Is a 9-valent human papillomavirus (HPV) vaccine more effective than a quadrivalent vaccine?
A new 9-valent HPV vaccine is generally similar in effectiveness to the older quadrivalent vaccine. There is a small benefit of the new vaccine compared with the older vaccine for women who are initially uninfected (2.4 vs. 4.2 cases per 1,000 person-years), but you would have to immunize approximately 160 women with the new vaccine to prevent one high-grade lesion over three years. It is possible that with additional follow-up, benefit would continue to accrue to the immunized women. (Level of Evidence = 1b)
The current HPV vaccine is quadrivalent (qHPV), meaning it is active against the four oncogenic HPV subtypes (6, 11, 16, and 18) that cause approximately 70% of cervical cancers. This industry-funded study examines the effectiveness of a 9-valent vaccine (9vHPV), which theoretically extends protection to subtypes that cause an additional 20% of cervical cancers. This was an “adaptive design” clinical trial, something we are seeing more frequently these days. The first phase of the trial is used to establish the most effective dosage, and then the second phase evaluates its effectiveness. These researchers initially randomized 1,242 women to receive one of three doses of 9vHPV or qHPV as a control group, and then an additional 13,598 women were randomized to receive the selected dose of 9vHPV or qHPV. The average age of participants was 22 years, with a range of 16 to 26 years, and the women came from treatment centers all over the world.
The study was powered to find a difference in outcomes regarding the five subtypes not covered by the qHPV vaccine. Analysis was per protocol (including only those who got all three immunizations within one year, were HPV-free at the beginning of the study, and had no protocol violations), rather than the preferred intention-to-treat analysis. The authors did report results for a modified intention-to-treat population that included all patients who received at least one dose of the vaccine. This is important, because based on data from the Centers for Disease Control and Prevention, only approximately two-thirds of women complete the series (http://www.cdc.gov/mmwr/preview/mmwrhtml/su6302a10.htm). Women in the study were followed up for up to 60 months.
Approximately one-half the participants were HPV-positive by serology or polymerase chain reaction at baseline. The primary outcome was the rate of high-grade cervical, vulvar, or vaginal disease caused by one of the five HPV subtypes not in the older vaccine, and that rate was significantly lower with the 9vHPV vaccine in the per-protocol population (0.1 vs. 1.6 per 1,000 person-years). There was no difference between groups with respect to the four HPV subtypes shared by both vaccines. The 9vHPV vaccine stimulated similar degrees of immunogenicity for HPV types 6, 16, and 18, with a slightly lower titer for type 11. In the modified intention-to-treat analysis, there was no overall difference in the incidence of the primary outcome between groups (14.0 vs. 14.0 cases per 1,000 person-years). When considering only women who were uninfected at baseline, there was a significant reduction in the incidence of HPV (2.4 vs. 4.2 cases per 1,000 person-years), and in particular cases associated with one of the nine subtypes among those who were initially uninfected (0.0 vs. 1.2 cases per 1,000 person-years). The overall incidence of adverse events was similar between groups, but more patients reported moderate to severe pain or swelling with the 9vHPV vaccine. Serious events were similar between groups.
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry
Reference: JouraEAGiulianoARIversenOEet alBroad Spectrum HPV Vaccine StudyA 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med2015; 372( 8): 711– 723.