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An Analysis of HPV Vaccine Efficacy in Preventing Cervical Cancer
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: In an analysis of four clinical trials designed to assess the efficacy of two different human papilloma virus (HPV) vaccines, the appearance of pre-neoplastic lesions and neoplastic cervical adenocarcinoma was dramatically reduced in vaccinated subjects. The three inoculation schedule was most effective, but, even for those who received less than the full number of injections, efficacy was clearly apparent. Duration of protection and overall cost effectiveness remains to be established.
Source: Ault KA, Future II Study Group. Effect of prophylactic 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 randomized clinical trials. Lancet. 2007;369:1861-1868.
Cervical cancer continues to be the second leading cause of cancer-related death in women under 45 years of age, resulting in more than 200,000 deaths per year worldwide. It has been well established that a significant majority of these cancers (approximately 70%) are caused by Human Papilloma Virus serotypes HPV 16 and HPV 18. Routine Pap testing has reduced the rates of squamous cell cervical cancer, but the rates of adenocarcinoma have actually increased as these lesions are not readily detected by cytology. Two vaccines targeted against these serotypes have been developed, including the monovalent vaccine against HPV 16 and a quadrivalent vaccine which targets HPV 6 and 11 in addition to HPV 16 and 18. The quadrivalent form has been approved by the FDA for prevention of cervical cancer and is produced by Merck marketed under the name GARDASIL®.
Cervical cancer risk is greatest in the 5-10 years following the first sexual experience (which in most cases worldwide is between the ages of 15 and 17 years). In addition, studies have established that antibody response is most robust in girls 10-15 year old, and significantly exceeds that found in women 16-23 years of age.1
This analysis was designed to evaluate vaccine efficacy in an unrestricted susceptible population of young women who were seronegative and PCR-negative to HPV 16 and 18. In addition, an intention to treat analysis was performed that included all women regardless of serostatus. Women between the ages of 16 and 26 years (n = 20,583) were randomized to receive either the monovalent or quadrivalent vaccine or placebo in 4 randomized placebo controlled trials between October 1998 and May 2003 worldwide. Of these, 17,129 met study criteria established for being "susceptible" (ie, seronegative/PCR negative for HPV16/18). Subjects were recruited from university health centers and urban clinics. Three doses of vaccine were administered: at day 1, and at month 2 and month 6. Participants were followed for a mean of 3 years following the first dose. Of a total of 8550 women in the placebo group, 85 developed HPV 16/18 related cervical intraepithelial neoplasia grades 2/3 (CIN2/3) or adenocarcinoma in situ (AIS) vs only 1 (CIN2/3) and no AIS of 8579 in the vaccine group. Based on this analysis, vaccine efficacy was found to be 98%.
In the intention to treat population in which the vaccine was administered to seronegative young women, but including those who did not receive the full course (three injections) or had other major protocol violations, 255 out of 10292 women developed HPV 16/18 related CIN2/3 or AIS in the placebo group, compared to 142 out of 10291 in the vaccine group. In this group, vaccination reduced the incidence of HPV 16/18 related CIN2/3 or AIS by 44%.
These findings show that prophylactic administration of a vaccine against HPV 16 or HPV 6/11/16/18 can lead to substantial reductions in cervical cancer worldwide. Although the current analysis is of relatively short term and HPV infection risk remains as long as women remain sexually active, it has been established that the highest risk for acquisition of HPV infection occurs in the first 5-10 years after initial sexual contact.2 Thus, although the duration of protection is not established, even over the short haul, widespread immunization programs would prevent HPV associated cervical cancer and its associated morbidity/mortality in a large number of women. Furthermore, a health economics analysis developed by the manufacturer predicts that universal administration of vaccine to girls between the ages of 11-12 with a catch-up program in the 12-24 year olds would prove cost effective.3 This type of analysis needs to be performed independently and on a larger scale. Decisions regarding the implementation of this major advance in preventive medicine should not be political, but based upon established evidence and humane principles.
1. Block SL, et al. 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. 2006;118:2135-2145.
2. Winer RL, et al. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218-226.
3. Elbasha EH, et al. Assessment of human papillomavirus (HPV) vaccination strategies: an integrated multi-type disease transmission model and economic evaluation. Emerg Infect Dis. 2007;13:28.