PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Human Papilloma Virus Vaccination: A Great Idea...for Boys? by Michael E. Watson, Jr., M.D., Ph.D.  Human Papilloma Virus (HPV) is the single most common sexually transmitted infection among women and men. In the United States alone, it infects an estimated 6.2 million new persons annually (17). The manifestations of infection with HPV vary depending on the serotype acquired, ranging from relatively benign genital warts caused by non-oncogenic types, to potentially invasive neoplastic conditions such as head and neck cancers, and anogenital (i.e., cervical, penile, vulvar, and anal) cancers caused by oncogenic types (3). The non-oncogenic HPV types 6 and 11 cause over 90% of all genital warts, and the oncogenic HPV types 16 and 18 cause head, neck, and anogenital cancers, and including over 70% of all cervical cancers (19). Costs for screening for cervical cancer in USA top $2 billion annually, while treatment of cervical dysplasia costs up to an additional $6 billion annually (23). The quadrivalent human papillomavirus L1 virus-like particle vaccine (Gardasil, Merck and Co., Inc., Whitehouse Station, NJ) was approved by the US Food and Drug Administration (FDA) in 2006 for girls and women aged 9- to 26-years-old (17). The vaccine is comprised of recombinant HPV L1 viral capsid protein, which self-folds into spheres capable of stimulating the immune system to produce neutralizing antibody; the spheres by themselves contain no DNA, or other viral components, and therefore cannot cause HPV infection. The vaccine was designed to protect against the 4 most prevalent HPV types causing clinically significant disease: HPV types 6, 11, 16, and 18.  Among women, several studies have shown the quadrivalent HPV vaccine to be effective, safe, and generally well-tolerated among adolescent and young women in protection from anogenital cancer and genital warts (9, 14). No studies have yet to show the full impact of prophylactic HPV vaccination on preventing invasive disease over time due to vaccine strains, although these studies are underway. One recognized risk factor for women acquiring HPV-related disease is the sexual behaviors of their male partners. Previous studies have demonstrated that men’s sexual behaviors affects their female partner’s risk of developing cervical neoplasia, even when controlling for female sexual activity (i.e., number of sexual partners and age at first intercourse) (1, 4). In one retrospective study, women with cervical cancer were 5.3 times as likely to be married to males with greater than 20 lifetime sexual partners, than women without disease (24). This and other studies suggest male behaviors and infection of males with HPV are very significant factors in female reproductive health, and additional measures to reduce the HPV burden among sexually active males should be investigated. Among men, acquisition of HPV occurs relatively quickly following sexual debut. Two recent studies found rates of anogenital HPV prevelance of 51% to 65% among sexually active men aged 18 to 40 years (20, 21). Known risk factors of HPV acquisition in males include having multiple sexual partners, smoking, and using condoms infrequently (21). However, the HPV vaccine is not currently approved for use in males in the United States. There is no biological reason males cannot be vaccinated; clinical trials have shown the quadrivalent HPV vaccine to be comparable in immunogenic responses between girls and boys aged 10 to 15 years and women aged 16 to 23 years (2). Efficacy of the HPV vaccine in males is currently being investigated; research from a phase III trial released to the public by Merck in November 2008 showed 90% protection from the development of external genital warts in males aged 16- to 26-years compared to controls receiving placebo inoculation (5). Why should we vaccinate males? Giuliano and Salmon have written previously as to the benefits of male HPV vaccination (11, 12). One reason would be to protect males from their risk of acquiring HPV-related disease. As mentioned previously, HPV in males, while often asymptomatic, can cause genital warts, penile and anal cancers, head and neck cancers, and recurrent respiratory papillomatosis. Among a study of 3.6 million privately insured individuals in the United States, males experienced a longer duration of active genital wart disease, and had higher medical costs for treatment than females. In that study, the costs per 1000 person-years were $1717 in males aged 25 to 29 years, and $1692 in women aged 20-24 years (15). Therefore, vaccination of males would help prevent male HPV disease and reduce overall health care costs. From a more altruistic perspective, another reason to vaccinate males would be to increase the overall “herd immunity” which would in theory further reduce HPV transmission from males to females and thereby reduce HPV-disease. Using a dynamic transmission model, Elbasha et al. showed that administration of HPV vaccine to 12-year-old male and females in addition to catch-up vaccination of 12- to 24-year-old males and females would be the most effective and cost efficient means of reducing HPV-associated disease with an estimated 91% reduction in cervical cancer incidence and a cost of $45,056 per quality-adjusted life years (7). Finally, given the extraordinarily high prevalence of HPV infection, a condition for which patients often seek medical advice at clinics for sexually transmitted infections (STIs), another study showed possible benefit in reducing the patient burden in STI clinics by 10%, without negatively impacting the diagnosis and treatment of other STIs (6). Therefore, multiple health and financial benefits to male HPV vaccination have been described.  Why shouldn’t we vaccinate males? Some critics argue that the burden of HPV-associated diseases in men is significantly less than in women, and therefore the potential public health benefits of male vaccination on this basis alone would be expected to be limited (22). In at least one mathematical model study where women achieve high vaccination compliance, no extra public health benefit was predicted by adding male vaccination (16). It should be noted that this study assumed at least 90% vaccine compliance among females in the target age group; a level with which the current vaccination level in the United States does not nearly approach. It has been estimated that without school entry requirements of HPV vaccination, it may be difficult to achieve greater than 30% vaccine compliance amongst target female populations (13). Finally, concerns have been raised of the financial cost of the three dose series, currently about $500 - $900 for the three dose Gardasil series, varying from practice to practice, further stressing an already limited health care budget (23). A lack of data regarding the overall long term efficacy in preventing disease in the population has led some to urge caution in expanding recommendations to include males, until further evidence of a positive cost: benefit ratio is more certain. Acceptance of vaccine among males has been studied. In the United States, a recent study on heterosexual male college students found that an altruistic message of informing males that vaccination may protect their female partners’ health does not increase vaccine acceptance more than informing them of the benefits to the men themselves (10). In a separate study, Ferris et al. found that men with a higher level of general education, men who engaged in more high-risk sexual behaviors (men with multiple partners, men who have sex with men), and men who had prior knowledge regarding HPV disease were more accepting of the HPV vaccine (8). The authors concluded that physicians could assist with male acceptance by emphasizing the health benefits towards men themselves rather than touting the HPV vaccine as a “cervical cancer” vaccine, providing actual data demonstrating the health benefits and risks, and increasing awareness of HPV-associated disease in general among lay persons. Clearly, if we desire to increase acceptance of the HPV vaccine among as many males as possible, then new strategies for male patient education are needed. In other parts of the world, males are currently being vaccinated against HPV. Gardasil®, sold in some countries under the name Silgard, is approved for females in over 70 countries around the world. In Australia, males ages 9-15 years and females ages 9-26 years have been receiving the quadrivalent HPV vaccine since 2006 (18). In addition to Australia, Mexico, and over 40 other countries throughout the world have currently approved licensing for the HPV vaccine in males. In summary, HPV is an extremely prevalent sexually transmitted infection with significant associated morbidity and mortality for both males and females. The vaccine has demonstrated efficacy, in at least the studies conducted to date, and many studies suggest that expanding vaccine recommendations to include males may have health benefits for the population as a whole. Clearly, further work is needed to address the longer term protective benefits provided by the vaccine, in addition to further work to increase awareness of HPV disease, particularly among males, to increase rates of acceptance. While there are controversies surrounding the use of the HPV vaccine in males, numerous developed countries around the world already have licensing for male HPV vaccination. References 1. Agarwal, S. S., A. Sehgal, S. Sardana, A. Kumar, and U. K. Luthra. 1993. Role of male behavior in cervical carcinogenesis among women with one lifetime sexual partner. Cancer 72:1666-9. 2. Block, S. L., T. Nolan, C. Sattler, E. Barr, K. E. Giacoletti, C. D. Marchant, X. Castellsague, S. A. Rusche, S. Lukac, J. T. Bryan, P. F. Cavanaugh, Jr., and K. S. Reisinger. 2006. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 118:2135-45. 3. Brentjens, M. H., K. A. Yeung-Yue, P. C. Lee, and S. K. Tyring. 2002. Human papillomavirus: a review. Dermatol Clin 20:315-31. 4. Buckley, J. D., R. W. Harris, R. Doll, M. P. Vessey, and P. T. Williams. 1981. Case-control study of the husbands of women with dysplasia or carcinoma of the cervix uteri. Lancet 2:1010-5. 5. Chitale, R. 2009. Merck hopes to extend gardasil vaccine to men. J Natl Cancer Inst 101:222-3. 6. Dempsey, A. F., L. A. Koutsky, and M. Golden. 2007. Potential impact of human papillomavirus vaccines on public STD clinic workloads and on opportunities to diagnose and treat other sexually transmitted diseases. Sex Transm Dis 34:503-7. 7. Elbasha, E. H., E. J. Dasbach, and R. P. Insinga. 2007. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 13:28-41. 8. Ferris, D. G., J. L. Waller, J. Miller, P. Patel, G. A. Price, L. Jackson, and C. Wilson. 2009. Variables associated with human papillomavirus (HPV) vaccine acceptance by men. J Am Board Fam Med 22:34-42. 9. Garland, S. M., M. Hernandez-Avila, C. M. Wheeler, G. Perez, D. M. Harper, S. Leodolter, G. W. Tang, D. G. Ferris, M. Steben, J. Bryan, F. J. Taddeo, R. Railkar, M. T. Esser, H. L. Sings, M. Nelson, J. Boslego, C. Sattler, E. Barr, and L. A. Koutsky. 2007. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 356:1928-43. 10. Gerend, M. A., and J. Barley. 2009. Human papillomavirus vaccine acceptability among young adult men. Sex Transm Dis 36:58-62. 11. Giuliano, A. R. 2007. Human papillomavirus vaccination in males. Gynecol Oncol 107:S24-6. 12. Giuliano, A. R., E. Lazcano-Ponce, L. L. Villa, R. Flores, J. Salmeron, J. H. Lee, M. R. Papenfuss, M. Abrahamsen, E. Jolles, C. M. Nielson, M. L. Baggio, R. Silva, and M. Quiterio. 2008. The human papillomavirus infection in men study: human papillomavirus prevalence and type distribution among men residing in Brazil, Mexico, and the United States. Cancer Epidemiol Biomarkers Prev 17:2036-43. 13. Giuliano, A. R., and D. Salmon. 2008. The case for a gender-neutral (universal) human papillomavirus vaccination policy in the United States: Point. Cancer Epidemiol Biomarkers Prev 17:805-8. 14. Group, T. F. I. S. 2007. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356:1915-27. 15. Insinga, R. P., E. J. Dasbach, and E. R. Myers. 2003. The health and economic burden of genital warts in a set of private health plans in the United States. Clin Infect Dis 36:1397-403. 16. Kim, J. J., B. Andres-Beck, and S. J. Goldie. 2007. The value of including boys in an HPV vaccination programme: a cost-effectiveness analysis in a low-resource setting. Br J Cancer 97:1322-8. 17. Markowitz, L. E., E. F. Dunne, M. Saraiya, H. W. Lawson, H. Chesson, and E. R. Unger. 2007. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 56:1-24. 18. May, J. 2007. HPV vaccination - a paradigm shift in public health. Aust Fam Physician 36:106-11. 19. Munoz, N., X. Castellsague, A. B. de Gonzalez, and L. Gissmann. 2006. Chapter 1: HPV in the etiology of human cancer. Vaccine 24 Suppl 3:S3/1-10. 20. Nielson, C. M., R. Flores, R. B. Harris, M. Abrahamsen, M. R. Papenfuss, E. F. Dunne, L. E. Markowitz, and A. R. Giuliano. 2007. Human papillomavirus prevalence and type distribution in male anogenital sites and semen. Cancer Epidemiol Biomarkers Prev 16:1107-14. 21. Nielson, C. M., R. B. Harris, E. F. Dunne, M. Abrahamsen, M. R. Papenfuss, R. Flores, L. E. Markowitz, and A. R. Giuliano. 2007. Risk factors for anogenital human papillomavirus infection in men. J Infect Dis 196:1137-45. 22. Parkin, D. M., and F. Bray. 2006. Chapter 2: The burden of HPV-related cancers. Vaccine 24 Suppl 3:S3/11-25. 23. Trimble, C. L. 2008. Human papillomavirus vaccination should be offered to young males: Counterpoint. Cancer Epidemiol Biomarkers Prev 17:809. 24. Zunzunegui, M. V., M. C. King, C. F. Coria, and J. Charlet. 1986. Male influences on cervical cancer risk. 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