Seven RCTs reported in 13 publications were included in the review (43,283 participants, range 552 to 18,644). All trials reported adequate allocation concealment and blinding and reported drop-outs/loss to follow-up and sample size calculation. Expected efficacy ranged from 0.70 to 0.90. All trials were industry funded.
HPV-16: Statistically significant reductions in risks of CIN2+ (RR 0.47, 95% CI 0.36 to 0.61, I2=87%; four RCTs), CIN1+ (RR 0.43, 95% CI 0.33 to 0.58, I2=76%; four RCTs) and persistent infection of at least six months (RR 0.15, 95% CI 0.10 to 0.23, I2=23%; two RCTs) were associated with HPV-16 was found with prophylactic vaccine use compared with controls in ITT cohorts.
HPV-18: Significant reductions in risks of CIN2+ (RR 0.16, 95% CI 0.08 to 0.34, I2=9%; three RCTs), CIN1+ (RR 0.22, 95% CI 0.10 to 0.44, I2=0%; three RCTs) and persistent infection of at least six months (RR 0.24, 95% CI 0.14 to 0.42, I2=0%; two RCTs) were associated with HPV-18 compared to control in ITT cohorts.
HPV-31, 33, 45, 52 and 58: Reductions in risks of CIN2+ (RR 0.79, 95% CI 0.67 to 0.92, I2=74%; two RCTs) and persistent infection of at least six months (RR 0.77, 95% CI 0.72 to 0.83, I2=66%; two RCTs) associated with non-vaccine oncogenic HPV types (31, 33, 45, 52 and 58) were found compared with control in ITT cohorts.
When cross-protection against six-month persistent infection was examined by HPV type, a significant reduction in risk was found for HPV-31 (RR 0.47 95% CI 0.40 to 0.55, I2=94%; two RCTs), HPV-33 (RR 0.65, 95% CI 0.53 to 0.80, I2=16%; two RCTs) and HPV-45 (RR 0.50, 95% CI 0.39 to 0.64, I2=94%; two RCTs). No significant between-group differences were found for risk of persistent infection of at least six months with HPV-52 and HPV-58.
Exclusion of the FUTURE trials increased efficacy estimates and reduced observed heterogeneity. Per protocol population cohort analyses showed larger effect sizes than the ITT analyses..
Adverse events: No significant between-group differences were found for participants who experienced one or more serious adverse events or vaccine-related serious adverse events.
The funnel plot indicated no significant publication bias for the primary endpoint (CIN2+) associated with HPV-16/18 in ITT cohorts (p=0.60).