associated with HPV when their partners have cervical intraepithelial neoplasms [95].

Anal cancer

Anal cancer is relatively rare although the incidence among both men and women has increased by more than two-fold over the last 40 years [96]. Globally, nearly 100,000 new cases of anal cancer were reported in 2002 [10]. Rates of anal cancer are considerably higher among homosexual men [97]. Similarly HIV-positive men and women, transplant recipients, and women with cervical squamous intraepithelial lesions are at a higher risk than the general population [96,97].

HPV is detected in 83 per cent to 95 per cent of anal cancers, with an attributable risk estimate of 90 per cent [1]. As in cervical cancer, HPVs 16 and 18 are the most common types in anal carcinoma specimens. The model of anal cancer pathogenesis is very similar to that of cervical cancer. HPV infection is associated with the development of low- and high-grade anal precursor lesions, with eventual progression to invasive anal cancer.

Given the similarity between cervical and anal carcinogenesis, the efficacy of HPV vaccines in preventing anal pre-cancers and cancer is expected to be analogous to findings for cervical lesions, although clinical data are not yet available. Results from the ongoing Gardasil® vaccine trial in homosexual men will be particularly revealing regarding efficacy against anal pre-cancers [55].

Head and neck cancer

In 2002, head and neck cancer (cancers of the oral cavity, pharynx, and larynx) was ranked as the sixth leading cause of cancer deaths worldwide, with extensive variation by sex and geographic region [10]. However, the results of many studies suggest that head and neck cancer, particularly oral tongue cancer, is increasing in young adults internationally [98].

Evidence supports the idea that head and neck squamous-cell carcinoma is a multi-factorial disease with at least two distinct pathogenesis models, a dominating one involving smoking and alcohol consumption, and the other driven by HPV [99]. An average of 40 per cent of cancers of the oral cavity and pharynx are HPV-positive, and attributable risk per cents are 5 per cent and 16 per cent, respectively [1]. The association is strongest in the oropharynx, particularly in the tonsil [100,101]. Sexual activity has been associated with increased risk and husbands of women who had cervical cancer are more likely to be diagnosed with these cancers [102]. Among HPV-positive head and neck cancers, HPV-16 and HPV-18 are most prevalent [87].

Ongoing vaccination trials have not included a protocol for identifying the onset of oral pre-cancerous lesions among study participants. Moreover, classification schemes for such pre-cancerous lesions are not yet widely used, particularly among young women, the main group included in vaccine trials and demonstration projects. This population group has very low risk of developing such oral lesions. Therefore, it is only via cancer surveillance post-vaccination deployment that it will be possible to ascertain any possible impact on head-and-neck cancers. Any such impact is not expected to be verifiable before a decade or more has passed since HPV vaccination.

Future developments in HPV vaccines

Outstanding research questions for current HPV vaccines

A multitude of research questions regarding the current bivalent and quadrivalent HPV vaccines are being posed by researchers and public health officials. In the very near future, updated results from the phase III trials are expected to become available. These findings will be important for more precise estimates of vaccine efficacy with longer follow-up of trial participants. Results from the phase II efficacy trials of the quadrivalent vaccine among males are also eagerly anticipated.

One of the key research questions is the duration of vaccine-induced immunity, a most influential variable in cost-effectiveness analyses. Only long-term follow-up of trial participants, large community-randomized trials, and phase IV surveillance post-introduction will determine whether induced immunity is long-lasting or if a booster will be required to maintain protective antibody titres. Such long-term data will also establish the minimum level of antibody titres required for immunity (a correlate of protection), which is unknown at this point. These studies will also provide data on long-term safety and cross-protection against HPV types not included in these vaccines.

Large community-randomized trials of HPV vaccination, such as those ongoing in Finland, will be ideal to investigate herd immunity [103], which is the phenomenon in which infectious disease spread may cease in a population, even though all are not immunized. As the proportion of immune individuals in a population rises, there are fewer opportunities for contacts between infected and susceptible persons. Therefore, less than 100 per cent vaccine coverage may still result in elimination of a pathogen. Many mathematical models have explored the extent of protection that may be achieved with various levels of vaccine coverage among girls alone, or among girls and boys [103]. The large community-randomized trials will be instrumental to determine whether the modelled effects hold true with empirical data [103].

There has been theoretical concern that elimination of some, but not all, circulating HPV types could lead to type replacement, in which the ecological niche vacated by HPV types 16 and 18 would simply be filled by other HR-HPV types. Although there is little biological plausibility for type replacement, this must be verified empirically in long-term studies [103]. Thus far, epidemiologic studies have not provided evidence that HPV types compete for specific ecological niches [104].

The most dramatic potential for an impact on cervical cancer rates will be in developing countries, many of which have only partial, ineffective, or absent screening programmes. In addition to cost barriers, the current VLP vaccines require refrigeration at 4°C and this may challenge their implementation in some developing countries [45]. New vaccine technologies eliminating the need for cold chain storage will be helpful for global efforts.

Second generation vaccines

The two currently available vaccines, Gardasil® (Merck & Co., Inc., NJ, USA) and Cervarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), are based on L1 VLP technology and were designed to target specific HPV types 16 and 18 (and additionally 6 and 11 in Gardasil®). Although some evidence of cross-protection against HPV types 31 and 45 is emerging, it would be desirable to broaden protection to additional oncogenic types. Availability of an HPV vaccine that prevented the full spectrum of HPV types that can cause cancers would be the ultimate cancer control strategy by obviating the need for screening programmes in the future.

One option is using polyvalent L1-based VLP vaccines that would target additional HR-HPV types. Merck is exploring this possibility with an octovalent vaccine against types 6, 11, 16, 18, 31, 45, 52, and 58 but results are not available yet [45]. Another option is an L2-based VLP vaccine, which could generate broad-spectrum antibodies against all alpha-papillomavirus types, eliminating the need for an approach targeted to specific types; such an L2-based vaccine is currently in development [45].

A critical caveat of prophylactic HPV vaccination is that it is ineffective against infections that have already become established, either productive or latent. Therefore, development of therapeutic HPV vaccines is a worthwhile pursuit. There is feverish research activity to this end, with many promising candidate vaccines, but, so far, few formulations have reached the stage of Phase II trials [45,105]. Ultimately, the availability of one or more efficacious therapeutic vaccines will contribute a key supplemental strategy towards the goal of cervical cancer eradication.

Conclusion

There is cautious optimism that universal implementation of HPV vaccination as pre-exposure prophylaxis of young adolescent women is likely to exert maximal impact on the future burden of cervical cancer in most countries. Optimism is without reservation when it comes to projections for developing countries, in which the beneficial impact is expected to be greater. There is also consensus that vaccination will not reduce risk of cancer for most women who are already genitally exposed to HPVs of the vaccine-targeted types.

Policymakers should not be misled by the promises of the new preventive technologies. A key objective for cervical cancer control is that the protection by HPV vaccination (based on today's technology which does not provide protection against all HR-HPVs) must be supplemented by the protection given by screening. Improper implementation of screening or relaxation of its safeguards may have a deleterious effect. As discussed in this chapter, worrisome scenarios may emerge as a result of misguided policies. For instance, uptake of vaccination mainly by the wrong age groups may occur if countries delay implementing universal vaccination of girls but aggressive marketing of vaccines leads to high uptake among older women who are already assiduous clients of screening. If the latter situation is eventually compounded by lower screening coverage, or relaxation of quality control activities required in screening programmes, cervical cancer rates may actually increase. Another concern is that countries may feel pressured to decrease expenditures needed to maintain cytology screening immediately following the investments committed to HPV vaccination. The cancer control dividends from HPV vaccination will take two or more decades to be realized via appreciable reductions in cervical cancer incidence. However, it is relatively easy to immediately lose the gains in reduction of disease burden that comes from screening. Policymakers in both high- and low-resource settings are urged to consider that primary (vaccination) and secondary (screening) prevention act by intervening at different points in the natural history of cervical cancer and imply actions in women of different ages. The constant changes in technology may pose a challenge to proper policy-making. As indicated in this chapter, the existing cytology screening paradigm will need to be re-considered post-vaccination in light of the strong evidence that is now available concerning the superiority of HPV DNA testing. To avoid missteps countries are urged to enforce only evidence-based decisions that are accepted by all stakeholders in the multi-disciplinary blend of disciplines that now characterizes cervical cancer prevention.

Acknowledgements

ANB is recipient of a pre-doctoral research studentship from the National Cancer Institute of Canada and the Canadian Cancer Society (NCIC/CCS). Funding for the HPV and cervical cancer research programme in the authors’ unit has been provided by multiple grants from the Canadian Institutes of Health Research, US National Institutes of Health, and NCIC/CCS. Supplemental unconditional funding has also been provided by Merck-Frosst for projects unrelated to HPV vaccination.

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Notes:

1 Ann N. Burchell, PhD, Division of Cancer Epidemiology, McGill University; and Eduardo L. Franco, MD, DrPH, Professor of Epidemiology and Oncology, Director, Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada.