Epidemiological approaches to evaluate clinical unmasking of HPV-associated cervical lesions in the HPV vaccination era

HPV vaccination reduces the risk of developing HPV-attributable cancers, including cervical cancer. However, an attenuation of HPV vaccine impact after the implementation of HPV vaccination may occur through clinical unmasking. Clinical unmasking is a distinct and complex phenomenon that arises in the absence of clinical interventions necessary to treat disease caused by high-risk vaccine-preventable HPV types (mainly HPV16) allowing uninterrupted progression of non-vaccine preventable types that are frequently present as co-infections. Clinical unmasking is distinct from viral unmasking, which is a diagnostic assay artifact, and from HPV type replacement, a theorized biological phenomenon requiring competition between HPV types, which has not yet been documented. All three processes could manifest as an apparent increase in cervical precancer/cancer by non-HPV vaccine types, resulting in a lower-than-anticipated vaccine impact based on projections derived from type attribution studies. Here, we describe these concepts and epidemiological approaches to evaluate clinical unmasking in the post-vaccination era. We propose a historical and a contemporaneous approach, highlighting key considerations and illustrating the potential outcomes with hypothetical data. Both approaches would have a similar outcome and interpretation: an increased incidence of precancerous lesions (CIN2+) due to non-vaccine preventable types among vaccinated versus unvaccinated women (historically in the pre-vaccination era, or contemporaneously) in the long term being indicative of clinical unmasking. Protection afforded by HPV vaccines against high-grade cervical precancers, irrespective of type, remains considerable. However, carefully designed studies are needed to investigate the potential impact of clinical unmasking and its implications on vaccine effectiveness in the post-vaccination era.