Estimating the direct effect of human papillomavirus vaccination on the lifetime risk of screen‐detected cervical precancer

Birth cohorts vaccinated against human papillomavirus (HPV) are now entering cervical cancer screening. Assessment of (pre)cancer (CIN3+) risk is needed to assess the residual screening need in vaccinated women. We estimated the lifetime (screen‐detected) CIN3+ risk under five‐yearly primary HPV screening between age 30 and 60, using HPV genotyping and histology data of 21,287 women participating in a screening trial with two HPV‐based screening rounds, 5 years apart. The maximum follow‐up after an HPV‐positive test was 9 years. We re‐estimated the CIN3+ risk after projecting direct vaccine efficacy for the bivalent and the nonavalent HPV vaccines, assuming life‐long protection. The lifetime CIN3+ risk was 4.1% (95% confidence interval 3.5‐4.9) and declined by 53.5% and 70.5% after bivalent vaccination without and with cross‐protection, respectively, translating into a residual lifetime CIN3+ risk of 1.9% (1.4‐2.4) and 1.2% (0.9‐1.5). The CIN3+ risk declined by 88.5% after nonavalent vaccination, translating into a residual lifetime CIN3+ risk of 0.5% (0.2‐0.7). The latter risk increased to 1.6% when vaccine protection only lasted until the first screening round at age 30. Among HPV‐positive women with abnormal adjunct cytology, the nine‐year CIN3+ risk was 16.9% (8.7‐32.4) after nonavalent vaccination. In conclusion, HPV vaccination will lead to a strong decline in the lifetime CIN3+ risk and the remaining absolute CIN3+ risk will be very low. Primary HPV testing combined with adjunct cytology at five‐year intervals still seems feasible even after nonavalent vaccination, although unlikely to be cost‐effective. Our results support a de‐intensification of screening programs in settings with high vaccination coverage.