The bivalent human papillomavirus (HPV) vaccine, which generates immunity to the cancer-causing types 16 and 18 of the virus, appears to be effective in protecting women older than 25 against infection and precancerous cervical lesions, according to a randomized trial conducted in 12 countries, including several developing nations.1 An interim analysis from the trial found that women with no history of HPV infection or disease who received all three doses of the vaccine had an 81% reduction in the risk of six-month persistent infection or precancerous cervical changes associated with HPV 16 or 18, compared with similar women in a control group who received a placebo.1 Furthermore, the vaccine protected against persistent infection with two other cancer-causing HPV types to which it was not designed to generate immunity. About one in 10 women in both the overall vaccine group and the control group reported a serious adverse event, but very few were related to the vaccine.
Although licensed in some countries for use among older individuals, HPV vaccines are generally aimed at teenagers and young adults. To examine vaccine efficacy among older women, the trial, known as the VIVIANE study, enrolled healthy nonpregnant, non–breast-feeding women older than 25 from Australia, Canada, Mexico, the Netherlands, Peru, Philippines, Portugal, Russia, Singapore, Thailand, the United Kingdom and the United States between 2006 and 2010. Enrollment in the seven-year trial was age-stratified such that approximately 45% of women were aged 26–35, 45% were aged 36–45 and 10% were 46 or older. To explore the vaccine’s effects among women previously exposed to the virus and to mirror real-world conditions, the study design specified that up to 15% of women in each age-group could have a history of HPV infection or disease, defined as having had two or more abnormal Pap smears in a row, an abnormal colposcopy, or cervical biopsy or treatment after an abnormal smear or colposcopy.
Participants were randomly assigned to receive the bivalent HPV vaccine (marketed as Cervarix) or a control vaccine on a double-blind basis. Cervical samples were collected for HPV DNA testing every six months and Pap testing every 12 months, and blood samples were collected every 6–12 months to assess levels of HPV antibodies. The interim analysis was performed after all women had completed the 48-month visit. For each group, the investigators computed the rate of HPV 16 or 18 infection lasting at least six months or of precancerous cervical changes (cervical intraepithelial neoplasia of grade 1 or higher, CIN1+); they calculated vaccine efficacy as 1 minus the rate ratio (the rate of events in the HPV vaccine group divided by the rate in the control group).
During the trial, 5,752 women received at least one dose of HPV vaccine or placebo and were included in the total vaccinated cohort; on average, women were 37 years old. At baseline, about one-third in each group tested positive for HPV 16 and a similar proportion for HPV 18; one-fourth had had six or more lifetime sexual partners.
Main efficacy analyses were based on the 4,505 women who received all three planned doses of vaccine or placebo, had normal or low-grade cervical cytology at baseline and had no history of HPV infection or disease; the mean duration of follow-up in this cohort was 40 months. The rate of persistent infection or CIN1+ associated with HPV 16 or 18 was 0.1 cases per 100 woman-years among women in the vaccine group and 0.6 cases per 100 woman-years among those in the control group; the difference translated to an overall vaccine efficacy of 81%. By age-group, efficacy was 84% among 26–35-year-olds and 77% among 36–45-year-olds; there were no cases of persistent infection or CIN1+ among women 46 or older. The vaccine had 94% efficacy against HPV 16 or 18 when assessed by an alternate cytology classification (atypical squamous cells of undetermined significance or greater, ASCUS+). And, in an apparent cross-protective effect, it was 79% and 77% effective against persistent HPV 31 and HPV 45 infections, respectively.
The vaccine also showed efficacy, although to a lesser extent, in supplementary analyses using other cohorts. For example, in analyses that excluded women who had had high-grade cytology or a history of HPV infection at baseline, but included women even if they had missed one or two doses, the vaccine had 74% efficacy against persistent infection or CIN1+ associated with HPV 16 or 18; among all women, regardless of cytology and HPV history, who received at least one dose, the vaccine’s efficacy was 44%. In post hoc exploratory analyses restricted to women who had a history of HPV infection at baseline, but included women even if they had missed one or two doses, the rate of persistent infection or CIN1+ associated with HPV 16 or 18 was 1.5 cases per 100 woman-years in the vaccine group and 2.9 cases per 100 woman-years in the control group. Vaccine efficacy for all vaccinated women excluding this subset was 42%—similar to that for all vaccinated women as a whole.
Safety results, assessed among the total vaccinated cohort, showed that a larger proportion of women in the HPV vaccine group than of peers in the control group reported an injection-site reaction when specifically asked about this side effect (85% vs. 67%). Overall, 10% of women in the vaccine group and 9% of those in the control group experienced serious adverse events; however, fewer than 1% of these events in each group were considered to be related to vaccination. Among women who conceived during the study, rates of spontaneous abortions and congenital anomalies were similar in the two groups.
“Adolescent girls before sexual debut will probably continue to be the main priority for population-level, publicly funded [HPV] vaccination programmes,” the investigators maintain. However, women continue to acquire new HPV infections during their adult life and may also become reinfected or have reactivation of latent infection, they note. “Our findings lend support [to] the contention that women older than 25 years can benefit from HPV vaccination, including those who have been previously exposed to HPV,” they conclude.—S. London
1. Skinner SR et al., Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study, Lancet, 2014, 384(9961):2213–2217.