Developing, validating and testing non-vaccine-preventable human papillomavirus to control for differences in sexual behaviour when evaluating HPV vaccination

BACKGROUND: Evaluating impact/effectiveness of human papillomavirus (HPV) vaccination generally assumes stability in factors driving transmission, which might not be valid. We aimed to develop, validate, and test a grouping of non-vaccine-preventable HPV (NVP-HPV) types as a molecular indicator associated with sexual behaviours to control for changes in HPV transmission risk. METHODS: We used data from the National Surveys of Sexual Attitudes and Lifestyles (Natsal-2, 1999-2001, N=1,849; Natsal-3, 2010-2012, N=2,407) to validate the association of NVP-HPV (26/53/66/70/73) with self-reported sexual behaviours. We calculated NVP-HPV-adjusted HPV16/18 vaccine impact/effectiveness estimates in two real-world scenarios: 1) Natsal-2/Natsal-3 (sexually-experienced women in Britain, 18-44yrs) and 2) England's HPV surveillance (women 16-24yrs) (2008, N=3,539; 2010-2020, N=24,707). Samples (urine/vulvo-vaginal swabs) were tested for 21 HPV genotypes (6/11/16/18/26/31/33/35/39/45/51/52/53/56/58/59/66/68/70/73/82) using an in-house multiplex PCR and Luminex-based genotyping assay. RESULTS: NVP-HPV infection was strongly associated with sexual behaviours (e.g., younger age sexual debut, partner numbers). In Natsal data, adjusting for NVP-HPV did not change vaccine impact estimates (unadjusted prevalence ratio (PR: 0.50 (0.27-0.95), adjusted PR: 0.45 (0.25-0.82)). In the second scenario, adjusting for NVP-HPV did not change the prevalence ratio for HPV16/18 comparing 2020 to 2010 (0.07 (0.030.15), unadjusted and adjusted PR). In both scenarios, prevalence of NVP-HPV did not change over time. CONCLUSIONS: We have demonstrated proof-of-concept that NVP-HPV is strongly associated with sexual behaviours. Adjusting for NVP-HPV in two datasets found that original estimates were robust. IMPACT: NVP-HPV might be used to control for changes in HPV transmission risk over time and between groups when evaluating vaccination impact/effectiveness.