Human papillomavirus genotype replacement: still too early to tell?

Background: Although human papillomavirus (HPV) vaccines are highly efficacious in protecting against HPV infections and related diseases, vaccination may trigger replacement by nontargeted genotypes if these compete with the vaccine-targeted types. HPV genotype replacement has been deemed unlikely, based on the lack of systematic increases in the prevalence of nonvaccine-type (NVT) infection in the first decade after vaccination, and on the presence of cross-protection for some NVTs. Methods: To investigate whether type replacement can be inferred from early postvaccination surveillance, we constructed a transmission model in which a vaccine type and an NVT compete through infection-induced cross-immunity. We simulated scenarios of different levels of cross-immunity and vaccine-induced cross-protection to the NVT. We validated whether commonly used measures correctly indicate type replacement in the long run. Results: Type replacement is a trade-off between cross-immunity and cross-protection; cross-immunity leads to type replacement unless cross-protection is strong enough. With weak cross-protection, NVT prevalence may initially decrease before rebounding into type replacement, exhibiting a honeymoon period. Importantly, vaccine effectiveness for NVTs is inadequate for indicating type replacement. Conclusions: Although postvaccination surveillance thus far is reassuring, it is still too early to preclude type replacement. Monitoring of NVTs remains pivotal in gauging population-level impacts of HPV vaccination.