Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine

Abstract

Background: Three-dose regimens for human papillomavirus (HPV) vaccines are expensive and difficult to complete, especially in settings where the need for cervical cancer prevention is greatest.

Methods: We evaluated the vaccine efficacy of fewer than three doses of the HPV16/18 vaccine Cervarix in our Costa Rica Vaccine Trial. Women were randomly assigned to receive three doses of the HPV16/18 vaccine or to a control vaccine and were followed for incident HPV16 or HPV18 infection that persisted in visits that were 10 or more months apart (median follow-up 4.2 years). After excluding women who had no follow-up or who were HPV16 and HPV18 DNA positive at enrollment, 5967 women received three vaccine doses (2957 HPV vaccine vs 3010 control vaccine), 802 received two doses (422 HPV vs. 380 control), and 384 received one dose (196 HPV vs. 188 control). Reasons for receiving fewer doses and other pre- and post-randomization characteristics were balanced within each dosage group between women receiving the HPV and control vaccines.

Results: Incident HPV16 or HPV18 infections that persisted for 1 year were unrelated to dosage of the control vaccine. Vaccine efficacy was 80.9% for three doses of the HPV vaccine (95% confidence interval [CI] = 71.1% to 87.7%; 25 and 133 events in the HPV and control arms, respectively), 84.1% for two doses (95% CI = 50.2% to 96.3%; 3 and 17 events), and 100% for one dose (95% CI = 66.5% to 100%; 0 and 10 events).

Conclusion: Four years after vaccination of women who appeared to be uninfected, this nonrandomized analysis suggests that two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses.

Figure 1

CONSORT diagram of women in the Costa Rica Vaccine Trial. The primary aim of the trial was to evaluate the efficacy of a three-dose regimen of the Cervarix vaccine to prevent persistent type-specific infection with HPV16 or HPV18 and the subsequent development of HPV-associated precancerous lesions. Although 7466 women were randomized to receive three doses of either Cervarix or control vaccine, approximately 20% received fewer than three doses of Cervarix or control vaccine mostly because of pregnancy and referral to colposcopy. Thus, we were able to investigate the protection afforded by two and one dose(s) of the HPV vaccine because the cost and logistical difficulties of the standard three-dose vaccine regimen compromises implementation. Asterisk indicates that four women received discordant vaccines (one woman was enrolled twice and received three doses of each vaccine and three women received two doses of one vaccine and one dose of the other vaccine). For the purpose of this analysis, the control dosing was ignored and they were categorized based on the number of HPV vaccines they received. Dagger indicates that women who were both HPV16 and HPV18 DNA positive at enrollment were excluded, as were women with no follow-up visits post-enrollment.