HPV 16/18 Vaccine Shows Protective Efficacy in Women Aged > 25 Years in 4-Year Interim Follow-up of VIVIANE Study


Key Points

  • HPV 16/18 vaccine was protective against persistent infection or CIN1+ in women aged > 25 years.
  • A significant protective effect was observed against atypical squamous cells of undetermined significance or greater associated with HPV 16/18.

In the 4-year interim follow-up of the VIVIANE study reported in The Lancet by Skinner et al, the human papillomavirus (HPV) 16/18 AS04-adjuvanted vaccine was found to be protective against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18 in women aged > 25 years.

Study Details

In this phase III double-blind trial, 5,752 healthy women aged > 25 years were randomly assigned to HPV vaccine (n = 2,881) or a control group (n = 2,871 control). Randomization was stratified for age, with approximately 45%, 45%, and 10% of subjects being in the 26- to 35-year, 36- to 45- year, and ≥ 46-year age strata in both study groups. Up to 15% of women in each age stratum could have a history of HPV infection or disease.

The primary endpoint was vaccine efficacy against 6-month persistent infection or CIN1+ associated with HPV 16/18. The primary analysis was performed in the according-to-protocol cohort, consisting of subjects who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease.

Protective Efficacy

A total of 4,505 women were included in the according-to-protocol cohort for efficacy, consisting of 2,264 in the vaccine group and 2,241 in the control group. After mean follow-up of 40.3 months, the vaccine exhibited protective efficacy in all age groups combined (81.1%, 97.7% confidence interval [CI] = 52.1–94.0), in the 26- to 35-year age group (83.5%, 97.7% CI = 45.0–96.8), and in the 36- to 45-year age group (77.2%, 97.7% CI = 2.8–96.9); no cases of persistent infection or CIN1+ associated with HPV 16/18 were observed in women aged ≥ 46 years.

The vaccine efficacy rate was 82.9% (97.7% CI = 53.8–95.1) for 6-month persistent infection. There were few cases of CIN1+ or CIN2+; efficacy rates for these outcomes were 86.1% (97.7% CI = −35.4 to 99.9) and 100% (97.7% CI = −100.7 to 100.0) for CIN2+. Significant protection was observed against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 (93.7%, 97.7% CI = 71.5–99.5).

Significant cross-protective efficacy against 6-month persistent infection with HPV 31 (79.1%, 97.7% CI = 27.6–95.9) and HPV 45 (76.9%, 97.7% CI = 18.5–95.6) was also observed.


Serious adverse events occurred in 10% of women in the vaccine group and 9% of those in the control group and were considered to be related to vaccination in < 1% of patients in both groups. A total of 17 patients died, including 14 (< 1%) in the vaccine group and 3 (< 1%) in the control group, with none of the deaths considered related to vaccination.

An unblinded review of deaths by the independent data monitoring committee indicated that the causes of death were variable and showed no clustering. Mean time from last vaccination to death was 682 days in the vaccine group and 496 days in the control group, suggesting an absence of temporal association.  

The investigators concluded: “In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45.”

S. Rachel Skinner, PhD, of University of Sydney, is the corresponding author for The Lancet article.

The study was funded by GlaxoSmithKline Biologicals SA. For full disclosures of the study authors, visit

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