Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in Males

Although the human papillomavirus (HPV) causes infections among males and females, there is a significantly higher occurrence of HPV-caused cancer among males than there is among females, chiefly of the penis, anus, and oropharynx. The rate of genital HPV infection among males and females is similar, but the immune response to HPV is different. A larger proportion of females are HPV-seropositive (17.9%, vs 7.9% of males), and females have higher titers of antibodies. Clinicians believe that this disparity may explain the higher incidence of infections and cancers among males and the prevalence of these conditions across the age spectrum. The investigators wished to evaluate the efficacy of quadrivalent HPV vaccine against anogenital infection and external genital lesions associated with HPV-6, -11, -16, or -18 in males between 16 and 26 years of age. For this study [N Engl J Med. 2011;364(5):401-411], the investigators enrolled 4065 healthy boys and men from 71 sites in 18 countries in a randomized, double-blind, placebo-controlled study. Of the subjects, 3463 were heterosexual (those who had sex only with females) and 603 were men who had sex with other males. Median follow-up was 2.9 years. Eligibility criteria for heterosexual subjects was age between 16 and 23 years and as many as 5 sexual partners in their lifetime; for those who had sex with other males, age was 16 to 26 years and 1 to 5 male or female partners in their lifetime. Those in either group who had or had had clinically detectible anogenital warts or genital lesions at screening that were suggestive of any sexually transmitted disease were excluded. Subjects were randomly assigned in a 1:1 ratio to receive quadrivalent HPV vaccine or placebo at day 1, month 2 (±3 weeks), and month 6 (±4 weeks). The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions associated with HPV-6, -11, -16, or -18, compared with placebo. The secondary efficacy objectives were to show that the vaccine reduced the incidence of persistent infection with these HPV types and the detection at any time of DNA associated with these viral types, compared with placebo. The investigators also analyzed the composite efficacy of the vaccine against the development of external genital lesions related to any HPV type aside from those mentioned above. Efficacy analyses were conducted in a per-protocol population, in which subjects received all 3 vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. A total of 2032 males were randomly assigned to the vaccine group and 2033 to the placebo group. Of the subjects who received vaccine or placebo, 2805 were eligible for the per-protocol population, with 1397 receiving the quadrivalent HPV vaccine and 1408 receiving placebo. The vaccine and placebo groups were similar with regard to reasons for discontinuing study participation and eligibility for inclusion in per-protocol analyses. In at least 97.4% of vaccinated subjects, seroconversion for HPV-6, -11, -16, and -18 occurred within 1 month after administration of the third dose of vaccine. The majority of subjects who were initially negative for all 4 vaccine HPV types had seroconversion for all 4 types by 1 month after the third dose. In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group, compared with 89 in the placebo group, resulting in an observed efficacy of 60.2% (95% confidence interval [CI], 40.8-73.8). Vaccine efficacy against lesions related to HPV-6, -11, -16, or -18 was 65.5% (95% CI, 45.8-78.6). There were significant reductions in the number of external genital lesions associated with HPV-6 (59.4%; 95% CI, 31.2-76.8) and HPV-11 (76.3%; 95% CI, 40.8-92.0). In the per-protocol population, 6 external genital lesions were observed in the vaccine group and 36 in the placebo group, resulting in an observed efficacy of 83.8% (95% CI, 61.2-94.4). Efficacy against external genital lesions associated with HPV types 6, 11, 16, or 18 was 90.4% (95% CI, 69.2-98.1).