The Role of Vaccination in the Prevention of Head and Neck Cancer

  • Johannes BerkhofEmail author


Human papillomavirus (HPV) is the main cause of cervical cancer and is also associated with head and neck cancer. The effect of prophylactic HPV vaccines on premalignant head and neck lesions is not measurable, but it is universally believed that HPV vaccines are able to prevent a considerable number of oropharyngeal cancers and a small proportion of oral cavity and larynx cancers. Recent studies on the effect of HPV vaccination on oral HPV infections provide further support of this hypothesis. The question then remains whether current vaccination programmes, in which only girls are vaccinated against HPV infections, should be extended to boys to increase the impact on future head and neck cancers. This question is particularly relevant because the burden of oropharyngeal cancer is on the rise in the United States and several other countries and it is disproportionally higher in men. The extension of a girls’ only HPV vaccination programme to a sex-neutral programme depends on a number of factors including herd effects received from the girls’ only programme and the price of the vaccine. HPV infection models predict a substantial impact of sex-neutral vaccination on future cancer in men and women when the coverage of the girls’ only vaccination programme is only 40–70%. At a higher uptake of 80%, a main argument in favour of sex-neutral vaccination is that it leads to near elimination of HPV16 and HPV18, thought to be responsible for the majority of the HPV-related head and neck cancers. Financial barriers to sex-neutral vaccination have been largely removed in countries that were successful in negotiating a low price for the vaccine.


Human papillomavirus Oropharynx Sex-neutral vaccination Herd effects Cost-effectiveness 



JB has received consultancy fees from Roche, GlaxoSmithKline, and Merck/ SPMSD; these fees were collected by his employer. JB was supported by the Comparing Health Services Interventions for the Prevention of HPV-Related Cancer project, under European Commission FP7 Framework Health 2013 Innovation 1 (grant 603019). JB is grateful to Federica Inturrisi, Thomas Klausch and Venetia Qendri for suggestions and comments.


  1. 1.
    de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017;141(4):664–70.CrossRefGoogle Scholar
  2. 2.
    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):4294–301.CrossRefGoogle Scholar
  3. 3.
    Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010;11(8):781–9.CrossRefGoogle Scholar
  4. 4.
    McDonald SA, Qendri V, Berkhof J, de Melker HE, Bogaards JA. Disease burden of human papillomavirus infection in the Netherlands, 1989-2014: the gap between females and males is diminishing. Cancer Causes Control. 2017;28(3):203–14.CrossRefGoogle Scholar
  5. 5.
    Carlander AF, Gronhoj Larsen C, et al. Continuing rise in oropharyngeal cancer in a high HPV prevalence area: a Danish population-based study from 2011 to 2014. Eur J Cancer. 2017;70:75–82.CrossRefGoogle Scholar
  6. 6.
    Wheeler CM, Castellsagué X, Garland SM, et al. Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13(1):100–10.CrossRefGoogle Scholar
  7. 7.
    Kavanagh K, Pollock KG, Cuschieri K, Palmer T, Cameron RL, Watt C, et al. Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study. Lancet Infect Dis. 2017;17(12):1293–302.CrossRefGoogle Scholar
  8. 8.
    Woestenberg PJ, King AJ, van Benthem BHB, et al. Bivalent vaccine effectiveness against type-specific HPV positivity: evidence for cross-protection against oncogenic types among Dutch STI clinic visitors. J Infect Dis. 2018;217(2):213–22.CrossRefGoogle Scholar
  9. 9.
    Ndiaye C, Mena M, Alemany L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol. 2014;15(12):1319–31.CrossRefGoogle Scholar
  10. 10.
    Ault KA. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet. 2007;369(9576):1861–8.CrossRefGoogle Scholar
  11. 11.
    Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4·5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367(9518):1247–55.CrossRefGoogle Scholar
  12. 12.
    Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland SM, Castellsagué X, et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13(1):89–99.CrossRefGoogle Scholar
  13. 13.
    Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928–43.CrossRefGoogle Scholar
  14. 14.
    Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med. 2011;364(5):401–11.CrossRefGoogle Scholar
  15. 15.
    Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001;345(26):1890–900.CrossRefGoogle Scholar
  16. 16.
    Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407–20.CrossRefGoogle Scholar
  17. 17.
    Mork J, Lie AK, Glattre E, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med. 2001;344(15):1125–31.CrossRefGoogle Scholar
  18. 18.
    Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013;8(7):e68329.CrossRefGoogle Scholar
  19. 19.
    Hirth JM, Chang M, Resto VA, Group HPVS. Prevalence of oral human papillomavirus by vaccination status among young adults (18-30years old). Vaccine. 2017;35(27):3446–51.CrossRefGoogle Scholar
  20. 20.
    Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of prophylactic human papillomavirus (HPV) vaccination on oral HPV infections among young adults in the United States. J Clin Oncol. 2018;36(3):262–7.CrossRefGoogle Scholar
  21. 21.
    Pinto LA, Kemp TJ, Torres BN, et al. Quadrivalent human papillomavirus (HPV) vaccine induces HPV-specific antibodies in the oral cavity: results from the mid-adult male vaccine trial. J Infect Dis. 2016;214(8):1276–83.CrossRefGoogle Scholar
  22. 22.
    Garnett GP, Kim JJ, French K, Goldie SJ. Chapter 21: Modelling the impact of HPV vaccines on cervical cancer and screening programmes. Vaccine. 2006;24(Suppl 3):S3/178–86.Google Scholar
  23. 23.
    Brisson M, Bénard É, Drolet M, et al. Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models. Lancet Public Health. 2016;1(1):e8–e17.CrossRefGoogle Scholar
  24. 24.
    Chow EPF, Machalek DA, Tabrizi SN, Danielewski JA, Fehler G, Bradshaw CS, et al. Quadrivalent vaccine-targeted human papillomavirus genotypes in heterosexual men after the Australian female human papillomavirus vaccination programme: a retrospective observational study. Lancet Infect Dis. 2017;17(1):68–77.CrossRefGoogle Scholar
  25. 25.
    Lehtinen M, Soderlund-Strand A, Vanska S, Luostarinen T, Eriksson T, Natunen K, et al. Impact of gender-neutral or girls-only vaccination against human papillomavirus-results of a community-randomized clinical trial (I). Int J Cancer. 2018;142(5):949–58.CrossRefGoogle Scholar
  26. 26.
    Scarbrough Lefebvre CD, Terlinden A, Standaert B. Dissecting the indirect effects caused by vaccines into the basic elements. Hum Vaccin Immunother. 2015;11(9):2142–57.CrossRefGoogle Scholar
  27. 27.
    Baussano I, Lazzarato F, Ronco G, Lehtinen M, Dillner J, Franceschi S. Different challenges in eliminating HPV16 compared to other types: a modeling study. J Infect Dis. 2017;216(3):336–44.CrossRefGoogle Scholar
  28. 28.
    Bogaards JA, Wallinga J, Brakenhoff RH, Meijer CJ, Berkhof J. Direct benefit of vaccinating boys along with girls against oncogenic human papillomavirus: Bayesian evidence synthesis. BMJ. 2015;350:h2016.CrossRefGoogle Scholar
  29. 29.
    Heideman DAM, Waterboer T, Pawlita M, et al. Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma. J Clin Oncol. 2007;25(29):4550–6.CrossRefGoogle Scholar
  30. 30.
    De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer. 2009;124(7):1626–36.CrossRefGoogle Scholar
  31. 31.
    Rietbergen MM, Leemans CR, Bloemena E, et al. Increasing prevalence rates of HPV attributable oropharyngeal squamous cell carcinomas in the Netherlands as assessed by a validated test algorithm. Int J Cancer. 2013;132(7):1565–71.CrossRefGoogle Scholar
  32. 32.
    Frisch M. Cancer in a population-based cohort of men and women in registered homosexual partnerships. Am J Epidemiol. 2003;157(11):966–72.CrossRefGoogle Scholar
  33. 33.
    Bogaards JA, Xiridou M, Coupe VM, Meijer CJ, Wallinga J, Berkhof J. Model-based estimation of viral transmissibility and infection-induced resistance from the age-dependent prevalence of infection for 14 high-risk types of human papillomavirus. Am J Epidemiol. 2010;171(7):817–25.CrossRefGoogle Scholar
  34. 34.
    Lin A, Ong KJ, Hobbelen P, et al. Impact and cost-effectiveness of selective human papillomavirus vaccination of men who have sex with men. Clin Infect Dis. 2017;64(5):580–8.PubMedGoogle Scholar
  35. 35.
    Brisson M, van de Velde N, Franco EL, Drolet M, Boily MC. Incremental impact of adding boys to current human papillomavirus vaccination programs: role of herd immunity. J Infect Dis. 2011;204(3):372–6.CrossRefGoogle Scholar
  36. 36.
    Bogaards JA, Kretzschmar M, Xiridou M, Meijer CJ, Berkhof J, Wallinga J. Sex-specific immunization for sexually transmitted infections such as human papillomavirus: insights from mathematical models. PLoS Med. 2011;8(12):e1001147.CrossRefGoogle Scholar
  37. 37.
    Krawczyk A, Perez S, King L, Vivion M, Dube E, Rosberger Z. Parents’ decision-making about the human papillomavirus vaccine for their daughters: II. Qualitative results. Hum Vaccin Immunother. 2015;11(2):330–6.CrossRefGoogle Scholar
  38. 38.
    Thompson EL, Rosen BL, Vamos CA, Kadono M, Daley EM. Human papillomavirus vaccination: what are the reasons for nonvaccination among U.S. adolescents? J Adolesc Health. 2017;61(3):288–93.CrossRefGoogle Scholar
  39. 39.
    Brinth LS, Pors K, Theibel AC, Mehlsen J. Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus. Vaccine. 2015;33(22):2602–5.CrossRefGoogle Scholar
  40. 40.
    Elfstrom KM, Lazzarato F, Franceschi S, Dillner J, Baussano I. Human papillomavirus vaccination of boys and extended catch-up vaccination: effects on the resilience of programs. J Infect Dis. 2016;213(2):199–205.CrossRefGoogle Scholar
  41. 41.
    Suijkerbuijk AW, Donken R, Lugner AK, et al. The whole story: a systematic review of economic evaluations of HPV vaccination including non-cervical HPV-associated diseases. Expert Rev Vaccines. 2017;16(4):361–75.CrossRefGoogle Scholar
  42. 42.
    Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, Barretos Cancer Hospital, Baylor College of Medicine, Beckman Research Institute of City of Hope, et al. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–84.CrossRefGoogle Scholar
  43. 43.
    Andrus JK, Sherris J, Fitzsimmons JW, Kane MA, Aguado MT. Introduction of human papillomavirus vaccines into developing countries - international strategies for funding and procurement. Vaccine. 2008;26(Suppl 10):K87–92.CrossRefGoogle Scholar
  44. 44.
    Garattini L, van de Vooren K, Curto A. Pricing human papillomavirus vaccines. PharmacoEconomics. 2012;30(3):213–7.CrossRefGoogle Scholar
  45. 45.
    Qendri V, Bogaards JA, Berkhof J. Health and economic impact of a tender-based, sex-neutral human papillomavirus 16/18 vaccination program in the Netherlands. J Infect Dis. 2017;216(2):210–9.CrossRefGoogle Scholar
  46. 46.
    Burger EA, Sy S, Nygard M, Kristiansen IS, Kim JJ. Prevention of HPV-related cancers in Norway: cost-effectiveness of expanding the HPV vaccination program to include pre-adolescent boys. PLoS One. 2014;9(3):e89974.CrossRefGoogle Scholar
  47. 47.
    Haeussler K, Marcellusi A, Mennini FS, et al. Cost-effectiveness analysis of universal human papillomavirus vaccination using a dynamic Bayesian methodology: the BEST II study. Value Health. 2015;18(8):956–68.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Amsterdam UMC, Vrije Universiteit Amsterdam, Epidemiology and Biostatistics, Amsterdam Public Health Research InstituteAmsterdamThe Netherlands

Personalised recommendations