From the Editor

Advances in protection against oncogenic human papillomaviruses: The 9-valent vaccine

OBG Manag. 2015 June;27(6):6–8.

Can the HPV vaccine help prevent oropharyngeal cancer—a disease that is predicted to become more common than cervical cancer in 5 years?

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References

1. zur Hausen H, Schulte-Holthausen H, Klein G, et al. EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature. 1970;228(5276):1056–1058.
2. zur Hausen H, Meinhof W, Scheiber W, Bornkamm GW. Attempts to detect virus-specific DNA sequences in human tumors: I. Nucleic acid hybridizations with complementary RNA of human wart virus. Int J Cancer. 1974;13(5):650–656.
3. Gissmann L, deVilliers EM, zur Hausen H. Analysis of human genital warts (condylomata acuminata) and other genital tumors for human papillomavirus type 6 DNA. Int J Cancer. 1982;29(2):143–146.
4. Dürst M, Gissman L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA. 1983;80(12):3812–3815.
5. Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheulen W, zur Hausen H. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J. 1984;3(5):1151–1157.
6. Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of human papillomavirus type 16 are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989;63(10):4417–4423.
7. Serrano B, Alemany L. Tous S, et al. Potential impact of a 9-valent vaccine in human papillomavirus related cervical disease. Infect Agent Cancer. 2012;7(1):38.
8. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomized study in young women. Lancet. 2009;374(9686):301–314.
9. Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928–1943.
10. FUTURE II Study Group. Quadrivalent vaccine against human papilloma virus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19):1915–1927.
11. Joura EA, Giuliano AR, Iversen OE, et al; Broad Spectrum HPV Vaccine Study. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8): 711–723.
12. Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012; 30(suppl 5):F12–F23.
13. de Sanjose S, Alemany L, Ordi J, et al. Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer. 2013;49(16):3450–3461.
14. Alemany L, Saunier M, Alvarado-Cabrero I, et al. Human papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J Cancer. 2015;136(1):98–107.
15. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011;365(17):1576–1585.
16. Kreimer AR, González P, Katki HA, et al. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncol. 2011;12(9):862–870.
17. Backes DM, Kurman RJ, Pimenta JM, Smith JS. Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control. 2009;20(4):449–457.
18. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294–4301.
19. D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944–1956.
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21. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomised clinical trial in Costa Rica. PLoS One. 2013;8(7):e68329.
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24. Michels KB, zur Hausen H. HPV vaccine for all. Lancet. 2009;374(9686):268–270.

When Dr. Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between human papillomavirus (HPV) infections and genital cancers, he completed a 40-year odyssey to prove that viruses caused human cancer. Initially, zur Hausen, working in the University of Pennsylvania laboratory of the noted virologists Drs. Werner and Gertrude Henle, discovered that the Epstein-Barr virus was involved in the development of Burkitt lymphoma.¹ On return to his native Germany, he sought a link between HPV and genital tumors.²

First he isolated HPV 6 and HPV 11 directly from genital warts.³ Then zur Hausen utilized the nucleic acid sequences from HPV6 and the technique of low stringency hybridization to discover HPV 16 and HPV 18 in cervical cancer specimens.^4,5 Oncogenic HPV DNA contains 2 genes that produce the oncoproteins E6 and E7. E6 increases the degradation of p53 and E7 inactivates the retino-blastoma protein.⁶ The double-hit inactivation of 2 tumor suppressor genes, p53 and retinoblastoma protein, increases the mitotic activity of the infected cells, eventually leading to cancer.

zur Hausen tried to persuade companies to develop anti-HPV vaccines but was rebuffed for years. Today, building on his research, we have HPV vaccines that are 2-valent (against HPV types 16 and 18), 4-valent (against HPV types 6, 11, 16, and 18), and 9-valent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). zur Hausen richly deserved the Nobel Prize for his life-saving discoveries.

Cervical, vulvar, and vaginal cancers
HPV types 16 and 18 cause about 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 cause about 20% of cervical cancers.⁷ The 2-, 4-, and 9-valent HPV vaccines have been demonstrated to prevent premalignant cervical disease, including cervical intraepithelial neoplasia (CIN) 2 and CIN 3 and adenocarcinoma in situ.^8–11 The development of a 9-valent HPV vaccine is an important advance because it provides more complete immunization against cancer causing viruses.

Approximately 70% of vaginal cancers are caused by HPV infections.¹² Among squamous cell vulvar cancers, HPV is detected in approximately 70% of cancers with warty or basaloid histology and 12% of cancers with keratinizing histology.¹³ In vulvar cancer, HPV 16, 33, and 18 are the most common types detected, representing 73%, 7%, and 5% of cases, respectively. The HPV 4- and 9-valent vaccines have been reported to reduce precancerous lesions of the vagina and vulva.^9,11 In most trials, vaccinations that occur before exposure to HPV through sexual encounters appear to provide greater protection than vaccinations that occur after HPV infection.

Anal cancer
Approximately 90% of anal cancers are caused by HPV infection, and HPV types 16 and 18 are detected in 81% and 4% of anal cancers, respectively.¹⁴ Among men who have sex with men, the HPV 4-valent vaccine reduced the rate of anal intraepithelial neoplasia, a precursor to anal cancer, by 50%.¹⁵ Women receiving the HPV 2-valent vaccine had an 84% reduction in the detection of anal cancer involving HPV types 16 and 18.¹⁶

Penile cancer
Approximately 48% of penile cancers harbor oncogenic HPV types.17 Among penile cancers the prevalence of HPV varies from 22% in verrucous cancer to 66% in basaloid and warty cancer. The most prevalent HPV types were 16, 6, and 18, which were observed in 31%, 7%, and 7% of the cancers, respectively.17 Penile cancer is not common and there are no studies directly demonstrating that HPV vaccination prevents penile cancer.

Oropharyngeal cancer
The rate of oropharyngeal cancer caused by HPV is rising rapidly and increasing more rapidly among men than among women.¹⁸ Remarkably, HPV-induced oropharyngeal cancer is projected to become more common than cervical cancer in 2020.¹⁸

In one report, 72% of oropharyngeal cancers harbored HPV 16, and antibodies against the HPV 16 oncoproteins E6 and E7 were detected in the blood of 64% of the cancer cases.¹⁹ In a case control study, having 6 or more lifetime oral-sex partners was associated with a 3.4-fold (95% confidence interval, 1.5 to 6.5) increased risk of developing oropharyngeal cancer.¹⁹

According to a population survey, 10% of men and 3.6% of women harbor HPV viruses in their oropharynx.²⁰ In this study approximately 50% of the HPV viruses detected were high-risk types, with the following rank-order prevalence from highest to lowest: 16, 66, 51, 39, 56, 52, 59, 18, 53, 45, 35, 33, and 31.²⁰ Theoretically, the 9-valent vaccine, with protection against HPV types 16, 18, 31, 33, 45, and 52, may be an optimal choice to prevent HPV-induced oropharyngeal cancer because of its broad coverage.