Abstract ED01-01: Preventing multiple types of cancer through HPV vaccination.

Abstract At least one-sixth of all cancers are attributable to infectious agents. Identification of an infectious agent as the cause of cancer offers the possibility of developing a vaccine - or antimicrobial agent - for the prevention or treatment of the cancers attributable to the infectious agent. In this regard, infection by a subset of HPVs, especially HPV16 and HPV18, is the primary cause of virtually all cases of cervical cancer, which worldwide is the third most common cause of cancer deaths in women. HPV16 and 18 cause about 70% of cervical cancers. HPV16 and 18 are also linked to a variable proportion of cancers beyond the cervix, including vulvar, vaginal, penile, anal, and oropharyngeal cancer. HPV16 and 18 account for about 90% of these non-cervical cancers. Infection by another subset of human papillomaviruses (HPV), especially HPV6 and 11, causes most cases of most cases of genital warts and recurrent respiratory papillomatosis. The importance of HPV as human pathogen has stimulated development of prophylactic HPV vaccines, based on the observation that the L1 main structural protein of the HPV virion can self-assemble into empty virus-like particles (VLPs) which contain the conformationally-dependent neutralization epitopes of L1 and can induce high levels of neutralizing antibodies. Two pharmaceutical companies, Merck and GlaxoSmithKline (GSK), have developed FDA-approved commercial versions of the VLP vaccine. Merck's is a quadrivalent vaccine composed of VLPs from HPV6, 11, 16, and 18, while GSK's is a bivalent vaccine composed of VLPs from HPV16 and 18. Both vaccines are administered in three doses, given over 6 months. The vaccines contain VLPs from more than one HPV type because preclinical data correctly predicted that strong protection would be predominantly HPV type-specific. Efficacy trials in young adults have shown that, for fully vaccinated subjects, both vaccines induce almost complete protection against incident persistent anogenital infection and the associated lesions attributable to the HPV types targeted by the vaccine. The efficacy trials of the Merck vaccine have been carried out in males and females, and it is FDA approved for both genders. The efficacy trials of the GSK vaccine have only been carried out in females, and it is only approved for females. Immunogenicity and protection induced by the vaccines are so strong that a two dose regimen is being used in some countries outside the United States, such as parts of Canada and Mexico. (NB: Following a two dose schedule in the US would be an off label schedule.) Experimental studies indicate that the neutralizing antibodies induced by the VLP vaccine are the main mechanism by which it protects against infection and disease. Consistent with results from preclinical studies, the vaccine can prevent new (incident) infections but is not effective against established (prevalent) infection. Since the vast majority of these infections are sexually transmitted, vaccination is most cost-effective if given before initiation of sexual activity. Vaccinated cohorts are protected against infection by the targeted HPV types for at least 8 years, the longest time they have been followed to date. According to the CDC, the vaccine has an acceptable safety profile. While the HPV vaccine has many characteristics that are similar to that of traditional preventive vaccines, the prevention of malignant disease, which is the main rationale for the vaccine, will not be seen until decades after HPV vaccine implementation, a much longer interval than with traditional vaccines. By contrast, a reduction in premalignant conditions, genital warts, and recurrent respiratory papillomatosis could be seen much sooner than the reduction in malignant disease. Dynamic transmission models of HPV infection suggest that widespread vaccination of one gender - girls, because of the importance of cervical cancer - should be sufficient to induce herd immunity in a population. In the United States, however, HPV vaccine uptake is substantially below the level needed for such immunity. In this situation, male vaccination can contribute to herd immunity, albeit less efficiently than female vaccination. From a public health perspective, the vaccine mimics some effects of cervical cancer screening, and has, in addition, at least three advantages over screening and two disadvantages. The similarity is that screening and vaccination can each substantially reduce the risk of cervical cancer. The advantages of vaccination include a reduction in the rate of cervical dysplasia, the ability to prevent most cases of cervical adenocarcinoma (screening efficiently reduces the risk for cervical squamous cell cancer but reduces cervical adenocarcinoma risk inefficiently), and, most importantly, the ability to prevent most of the HPV-associated cancers at sites beyond the cervix, whose incidence in the US is close to that of cervical cancer. Compared with vaccination, the main advantages of screening are that it can be used to screen women at any age for cervical precancer and cancer, which means it can reduce the incidence of cervical cancer faster than vaccination, and that it can identify serious HPV infections caused by types not targeted by the vaccine. Therefore, even vaccinated women continue to need to be screened. In the developing world, since screening can have an impact on cervical cancer in a much shorter time-frame than vaccination, a combined approach of screening for adult women and vaccination for adolescent girls should be considered. The limitations of the current HPV vaccines provide a rationale for development of candidate second generation vaccines. One could envision second generation vaccines with a therapeutic component, those that could induce strong protection from fewer doses, those that would be less costly, or those that would protect against a broader range of HPV types, to target a higher proportion of potentially oncogenic HPV infections. Second generation vaccines that could induce low cost, long-term protective immunity with fewer doses would be especially attractive for the developing world. For the industrialized world, second generation vaccines with activity against a broader range of HPV types that cause cervical cancer would appear to have the highest priority. If successful, such vaccines have the potential to further reduce the incidence of cancer-inducing cervical HPV infections. The reduction might be sufficient that widespread implementation of such vaccines could lead to major changes in cervical cancer screening recommendations, which might reduce the costs of screening by more than the costs of vaccination. Suggested bibliography: Muñoz N, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 2010 Mar 3;102(5):325–39. Epub 2010 Feb 5. Day PM et al. In vivo mechanisms of vaccine-induced protection against HPV infection. Cell Host Microbe. 2010 Sep 16;8(3):260–70. Schiller JT, Lowy DR. Vaccines to prevent infections by oncoviruses. Annu Rev Microbiol. 2010 Oct 13;64:23–41. Szarewski A et al. Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15–25 years with and without serological evidence of previous exposure to HPV-16/18. Int J Cancer. 2011 Aug 19. doi: 10.1002/ijc.26362. [Epub ahead of print] Kreimer AR et al. Proof-of-Principle Evaluation of the Efficacy of Fewer Than Three Doses of a Bivalent HPV16/18 Vaccine. J Natl Cancer Inst. 2011 Sep 9. [Epub ahead of print] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr ED01-01.

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