In the FUTURE I trial,5 rates of grades 1 to 3 cervical intraepithelial neoplasia or adenocarcinoma in situ per 100 person-years were 4.7 in vaccinated women and 5.9 in unvaccinated women, an efficacy of 20%. Analyses by lesion type indicate that this reduction was largely attributable to a lower rate of grade 1 cervical intraepithelial neoplasia in vaccinated women; no efficacy was demonstrable for higher-grade disease,
In the larger FUTURE II trial,6 rates of grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ were 1.3 in vaccinated women and 1.5 in unvaccinated women, an efficacy of 17%. In analyses by lesion type, the efficacy appears to be significant only for grade 2 cervical intraepithelial neoplasia; no efficacy was demonstrable for grade 3 cervical intraepithelial neoplasia or adenocarcinoma in situ.
Another factor explaining the modest efficacy of the vaccine is the role of oncogenic HPV types not included in the vaccine. At least 15 oncogenic HPV types have been identified,4 so targeting only 2 types may not have had a great effect on overall rates of preinvasive lesions In contrast to a plateau in the incidence of disease related to HPV types 16 and 18 among vaccinated women, the overall disease incidence regardless of HPV type continued to increase, raising the possibility that other oncogenic HPV types eventually filled the biologic niche left behind after the elimination of HPV types 16 and 18. An interim analysis of vaccine trial data submitted to the FDA11 showed a disproportionate, but not statistically significant, number of cases of grade 2 or 3 cervical intraepithelial neoplasia related to nonvaccine HPV types among vaccinated women. Updated analyses of data from these ongoing trials will be important to determine the effect of vaccination on rates of preinvasive lesions caused by nonvaccine HPV types
What can be inferred from these data about the potential effect of vaccination among girls 11 and 12 years of age? The FUTURE trials did not enroll subjects in this age group.
In this issue of the Journal, reports on two large, ongoing, randomized, placebo-controlled trials show the effect of this vaccine on important clinical outcomes, including rates of adenocarcinoma in situ and cervical intraepithelial neoplasia after an average of 3 years of follow-up.5,6 Investigators in these trials have hit their mark soundly: the vaccine showed significant efficacy against anogenital and cervical lesions related to vaccine type in women with no evidence of previous exposure to vaccine-specific types; the vaccine also appeared to be safe. In addition, the studies report outcomes in all subjects regardless of HPV status at baseline and regardless of whether outcomes were related to HPV types targeted by the vaccine. Policymakers now have more evidence to assess the benefits and risks of widespread vaccination.
. . .Policymakers, clinicians, and parents have a keen sense of urgency about HPV vaccination. On one hand, the vaccine has high efficacy against certain HPV types that cause life-threatening disease, and it appears to be safe; delaying vaccination may mean that many women will miss an opportunity for long-lasting protection. On the other hand, a cautious approach may be warranted in light of important unanswered questions about overall vaccine effectiveness, duration of protection, and adverse effects that may emerge over time. HPV vaccination has the potential for profound public health benefit if the most optimistic scenario of effectiveness is realized.