Effects of quadrivalent human papillomavirus vaccination

Abstract

The pooled per-protocol results of the phase II and III trials at 36 months of follow-up confirm that the quadrivalent Gardasil vaccine offers quasi-100% protection against cervical intraepithelial neoplasia of grade II or worse (CIN2+) or adenocarcinoma in situ (AIS) related to the human papillomavirus (HPV) vaccine types if women are not infected with these types at enrolment. In the intention-to-treat (ITT) population also involving non-naive women protection against any disease or HPV-16/18-related disease was 18% and 44% respectively. This trial also reported on the protection against CIN2+/AIS associated with any HPV type among women who were baseline HPV 16/18 negative: 27% (95% CI 4-44). These rates of protection against overall CIN2+ are lower than expected from meta-analyses describing the association between HPV types and cervical cancer precursors and used in several cost-effectiveness analyses. To address the question of whether replacement of vaccine-induced HPV type could offer a plausible explanation I examined the rate of CIN2+ or AIS due to non-HPV-16/18 types by subtracting the number of HPV-16/18-related CIN2+ cases from the number of CIN2+ cases associated with any HPV type in the combined analysis. I found a non-significant increase in the rate of non-HPV-16/18-related CIN2+ in the vaccinated compared with the placebo group: -11% (95% CI -32 to 7). These findings underline the need for more detailed type-specific analyses on uniformly defined outcomes to allow meta-analytical pooling and stratification by initial HPV infection status to disentangle the type-specific events that determine the vaccines effect on the burden of cervical cancer precursors. In populations where HPV vaccination programmes are introduced the potential occurrence of type replacement escape of viral mutants and cross-protection should be assessed by careful surveillance. (excerpt)