Evidence for missing HPV-45 and -59 positives with the SPF-DEIA-LiPA (version 1) platform compared to the type-specific qPCR assays and the impact on vaccine effectiveness estimates.

Human papillomavirus (HPV) epidemiological and vaccine studies require highly sensitive HPV detection systems. The widely used broad-spectrum SPF10-DEIA-LiPA25 (SPF10 method) has reduced sensitivity towards HPV-45 and -59. Therefore, anogenital samples from the PASSYON study were retrospectively analyzed with type-specific (TS) HPV-45 and -59 qPCR assays. The SPF10 method missed 51.1% of HPV-45 and 76.1% of HPV-59 infections, detected by the TS qPCR assays. Viral copy number (VCn) of SPF10 missed HPV-45 and -59 was significantly lower than SPF10 detected HPV-45 and -59 (p<0.0001 for both HPV types). Sanger sequencing showed no phylogenetic distinction between SPF10 missed and detected HPV-59 variants, but variants bearing the A6562G SNP in the SPF10 target region were more likely to be missed (p=0.0392). HPV co-occurrence slightly influenced the detection probability of HPV-45 and -59 with the SPF10 method. Moreover, HPV-59 detection with the SPF10 method was hampered more in non-vaccinated women than vaccinated women, likely due a stronger masking effect by increased HPV co-occurrence in the former group. Consequentially, the SPF10 method led to a strong negative vaccine effectiveness (VE) of -84.6% against HPV-59 while the VE based on TS qPCR was 3.1%. For HPV45, the relative increase in detection in non-vaccinated women compared vaccinated women was more similar, resulting in comparable VE estimates. In conclusion, this study shows that HPV-45 and -59 detection with SPF10 method is dependent on factors including VCn, HPV co-occurrence, and vaccination, thereby showing that knowledge of the limitations of the HPV detection method used is of great importance

Effect of the bivalent HPV vaccine on viral load of vaccine and non-vaccine HPV types in incident clearing and persistent infections in young Dutch females.

HPV vaccination with the bivalent vaccine is efficacious against HPV16 and 18 infections and cross-protection against non-vaccine HPV types has been demonstrated. Here, we assessed (cross-) protective effects of the bivalent HPV16/18 vaccine on incident and persistent infections and viral load (VL) of fifteen HPV types in an observational cohort study monitoring HPV vaccine effects. Vaginal samples were obtained annually. Type-specific VL assays were developed for HPV6,11,31 33,35,39,45,51,52,56,58,59 and 66 and used in addition to existing HPV16 and 18 assays. Rate differences of incident clearing and persistent infections were correlated with differences in VL and vaccination status. HPV16/18 vaccination resulted in significantly lower incidence of HPV16/18 infections and significantly lower VL in breakthrough HPV16 (p<0.01) and 18 infections (p<0.01). The effects of vaccination on non-vaccine type VL were ambiguous. Incidence and/or persistence rates of HPV31, 33, 35 and 45 were reduced in the vaccinated group. However, no significant type specific VL effects were found against HPV31, 33, 45, 52 in the vaccinated group. For HPV 6, 59 and 66 no significant reductions in numbers of incident and persistent infections were found, however borderline) VL reductions following vaccination were observed for HPV6 (p = 0.01), 59 (p = 0.10) and 66 (p = 0.03), suggesting a minor effect of the vaccine on the VL level of these HPV types. Overall, vaccination resulted in infections with slightly lower VL, irrespective of HPV type. In conclusion, vaccination with the bivalent HPV16/18 vaccine results in significantly reduced numbers of HPV16 and 18 incidence rates and reduced VL in breakthrough infections. Significant reductions in incident and/or persistent HPV31, 33, 35 and 45 infections were found, but no significant effect was observed on the VL for infections with these types. For the other non-vaccine HPV types no reduction in incident and/or persistent infections were found, but overall the VL tended to be somewhat lower in vaccinated women

Persisting Antibody Response Nine Years after Bivalent HPV Vaccination in A Cohort of Dutch Women: Immune Response and the Relation with Genital HPV Infections.

The bivalent human papillomavirus (HPV) vaccine is highly effective and induces robust serological responses. Using a Dutch prospective cohort initiated in 2009, including 744 vaccinated and 294 unvaccinated girls (1993-1994) who provide a vaginal self-swab sample, serum sample, and questionnaire yearly, we report a high, persisting antibody response up to 9 years after vaccination for vaccine types HPV-16 or HPV-18. Antibodies against nonvaccine HPV types 31, 33, 45, 52, and 58 were lower but still significantly higher than in unvaccinated individuals. This was also reflected in the seroprevalence. We compared participant characteristics and antibody levels between vaccinated women with and those without HPV infections 1 year before infection (204 incident and 64 persistent infections), but we observed no consistent difference in type-specific antibody levels. Having a high-risk HPV infection was associated with sexual risk behavior and smoking 1 year before infection. Although high antibody levels are necessary for protection, our study suggests that on the individual level other factors such as HPV exposure or antibody avidity could be important