Clinical Review

2 HPV vaccines, 7 questions that you need answered

OBG Manag. 2010 August;22(8):32-46

References

1. The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19):1915-1927.

2. Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, Wheeler CM, et al. HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369(9580):2161-2170.

3. Paavonen J, Naud P, Salmeron J, et al. For the HPV PATRICIA Study Group. 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, randomised study in young women. Lancet. 2009;374(9686):301-314.

4. DiMario FJ, Hajjar M, Ciesielski T. A 16-year-old girl with bilateral visual loss and left hemiparesis following an immunization against human papillomavirus. J Child Neurology. 2010;25(3):321-327.

5. Sutton I, Lahoria R, Tan I, Clouston P, Barnett M. CNS demyelination and quadrivalent HPV vaccination. Multiple Sclerosis. 2009;15(1):116-119.

6. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis. 2010;10(5):338-349.

7. Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin. 2009;5(10):705-719.

8. GlaxoSmithKline Vaccine HPV-007 Study Group. Sustained efficacy and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 8.4 years. Presented at: 28th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID); May 4-8, 2010; Nice, France.

9. Muñoz N, Kjaer SK, Sigurdsson K, 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;102(5):325-339.

10. Brown DR, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naïve women aged 16-26 years. J Infect Dis. 2009;199(7):926-935.

11. Rowhani-Rahbar A, Mao C, Hughes JP, et al. Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine. 2009;27(41):5612-5619.

12. Harper DM, Williams KB. Prophylactic HPV vaccines: current knowledge of impact on gynecologic premalignancies [published online ahead of print July 3, 2010]. Discovery Medicine. 2010;10(50).http://www.discoverymedicine.com/Diane-M-Harper/2010/07/03/prophylactichpv-vaccines-current-knowledge-of-impact-ongynecologic-premalignancies. Accessed July 13, 2010.

13. Cervarix [human papillomavirus bivalent (types 16 and 18) vaccine recombinant]. Food and Drug Administration. Initial US approval: 2009:1–12.

14. 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):1928-1943.

15. World Health Organization. Human papillomavirus vaccines: WHO position paper. Weekly Epidemiological Record. 2009;84(15):118-131.http://www.who.int/wer/2009/wer8415/en/index.html. Published April 10, 2009. Accessed July 13, 2010.

16. Ault KA. For Future II Study Group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on the 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):1861-1868.

17. Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ. 2008;337:a1284.-Doi: 10.1136/bmj.a1284.

18. Paavonen J. For the HPV PATRICIA Study Group. Efficacy of HPV 16/18 ASO4-adjuvanted vaccine against abnormal cytology, colposcopy referrals, and cervical procedures. Abstract SS 4–1. Data presented at Cervical Cancer Prevention, EuroGin 2010. European Research Organisation on Genital Infection and Neoplasia (EUROGIN); February 17-20, 2010; Monte Carlo, Monaco.http://www.eurogin.com/2010/programoverview.html. Accessed July 13, 2010.

19. Centers for Disease Control and Prevention. Reports of health concerns following HPV vaccination. 2010;1-3.http://www.cdc.gov/vaccinesafety/Vaccines/HPV/gardasil.html. Published June 21, 2010. Accessed July 13, 2010.

20. Myers ER. The economic impact of HPV vaccines: not just cervical cancer. Am J Obstet Gynecol. 2008;198(5):487-488.

21. Gardasil [human papillomavirus quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant]. Food and Drug Administration; 2009. Initial Approval 2006;1-26.

22. Olsson SE, Kjaer SK, Sigurdsson K, et al. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection. Hum Vaccin. 2009;5(10).

23. Pirotta M, Ung L, Stein A, et al. The psychosocial burden of human papillomavirus related disease and screening interventions. Sex Transm Infect. 2009;85(7):508-513.

24. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med. 2008;359(8):821-832.

25. Cox JT. Is the HPV test effective as the primary screen for cervical cancer? Examining the Evidence. OBG Management. 2010;22(7):10-11.

Dr. Felix: As for overlapping immunity to HPV types not included in the vaccines, it has been described for both Cervarix and Gardasil. In the case of Cervarix, the manufacturer demonstrated unexpectedly high rates of protection against all CIN 2+ and CIN 3+ lesions—70% and 87%, respectively. These rates were too high to be explained by protection against types 16, 18, 31, and 45 alone. It is possible, therefore, that Cervarix may protect against other high-risk HPV types.¹³

Gardasil has proved to be effective against HPV types 31, 33, 52, and others.¹⁰ When total protection against CIN 2+ and CIN 3+ lesions is examined from Phase-3 trials of the vaccine, however, the rates are only 42% and 43%, respectively. These data are difficult to interpret because HPV 16 and 18 together are thought to account for 70% of CIN 3. Some reassurance can be gained from the fact that the number of incident cases of CIN 2+ and CIN 3+ caused by HPV 16 and 18 in the vaccinated group in the Gardasil trial was identical to the number seen in the Cervarix trial.^3,10 The reason for the discrepancy in total number of cases of CIN 2+ and CIN 3+ between the two trials—and, therefore, between the two vaccines—cannot be explained by cross-protection alone and is probably attributable to differences in study populations. The Gardasil trial had a higher baseline prevalence of HPV 16 and 18 (9% and 4%, respectively) than the Cervarix trial did (5% and 2%, respectively), a fact that may be explained by the different demographics of their respective populations.^2,14

Ultimately, it is hazardous to compare trials, particularly when they are conducted in significantly different populations. On this issue, I concur with the World Health Organization (WHO), which recommended that such comparisons be avoided in the determination of which type of HPV vaccine to recommend.¹⁵

Dr. Huh: I agree that it would be inappropriate to make cross-trial comparisons, given differences in the way the trials were designed and conducted. To draw conclusions about clinical efficacy of these two excellent vaccines, based on a comparison of their trials, is completely unscientific. Only a true head-to-head study that has efficacy as its endpoint can tell us which vaccine is superior—and such a trial would require thousands (if not tens of thousands) of subjects and a considerable amount of time to complete. In my opinion, such a study would be counterproductive to our goal of vaccination.

Dr. Harper: I disagree. The whole purpose of this roundtable is to compare vaccines. It is not “unscientific” to compare the trials.

Dr. Huh: On the contrary—it is completely inappropriate to directly compare the Phase-3 clinical trials from Merck and GlaxoSmithKline. One can speculate about the differences between them, but any clinical trialist knows that a direct, scientific comparison cannot be made. Only a real head-to-head study powered for efficacy can do this.

For practice, take-home points on HPV vaccination

Both the bivalent and quadrivalent vaccines appear to be excellent products. Besides protecting against the main oncogenic strains of human papillomavirus (HPV) (types 16 and 18 for both vaccines, and the genital-wart-associated strains 6 and 11 for the quadrivalent vaccine), both Cervarix and Gardasil offer some degree of cross-protection against additional HPV strains.
Vaccination of the sexually naïve patient with either vaccine provides significant protection against cervical intraepithelial neoplasia 2 (CIN 2) or worse.
HPV vaccination is expected to reduce the rate of abnormal Pap tests and the need for common excisional treatments for cervical dysplasia in vaccinated women. It will do the same in the population as a whole if rates of vaccination are sufficient to provide “herd” immunity.

3. Is one vaccine more effective than the other?

Dr. Lonky: How do the vaccines compare in terms of efficacy?

Dr. Smith-McCune: In discussing efficacy, I think we should focus on CIN 3 because it is the immediate surrogate for cancer, whereas CIN 2 lesions can be transient in younger women. I think it is also important to focus on outcomes regardless of the HPV types associated with the lesions. This approach is more clinically relevant, as we don’t perform HPV typing of lesions in clinical practice. Nor do we manage lesions differently depending on the HPV type in the lesion.

That said, it is difficult to compare efficacy of the vaccines for several reasons, a few of which we have already discussed. For example, the bivalent and quadrivalent vaccines were studied in separate randomized trials. Although the study populations were similar, they were not identical. Women in both trials were relatively sexually naïve, but the cutoff for number of lifetime sexual partners was different (5 for Gardasil versus 7 for Cervarix). In trials of Gardasil, women who had a history of abnormal cytology or genital warts were excluded. In trials of Cervarix, women who had a history of colposcopy were excluded. In Gardasil trials, approximately 3% of women were from the Asian Pacific, versus 34% in the Cervarix trials, and so on.^3,16