Prophylactic human papillomavirus vaccination and primary prevention of cervical cancer: issues and challenges

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1 REVIEW /j x Prophylactic human papillomavirus vaccination and primary prevention of cervical cancer: issues and challenges M. Poljak Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Abstract Two prophylactic human papillomavirus (HPV) vaccines have been recently approved: one quadrivalent and the other a bivalent vaccine. When administered in a three-dose course to HPV-naive individuals, both vaccines exhibited excellent safety profiles and were highly efficacious against targeted clinical endpoints in large-scale international phase III clinical trials. Where coverage has been high for the appropriate target population, a reduction of HPV-related diseases with the shortest incubation periods has already been seen. By March 2012, universal HPV vaccination had been introduced into national vaccination programmes in more than 40 countries, but only in a few low-income and middle-income countries. With the growing market for HPV vaccines and competition between manufacturers, negotiated prices are already beginning to decline although they still remain out of reach of many countries. The great majority of countries are struggling to reach a level of coverage that will have the most impact on cervical cancer rates. Increasing coverage and improving completion of the HPV vaccine schedule, particularly of sexually naive females, is now the most important public-health issue in HPV vaccine efforts. A clear strategy for integrating primary (HPV vaccination) and secondary (screening) cervical cancer prevention must be agreed as soon as possible. Several second-generation prophylactic vaccines are being developed with the aim of resolving some of the limitations of the two current HPV prophylactic vaccines. Keywords: Cervical cancer, human papillomaviruses, vaccination Original Submission: 25 March 2012; Accepted: 9 May 2012 Editor: M. Paul Clin Microbiol Infect 2012; 18 (Suppl. 5): Corresponding author: M. Poljak, Institute of Microbiology and Immunology, Medical Faculty, Zaloška 4, 1105 Ljubljana, Slovenia mario.poljak@mf.uni-lj.si Human papillomaviruses Human papillomaviruses (HPV) are aetiologically linked to various benign and malignant neoplastic lesions of mucosal and skin epithelia. At present, 148 distinct HPV types are officially recognized, ranging from HPV-1 to HPV-152 (HPV- 46, HPV-55, HPV-64 and HPV-79, which have not met the criteria as unique HPVs, are now classified as subtypes) [1]. All known HPV types are classified on the basis of the similarity of their genome into five genera (a, b, c, l, m) and 33 species. Approximately 40 HPV types from the a genus infect the mucosal epithelium, with a subset of 12 types that are associated with lesions that can progress to cancer [2]. These cancer-associated or high-risk HPVs are the aetiological agents of virtually all cervical carcinomas and their immediate precursors high-grade cervical intraepithelial neoplasias. The two most important high-risk types are HPV- 16 and HPV-18, which are found in 70% of cases of cervical cancer. In addition to cervical carcinoma, high-risk HPVs also play the leading aetiological role in the development of anal and vaginal cancers and a substantial proportion of penile, vulvar and oropharyngeal (tonsillar) cancers. Low-risk HPV genotypes (the most important are HPV-6 and HPV-11) are causally involved in the development of virtually all genital warts and laryngeal squamous cell papillomas of both genders. The burden of HPV-associated vaccine-preventable tumours Cervical cancer is the third most common cancer in women, causing an estimated cases and deaths in 2008 [3]. Cytological screening has dramatically reduced the burden of cervical cancer in countries that have implemented wide-scale screening programmes. The major burden of cervical cancer (over 85%) today therefore occurs in developing countries with little or no access to screening programmes [4]. Although other HPV-associated cancers are significantly rarer than cervical cancer, a recent analysis of US cancer Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases

2 CMI Poljak HPV vaccination: issues and challenges 65 registry data estimated that the total HPV-related cancer burden for non-cervical cancers in the USA is of the same magnitude as their cervical cancer burden [5]. A recent study showed a remarkable increase in the population-level incidence of HPV-positive oropharyngeal cancers from 1988 to 2004 in the USA and predicted that by 2020, the annual number of HPV-positive oropharyngeal cancers will surpass that of cervical cancers [6]. Genital warts are common and frequently self-limiting benign tumours but they pose a considerable burden because of the embarrassment, shame, pain and financial costs of treatment [4]. Laryngeal squamous cell papillomas are a rare disease (incidence 1 4 per ) associated with high morbidity and with potentially devastating consequences for the patient. Current HPV prophylactic vaccines Two prophylactic HPV vaccines have so far been approved by the European Medicines Agency and the US Food and Drug Administration: a quadrivalent vaccine targeting HPV-6, HPV-11, HPV-16 and HPV-18 (Gardasil or Silgard; Merck and Co., Whitehouse Station, NJ, USA) and a bivalent vaccine targeting HPV-16 and HPV-18 (Cervarix; GlaxoSmithKline, London, UK). Current European Medicines Agency and US Food and Drug Administration indications for both vaccines are presented in Table 1. Both vaccines contain L1 virus-like particles of the respective HPV types, which contain no HPV DNA and are neither infectious nor oncogenic. The quadrivalent vaccine uses an aluminium salts adjuvant and the bivalent vaccine uses an AS04 adjuvant system. When administered in a three-dose course to HPV-naive individuals, both vaccines exhibited excellent safety profiles and were highly efficacious against targeted clinical endpoints in large-scale international phase III clinical trials [7 14]. In addition, the first evidence of the impact of HPV vaccination in the general population recently came from Australia, one of the first countries to introduce free universal HPV vaccination, with a three-dose coverage of 70% in women aged years [15]. Studies from Australian sexual health clinics have shown a remarkable decline in the incidence of genital warts [16,17] and from the Victorian Cervical Cytology Registry a modest but significant decline in histologically confirmed high-grade cervical lesions since the implementation of HPV vaccination with the quadrivalent HPV vaccine in 2007 [18]. There was also a 39% decline in the incidence of genital warts among heterosexual men of the same age (nonvaccinated population), but not among older women or men who have sex with men, which provides the first evidence of a possible herd immunity effect of HPV vaccine [16]. Several in-depth reviews of the safety and efficacy of current prophylactic HPV vaccines are available in the literature [11,19 23]. The purpose of this review is to provide a brief summary of the most important current issues and challenges. Current status of HPV vaccine implementation Since 2006, the quadrivalent and bivalent vaccines have each been licensed in more than 110 countries. Over 120 million doses of the vaccines have already been distributed. By March 2012, universal HPV vaccination had been introduced into national vaccination programmes in more than 40 countries across all continents. The USA, Australia and Canada were among the first countries to introduce HPV vaccine into their national immunization programmes, followed by several European countries (currently 23 European countries). TABLE 1. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) indications for quadrivalent vaccine (Gardasil) and a bivalent vaccine (Cervarix), as of March 2012 FDA EMA Gardasil Ò Cervarix Ò Gardasil is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by human papillomavirus (HPV) types included in the vaccine: cervical, vulvar, vaginal and anal cancer caused by HPV types 16 and 18 and genital warts (condyloma acuminata) caused by HPV types 6 and 11 and the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18: cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grade 1, vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3, vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3 and anal intraepithelial neoplasia (AIN) grades 1, 2 and 3 Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine: anal cancer caused by HPV types 16 and 18 and genital warts (condyloma acuminata) caused by HPV types 6 and 11 and the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18: anal intraepithelial neoplasia (AIN) grades 1, 2 and 3 Cervarix is a vaccine indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18: cervical cancer, cervical intraepithelial neoplasia (CIN) grade 2 or worse and adenocarcinoma in situ, and cervical intraepithelial neoplasia (CIN) grade 1. Cervarix is approved for use in females 9 through 25 years of age Gardasil is a vaccine for use from the age of 9 years for the prevention of: premalignant genital lesions (cervical, vulvar and vaginal) and cervical cancer causally related to certain oncogenic human papillomavirus (HPV) types and genital warts (condyloma acuminata) causally related to specific HPV types Cervarix is a vaccine for use from the age of 9 years for the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic human papillomavirus (HPV) types

3 66 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012 CMI Unfortunately, only a few low-income and middle-income countries had implemented vaccination in their national vaccination programmes by March 2012, mainly because of the high cost of vaccines. Panama and Mexico were among the first middle-income countries to introduce the HPV vaccine; Rwanda and Bhutan initiated national programmes only after having received vaccine through donations. The majority of countries implementing HPV vaccination have similar core vaccine recommendations, primarily targeting 9 14-year-old females (several countries only a single age group) but they differ significantly in catch-up recommendations (from none to all females of years of age). Public financing for HPV vaccination applies several approaches, ranging from free of charge availability to recommended populations (the majority of countries), free of charge availability to selected populations (e.g. US Vaccines for Children Program) or availability against reimbursement, including patient co-payment (e.g. France) [24]. Unresolved fundamental issues There are still several gaps in our understanding of the current performance of HPV vaccines. The most important unresolved fundamental issues are the duration of protection and the question of whether booster vaccinations are necessary and, if so, when. The duration of protection provided by the current vaccines is unknown but is over 8.4 years for the bivalent vaccine, over 5 years for the quadrivalent vaccine and over 9 years for the monovalent HPV-16 vaccine a non-commercial precursor to the quadrivalent vaccine [4]. It is also unclear whether a higher level of serum antibodies correlates with longer disease protection, because the minimum level of serum antibodies required to protect women from genital infection (immune correlate of protection) has not been established, and particularly because of the extremely small number of breakthrough infections detected in the clinical trials [25]. A recent finding that mice are protected from cervicovaginal challenge with HPV-16 pseudovirions, even if they have serum levels of antibodies that are 500-fold lower than the minimum that can be detected in an in vitro neutralization assay [26], suggests the possibility that detection of any vaccine-induced serum antibodies in women using standard assays indicates a level that is well above the minimum needed for protection [27]. Another important unresolved basic issue is the clinical significance of cross-protection or the efficacy of HPV vaccines against HPV types not specifically targeted by inclusion of the corresponding virus-like particles in the vaccine. Cross-protection against non-vaccine types is an important consideration, because non-vaccine HPV types are associated with c.30% of cervical cancers worldwide [27]. Although none of the phase III trials was specifically designed to evaluate cross-protection, both vaccines have been post hoc evaluated for protection against infection and cervical disease associated with HPV types phylogenetically related to HPV-16 and HPV- 18 [25]. Some cross-protection has been demonstrated for both vaccines in these analyses [13,28], although with a lower level of efficacy, with lower cross-neutralizing antibody titres and an unknown duration of clinical efficacy [18]. Evidence from a long-term follow up of a phase IIb trial of bivalent vaccine [29], suggests that the cross-protection recorded in the clinical trials might preferentially wane over time. Another question often raised is whether type replacement a viral population dynamics phenomenon defined as the elimination of some types, causing an increase of others, will be seen after the implementation of large-scale vaccination [30]. Type replacement occurs when partial competition exists among different types during natural infection and the vaccine does not provide cross-protection against competing types [31]. In HPV, natural competition does not appear to exist so type replacement is highly unlikely [30]. There is also a potential theoretical risk that a vaccine will generate new viral variants that are equally or even more oncogenic but not recognized by vaccine-induced antibodies. However, as HPV uses host cell DNA polymerases and has an extremely slow mutation rate, this risk is also minimal [30]. Increasing coverage and improving completion of the HPV vaccine schedule The proof-of-principle phase of HPV vaccine development is over [32]. Increasing coverage and improving completion of the HPV vaccine schedule, particularly of sexually naive preadolescent and adolescent females, is therefore now the most important public-health issue in HPV vaccine efforts [32,33]. At least 80% of sexually naive females need to be vaccinated against HPV if a major reduction in cervical cancer rates in women aged years is to be achieved by Unfortunately, the great majority of countries are struggling to achieve high coverage or to reach the level of coverage that will have the maximum impact on cervical cancer rates [19,24,34]. Numerous factors have contributed to the markedly different levels of coverage achieved to date, including public financing for vaccines, organized outreach to parents and girls, and acceptability, in addition to several paramedical reasons. In general, countries with school-based vaccination programmes have achieved higher coverage than those with opportunistic, clinic-based or primary care based programmes [35]. However, many countries lack any infra-

4 CMI Poljak HPV vaccination: issues and challenges 67 structure or experience in school-based vaccine delivery and school attendance among girls is low in some developing countries, so school-based vaccination is not necessarily the best option for all countries [4]. Anti-immunization groups spreading unfounded rumours and misinformation about HPV vaccine safety and claims that the vaccine is licensed and recommended only to increase corporate profits have severely damaged HPV immunization efforts in many countries, including some European countries [24]. Most misinformation about HPV involves rumours that HPV vaccines have caused deaths among vaccine recipients. Responsible investigation of these incidents, however, has shown that no deaths have ever been related to the vaccine [24,36]. In Romania, a national school-based programme to vaccinate females aged 11 was launched but has already temporarily been suspended twice (in 2008 and 2010/11) because of negative public reaction, lack of proper communication and a resulting low coverage of the target population, which did not reach 5%. In contrast, the UK has achieved remarkably high coverage in their targeted primary cohorts, through school-based delivery [24]. Whether this is a result of intensive follow up at the local level, facilitated by the availability of identification of individuals within each area s responsibility for vaccination, effective social marketing or supportive community attitudes following a highly publicized death of a young woman from cervical cancer is unclear [4]. Monitoring long-term safety and vaccine disease efficacy Given the likely absence of further large phase III clinical trials, it is extremely important that countries that have already implemented national vaccination programmes comprehensively evaluate long-term safety and any breakthrough infections of HPV vaccine types over the short and longer term [37]. Additionally, there are various ongoing international efforts to monitor the post-licensure impact of HPV vaccine on a global scale. Both manufacturers have strict post-licensure commitments to tightly monitor a proportion of women who were enrolled in the phase III trials [35]. A substantial amount of post-licensure safety data have already been accumulated and available data are reassuring [35,36]. Integration of primary and secondary cervical cancer prevention A clear strategy for integrating primary (HPV vaccination) and secondary (screening) cervical cancer prevention must be agreed as soon as possible [4,19,37]. An immediate necessary step is the linkage of an individual s HPV vaccination and cervical screening history. The implementation of HPV vaccination in each country should therefore be accompanied by the immediate establishment of a central (national/regional) HPV vaccination register, which should be linked with the cervical cancer screening register and central cancer register. In addition, cervical screening guidelines must be reviewed in the next 5 10 years. Because current HPV vaccines do not cover all cancer-associated HPV types, vaccination cannot yet replace screening. New cervical screening algorithms will certainly incorporate an HPV DNA test as the initial screening test (at least for vaccinated cohorts), because it provides superior and more durable negative predictive value against high-grade cervical disease than cytology and allows safe prolonged screening rounds [4]. A primary HPV DNA test has the advantage of immediately stratifying women into a current risk group based on the presence of high-risk HPVs at the time of screening, regardless of vaccination history [4,38]. HPV DNA-positive women will need a further triage using cytology, partial HPV typing or progression markers, because >90% of these women will have transient HPV infection that will resolve spontaneously and not progress to cancer. Gender-neutral HPV vaccination HPV vaccination efforts have so far been primarily targeted at females. However, after recent US Food and Drug Administration approval of a quadrivalent vaccine for males and the recent recommendations of the Advisory Committee on Immunization Practices of the US Centers for Disease Control and Prevention [39] and American Academy of Pediatrics [40] for the routine use of quadrivalent vaccine in boys aged 11 or 12 years, HPV vaccination can no longer be viewed as a female-only issue. Although the routine HPV vaccination of males is still controversial in many settings, partially because of the conflicting results of cost-effectiveness studies [41], ever more professionals are persuaded that gender neutral HPV vaccination is the only way forward. A universal HPV vaccination programme including males would not only provide direct protection against HPV-related diseases in males (genital warts, anal, penile and oropharyngeal cancers, particularly among men who have sex with men) but would also have significant indirect effects by providing herd immunity benefits to their female partners [4]. Such herd immunity benefits may be of utmost importance, and be a fairly cost-effective option, especially in countries in which female coverage cannot be feasibly increased [4,41].

5 68 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012 CMI Achieving a more affordable price of HPV vaccines The arrival of HPV vaccines heralded a new era for cervical cancer prevention but unless there are mechanisms to make them affordable, their benefits will not be fully realized in many settings. HPV vaccines are the most expensive vaccines to have been developed [4]. Given the growing market for HPV vaccines and competition between manufacturers, negotiated prices are already beginning to decline, although they still remain beyond the reach of many countries. In 2009, the WHO issued important recommendations for HPV vaccination and prequalified both HPV vaccines, so allowing procurement by the United Nations Children s Fund (UNICEF) and other United Nations agencies. The GAVI Alliance, which strongly supports widespread implementation of vaccines in the developing world, recently added HPV vaccines to its list of vaccines subsidized in the poorest countries, thanks in part to tiered pricing by the manufacturers, which dramatically reduces the cost of each dose, even to as low as US$5.00 per dose [27]. Other mechanisms include making use of the collective purchase potential of countries in negotiating prices together. The Pan American Health Organization Revolving Fund is one such example, whereby countries pay for vaccines obtained at very low prices and as negotiated by the Pan American Health Organization; a price of US$14 per dose has been recently achieved through this effort [34]. Another possibility of reducing the price of HPV vaccination is modification of the current three-dose vaccination schedule. Recent studies of the efficacy of a two-dose schedule versus the standard three-dose schedule have shown that a two-dose schedule is immunogenic and generally well tolerated, and may be sufficient for long-term efficacy [42,43]; however, further data are required. Second generation of HPV prophylactic vaccines Several second-generation prophylactic vaccines are being developed, aimed at resolving some of the limitations of the two current HPV prophylactic vaccines. A nonavalent vaccine, which, in addition to the four HPV types in the current quadrivalent vaccine, contains L1 viral-like proteins of HPV- 31, HPV-33, HPV-45, HPV-52 and HPV-58, is in the advanced stage of phase III efficacy trials. Other candidates for secondgeneration vaccines that have shown promising results in preclinical studies are vaccines based on L1-pentameric subunits and vaccines based on the minor virion protein L2. For timely evaluation of the clinical efficacy of these potentially broad-range vaccines targeting several HPV types, we will need more frequent and shorter-term vaccine efficacy endpoints, because clinical trials of second-generation vaccines against less-prevalent HPV types with cervical intraepithelial grade 2+ as a primary outcome, will be prohibitively expensive and will take many years to complete [37]. Conclusions Two HPV vaccines have been proven to be safe and effective and are licensed in more than 110 countries; they are already implemented in national vaccination programmes in over 40 countries across the globe. The primary focus must now be on practical implementation issues and adaptations to specific regional circumstances so as to maximize the delivery of the vaccines to the individuals that are most likely to benefit from them [32,37]. Transparency declaration Dr Poljak has been an advisory board member for Glaxo- SmithKline, has received speaker s honoraria and travel grants from GlaxoSmithKline and Merck and Co., and research grants from Merck and Co. Conflicts of interest The author has no other conflicts of interest to declare other then those listed in Transparency declaration. References 1. Bernard HU, Burk RD, Chen Z, van Doorslaer K, zur Hausen H, de Villers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010; 401: Bouvard V, Baan R, Straif K et al. A review of human carcinogens Part B: biological agents. Lancet Oncol 2009; 10: Arbyn M, Castellsagué X, de Sanjosé S et al. Worldwide burden of cervical cancer in Ann Oncol 2011; 22: Brotherton JM, Gertig DM. Primary prophylactic human papillomavirus vaccination programs: future perspective on global impact. Expert Rev Anti Infect Ther 2011; 9: Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 2008; 113: Chaturvedi AK, Engels EA, Pfeiffer RM et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29:

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