Effects of 2 and 3 Vaccinations With the Bivalent Human Papillomavirus (HPV) Vaccine on the Prevalence and Load of HPV in Clearing and Persistent Infections in Young Women.

BACKGROUND: Human papillomavirus (HPV) viral load (VL) is associated with persistence, which increases cervical cancer risk. The bivalent vaccine protects against oncogenic HPV-16/18 and cross-protects against several nonvaccine types. We examined the effect of 2-dose (2D) and 3-dose (3D) vaccination on HPV prevalence and VL in clearing infections and persistent infections, 6 years and 12 years postvaccination, respectively. METHODS: Vaginal swabs collected from the "HPV Amongst Vaccinated and Non-vaccinated Adolescents" study (HAVANA, 3D-eligible) and HAVANA-2 (2D-eligble) participants were genotyped for HPV with the SPF10-DEIA-LiPA25 system. HPV VL was measured with type-specific quantitative polymerase chain reaction (qPCR). RESULTS: HPV-16, -18, -31, -33, and -45 clearing and/or persistent infection prevalence and HPV-16, -18, and -31 VLs in clearing infections were significantly reduced in 3D-vaccinated women compared to unvaccinated women. Except for HPV-11 and -59 clearing infections, no significant VL differences were observed among vaccinated women, ≤6 and >6 years post-vaccination. Infection numbers were low in 2D-eligible women, with no HPV-16/18 in vaccinated women. No VL differences for the remaining types were found. CONCLUSIONS: 3D vaccination reduces HPV prevalence in clearing infections and persistent infections and decreases HPV VLs in clearing infections, 12 years post-vaccination for vaccine and several nonvaccine types. 2D-eligible women had low infection numbers, with no HPV-16/18 among vaccinated women.

Vaccine Effectiveness Following Routine Immunization With Bivalent Human Papillomavirus (HPV) Vaccine: Protection Against Incident Genital HPV Infections From a Reduced-Dosing Schedule.

BACKGROUND: In the Netherlands, the bivalent human papillomavirus (HPV) vaccine has been offered to preadolescent girls via the National Immunization Program in a 2-dose schedule since 2014. The current study estimates vaccine effectiveness (VE) against HPV infections up to 4 years postvaccination among girls eligible for routine 2-dose immunization. METHODS: A cohort study (HAVANA2) was used in which participants annually filled out an online questionnaire and provided a vaginal self-sample for determination of HPV by the SPF10-LiPA25 assay, able to detect 25 HPV types. VE against incident type-specific infections and pooled outcomes was estimated by a Cox proportional hazards model with shared frailty between the HPV types. RESULTS: In total, 2027 girls were included in the study, 1098 (54.2%) of whom were vaccinated with 2 doses. Highest incidence rate was 5.0/1000 person-years (HPV-51) among vaccinated participants and 9.1/1000 person-years (HPV-74) among unvaccinated participants. Adjusted pooled VE was 84.0% (95% confidence interval [CI], 27.0%-96.5%) against incident HPV-16/18 infections and 86.5% (95% CI, 39.5%-97.08%) against cross-protective types HPV-31/33/45. CONCLUSIONS: Four years postvaccination, 2 doses of bivalent HPV vaccine were effective in the prevention of incident HPV-16/18 infections and provided cross-protection to HPV-31/33/45. Our VE estimates rival those from 3-dose schedules, indicating comparable protection by 2-dose schedules.

Type-specific concurrent anogenital HPV detection among young women and MSM attending Dutch sexual health clinics.

OBJECTIVES: This study aimed to investigate type-specific concurrent anogenital human papillomavirus (HPV) detection and examine associations with concurrent detection. METHODS: Data from a Dutch repeated cross-sectional study among young sexual health clinic visitors (Papillomavirus Surveillance among STI clinic Youngsters in the Netherlands) between 2009 and 2019 were used. Cohen's kappa was used to assess the degree of type-specific concordance of HPV detection between anal and genital sites for 25 HPV genotypes for women and men who have sex with men (MSM) separately. Associations with type-specific concurrent HPV were identified. Receptive anal intercourse (RAI) was forced into the model to investigate its influence. RESULTS: Among women (n=1492), type-specific concurrent anogenital detection was common; kappa was above 0.4 for 20 genotypes. Among MSM (n=614), kappa was <0.4 for all genotypes. The only significant association with type-specific concurrent anogenital detection among women was genital chlamydia (adjusted OR 1.5, 95% CI 1.1 to 2.2). RAI was not associated. CONCLUSIONS: Type-specific concurrent anogenital HPV detection was common among young women, and uncommon among MSM. For women, concurrent HPV detection was associated with genital chlamydia. Our results are suggestive of autoinoculation of HPV among women.

Population Impact of Girls-Only Human Papillomavirus 16/18 Vaccination in The Netherlands: Cross-Protective and Second-Order Herd Effects.

BACKGROUND: Human papillomavirus (HPV) vaccination programs achieve substantial population-level impact, with effects extending beyond protection of vaccinated individuals. We assessed trends in HPV prevalence up to 8 years postvaccination among men and women in the Netherlands, where bivalent HPV vaccination, targeting HPV types 16/18, has been offered to (pre)adolescent girls since 2009 with moderate vaccination coverage. METHODS: We used data from the PASSYON study, a survey initiated in 2009 (prevaccination) and repeated biennially among 16- to 24-year-old visitors of sexual health centers. We studied genital HPV positivity from 2009 to 2017 among women, heterosexual men, and unvaccinated women using Poisson generalized estimating equation models, adjusted for individual- and population-level confounders. Trends were studied for 25 HPV types detected by the SPF10-LiPA25 platform. RESULTS: A total of 6354 women (64.7% self-reported unvaccinated) and 2414 heterosexual men were included. Percentual declines in vaccine types HPV-16/18 were observed for all women (12.6% per year [95% confidence interval {CI}, 10.6-14.5]), heterosexual men (13.0% per year [95% CI, 8.3-17.5]), and unvaccinated women (5.4% per year [95% CI, 2.9-7.8]). We observed significant declines in HPV-31 (all women and heterosexual men), HPV-45 (all women), and in all high-risk HPV types pooled (all women and heterosexual men). Significant increases were observed for HPV-56 (all women) and HPV-52 (unvaccinated women). CONCLUSIONS: Our results provide evidence for first-order herd effects among heterosexual men against HPV-16/18 and cross-protective types. Additionally, we show second-order herd effects against vaccine types among unvaccinated women. These results are promising regarding population-level and clinical impact of girls-only bivalent HPV vaccination in a country with moderate vaccine uptake.

Persisting Antibody Response 9 Years After Bivalent Human Papillomavirus (HPV) Vaccination in a Cohort of Dutch Women: Immune Response and the Relation to 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.

Bivalent Vaccine Effectiveness Against Anal Human Papillomavirus Positivity Among Female Sexually Transmitted Infection Clinic Visitors in the Netherlands.

Human papillomavirus (HPV) vaccines are indicated for anal cancer prevention, but evidence for vaccine effectiveness (VE) against anal HPV infections among women is limited. We estimated the VE (≥1 dose) against anal HPV positivity of the bivalent vaccine, whose target types HPV-16/18 are associated with approximately 90% of HPV-related anal cancers. Among 548 female STI clinic visitors 16-24 years old who provided an anal swab sample as part of a repeated cross-sectional survey, VE against HPV-16/18 was 89.9% (95% confidence interval, 63.0%-97.2%). Type-specific VE correlated well with VE against cervicovaginal HPV (Spearman ρ = 0.76), suggesting comparable effectiveness of HPV-16/18 vaccination against genital and anal infections.

Evidence for Missing Positive Results for Human Papilloma Virus 45 (HPV-45) and HPV-59 with the SPF10-DEIA-LiPA25 (Version 1) Platform Compared to Type-Specific Real-Time Quantitative PCR Assays and 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 toward HPV-45 and -59. Therefore, anogenital samples from the PASSYON study were retrospectively analyzed with type-specific (TS) HPV-45 and -59 real-time quantitative PCR (qPCR) assays. The SPF10 method missed 51.1% of HPV-45 and 76.1% of HPV-59 infections that were detected by the TS qPCR assays. The 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 SPF10-detected HPV-59 variants, but variants bearing the A6562G single-nucleotide polymorphism (SNP) in the SPF10 target region were more likely to be missed (P = 0.0392). HPV cooccurrence 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 nonvaccinated women than vaccinated women, likely due to a stronger masking effect by increased HPV cooccurrence in the former group. Consequently, 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 HPV-45, the relative increase in detection in nonvaccinated women compared vaccinated women was more similar, resulting in comparable VE estimates. In conclusion, this study shows that HPV-45 and -59 detection with the SPF10 method is dependent on factors including VCn, HPV cooccurrence, and vaccination, thereby showing that knowledge of the limitations of the HPV detection method used is of great importance.

Bivalent Human Papillomavirus (HPV) Vaccine Effectiveness Correlates With Phylogenetic Distance From HPV Vaccine Types 16 and 18.

To substantiate cross-protection reported across AS04-adjuvanted bivalent human papillomavirus (HPV) vaccine (2vHPV) studies, we reevaluated vaccine effectiveness against type-specific HPV positivity as a function of phylogenetic distance to vaccine target types HPV-16 and -18. We provide evidence of sustained cross-protection up to 8 years postvaccination in a high-risk population in the Netherlands. Moreover, our findings suggest that genomic distance better explains cross-protection than distance measures based on capsid antigens only. Taken together, 2vHPV is predicted to provide partial cross-protection against HPV-31, -33, -35, -45, -52, and possibly -58, that is, acknowledged oncogenic types with close phylogenetic relationships to HPV-16 or -18.

Virological and Serological Predictors of Anal High-grade Squamous Intraepithelial Lesions Among Human Immunodeficiency Virus-positive Men Who Have Sex With Men.

BACKGROUND: Our objective was to identify virological and serological predictors of anal high-grade squamous intraepithelial lesions (HSIL) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). METHODS: HIV-positive MSM were recruited from a longitudinal study during which anal self-swabs and serum were collected at up to 5 bi-annual visits. Swabs were human papillomavirus (HPV) genotyped, and the type-specific HPV viral load in the anal swabs was determined. Serum antibodies to the E6, E7, E1, E2, and L1 proteins of 7 high-risk HPV (hrHPV) types and HPV6 and 11 were analyzed. The participants who had a high-resolution anoscopy after the last study visit were included in the current analysis. Anal HSIL was diagnosed by histopathological examinations of anal biopsies. The causative HPV type of anal HSIL was determined in whole tissue sections (WTS) and by laser capture micro-dissection if more than one HPV-type was found in WTS. Multivariable logistic regression was used to study whether persistent anal HPV infections, HPV viral loads, and seropositivity for HPV were predictors of anal HSIL, either in general or caused by the concordant HPV type. RESULTS: Of 193 HIV-positive MSM, 50 (26%) were diagnosed with anal HSIL. HrHPV persistence in anal swabs was common, varying by hrHPV type between 3-21%. Anal HPV persistence was the only determinant independently associated with anal HSIL, both in general and by concordant, causative HPV type. CONCLUSIONS: Persistent HPV infections were strongly associated with anal HSIL, in general as well as for the concordant HPV type.

Assessment of herd effects among women and heterosexual men after girls-only HPV16/18 vaccination in the Netherlands: A repeated cross-sectional study.

Data on the impact of human papillomavirus (HPV) vaccination on the population HPV prevalence are largely obtained from women. We assessed the impact of the girls-only HPV16/18 vaccination program in the Netherlands that started in 2009, on trends in HPV prevalence among women and heterosexual men, using data from the PASSYON study. In this cross-sectional study, the HPV prevalence among 16- to 24-year-old visitors to sexually transmitted infection clinics was assessed in 2009, 2011, 2013, and 2015. We compared the genital postvaccination HPV prevalence with the prevaccination prevalence (2009) using Poisson GEE models. In total, we included 4,996 women and 1,901 heterosexual men. The percentage of women who reported to be vaccinated increased from 2.3% in 2009 to 37% in 2015. Among all women, the HPV16/18 prevalence decreased from 23% prevaccination to 15% in 2015 (adjusted prevalence ratio [aPR] 0.62, ptrend < 0.01). Among heterosexual men, the HPV16/18 prevalence decreased from 17% prevaccination to 11% in 2015 (aPR 0.52, ptrend < 0.01). Of the heterosexual men with a steady partner, HPV16/18 prevalence was lower among those whose steady partner had been vaccine-eligible in the national immunization program (aPR 0.13). Among unvaccinated women, the HPV16/18 prevalence in 2015 was not different from prevaccination. The decreasing HPV16/18 prevalence among heterosexual men and the reduced HPV16/18 prevalence among heterosexual men with a vaccine-eligible steady partner strongly suggests herd protection from girls-only vaccination. Absence of notable herd effects among unvaccinated women 6 years postvaccination may be due to the moderate vaccine uptake among girls in the Netherlands.

Bivalent Vaccine Effectiveness Against Type-Specific HPV Positivity: Evidence for Cross-Protection Against Oncogenic Types Among Dutch STI Clinic Visitors.

Background: Observational postmarketing studies are important to assess vaccine effectiveness (VE). We estimated VE from the bivalent human papillomavirus (HPV) vaccine against HPV positivity of vaccine and nonvaccine types in a high-risk population. Methods: We included all vaccine-eligible women from the PASSYON study, a biennial cross-sectional survey in Dutch sexually transmitted infection clinics. Vaginal swabs were analyzed using a polymerase chain reaction-based assay (SPF10-LiPA25) able to detect the 12 high-risk HPV (hrHPV) types 16/18/31/33/35/39/45/51/52/56/58/59. We compared hrHPV positivity between self-reported vaccinated (≥1 dose) and unvaccinated women, and estimated VE by a logistic mixed model. Results: We included 1087 women of which 53% were hrHPV positive and 60% reported to be vaccinated. The adjusted pooled VE against HPV-16/18 was 89.9% (81.7%-94.4%). Moreover, we calculated significant VE against nonvaccine types HPV-45 (91%), HPV-35 (57%), HPV-31 (50%), and HPV-52 (37%). Among women who were offered vaccination 5/6 years ago, we estimated similar VE against HPV-16/18 (92%) and all hrHPV types (35%) compared to women who were offered vaccination <5 years ago (83% and 33%, respectively). Conclusion: We demonstrated high VE of the bivalent vaccine against HPV-16/18 and cross-protection against HPV-45/35/31/52. Protection against HPV-16/18 was sustained up to 6 years postvaccination.

Whole-Genome Sequencing and Variant Analysis of Human Papillomavirus 16 Infections.

Human papillomavirus (HPV) is a strongly conserved DNA virus, high-risk types of which can cause cervical cancer in persistent infections. The most common type found in HPV-attributable cancer is HPV16, which can be subdivided into four lineages (A to D) with different carcinogenic properties. Studies have shown HPV16 sequence diversity in different geographical areas, but only limited information is available regarding HPV16 diversity within a population, especially at the whole-genome level. We analyzed HPV16 major variant diversity and conservation in persistent infections and performed a single nucleotide polymorphism (SNP) comparison between persistent and clearing infections. Materials were obtained in the Netherlands from a cohort study with longitudinal follow-up for up to 3 years. Our analysis shows a remarkably large variant diversity in the population. Whole-genome sequences were obtained for 57 persistent and 59 clearing HPV16 infections, resulting in 109 unique variants. Interestingly, persistent infections were completely conserved through time. One reinfection event was identified where the initial and follow-up samples clustered differently. Non-A1/A2 variants seemed to clear preferentially (P = 0.02). Our analysis shows that population-wide HPV16 sequence diversity is very large. In persistent infections, the HPV16 sequence was fully conserved. Sequencing can identify HPV16 reinfections, although occurrence is rare. SNP comparison identified no strongly acting effect of the viral genome affecting HPV16 infection clearance or persistence in up to 3 years of follow-up. These findings suggest the progression of an early HPV16 infection could be host related.IMPORTANCE Human papillomavirus 16 (HPV16) is the predominant type found in cervical cancer. Progression of initial infection to cervical cancer has been linked to sequence properties; however, knowledge of variants circulating in European populations, especially with longitudinal follow-up, is limited. By sequencing a number of infections with known follow-up for up to 3 years, we gained initial insights into the genetic diversity of HPV16 and the effects of the viral genome on the persistence of infections. A SNP comparison between sequences obtained from clearing and persistent infections did not identify strongly acting DNA variations responsible for these infection outcomes. In addition, we identified an HPV16 reinfection event where sequencing of initial and follow-up samples showed different HPV16 variants. Based on conventional genotyping, this infection would incorrectly be considered a persistent HPV16 infection. In the context of vaccine efficacy and monitoring studies, such infections could potentially cause reduced reported efficacy or efficiency.

Association of HIV Infection With Anal and Penile Low-Risk Human Papillomavirus Infections Among Men Who Have Sex With Men in Amsterdam: The HIV & HPV in MSM Study.

BACKGROUND: This study among men who have sex with men (MSM) aimed to (1) assess prevalence of anogenital low-risk human papillomavirus (lrHPV) infections, (2) evaluate associations with HIV infection, and (3) investigate lrHPV concordance. METHODS: In 2010 to 2011, MSM 18 years or older were recruited in Amsterdam, the Netherlands, and provided anal and penile self-swabs (HIV & HPV in MSM study). Using the HPV SPF10-PCR/DEIA/LiPA25 system, the presence of lrHPV types 6, 11, 34, 40, 42, 43, 44, 53, 54, 66, 68/73, 70, and 74 could be detected. Logistic regression with generalized estimating equations was used to assess the independent effect of HIV on lrHPV infections. The model was repeated for lrHPV subcategories (nononcogenic and weakly oncogenic infections separately). Concordance was defined as detection of the same lrHPV type in both self-swabs of one individual. RESULTS: A total of 778 MSM were included, of whom 317 (41%) were HIV positive (median CD4 count at enrollment, 530 cells/mm). Prevalence of anal lrHPV was 45% (95% confidence interval [CI], 41%-50%) in HIV-negative MSM and 69% (95% CI, 64%-74%) in HIV-positive MSM. Prevalence of penile lrHPV was 20% (95% CI, 16%-24%) and 37% (95% CI, 31%-42%), respectively. In multivariable analysis, HIV infection was independently associated with anal (adjusted odds ratio [aOR], 1.9; 95% CI, 1.5-2.3) and penile lrHPV (aOR, 2.0; 95% CI, 1.4-2.7). Nononcogenic and weakly oncogenic lrHPV subcategories showed a similar pattern of association. Anal lrHPV infections were strongly associated with the presence of a type-concordant penile infection (aOR, 5.8; 95% CI, 4.4-7.5) and vice versa (aOR, 5.7; 95% CI, 4.4-7.5). CONCLUSIONS: Anal and penile infections with lrHPV are common in MSM. HIV infection was an independent determinant for lrHPV infections.

Population- and type-specific clustering of multiple HPV types across diverse risk populations in the Netherlands.

In view of possible type replacement upon introduction of human papillomavirus (HPV) vaccination, we aimed to explore patterns of type-specific clustering across populations with various background infection risks. A total of 3,874 women from 3 cross-sectional studies in the Netherlands (in 2007-2009) provided vaginal self-samples, which were tested for 25 HPV genotypes by a sensitive molecular assay (SPF10 line probe assay, DDL Diagnostic Laboratory, Voorburg, the Netherlands). The number of concurrent HPV infections per woman was studied by Poisson regression. Associations between HPV types were investigated by generalized estimating equation analyses. The prevalence of any HPV type was 14% in a population-based study, 54% in a chlamydia screening intervention study, and 73% in a study among attendees of sexually transmitted infection clinics. Overall, multiple HPV infections were detected in 26% of the women. The number of concurrent HPV infections conformed to an overdispersed Poisson distribution, even after correction for known risk factors. Types differed significantly in their tendencies to be involved in coinfections, but no evidence for particular type-type interactions was found. Moreover, the strongest associations were observed in the lowest-risk population and vice versa.We found no indications of pairwise interactions, but our findings do suggest that clustering differs among HPV types and varies across risk groups.

Twelve-month incidence and clearance of oral HPV infection in HIV-negative and HIV-infected men who have sex with men: the H2M cohort study.

BACKGROUND: Our aim was to compare the 12-month incidence and clearance of oral high-risk HPV infection between HIV-infected men who have sex with men (MSM) and HIV-negative MSM. METHODS: MSM aged 18 years or older were recruited in Amsterdam, the Netherlands. Questionnaire data and oral-rinse and gargle samples were collected at baseline, and after 6 and 12 months. HPV DNA was genotyped using the SPF10-PCR & DEIA-LiPA25 system (version 1). Determinants of oral HPV incidence and clearance were explored using Cox and logistic regression analyses respectively. RESULTS: 433 HIV-negative and 290 HIV-infected MSM were included in these analyses. The median follow-up time per participant was 12 months (range 3-15). During follow-up, 114 incident oral high-risk HPV infections were observed. The incidence rate of HPV-16 was 3.5/1000 person-months (PM) in HIV-infected and 0.9/1000 PM in HIV-negative MSM (IRR 4.1; 95% CI 1.3-13.2). The incidence rates of other high-risk HPV types ranged between 1.3-3.5/1000 PM in HIV-infected and 0.0-1.1/1000 PM in HIV-negative MSM. In multivariable analyses, HIV infection (adjusted hazard ratio [aHR] 3.8; 95% CI 2.3-6.2) and a higher number of recent oral sex partners (aHR 2.4 for ≥8 partners compared to ≤2; 95% CI 1.4-4.2) were associated with HPV incidence. Of the 111 baseline oral high-risk infections, 59 (53.2%) were cleared. In multivariable analyses, only a higher number of recent oral sex partners was associated with HPV clearance (adjusted odds ratio 3.4 for ≥8 compared to ≤2 partners; 95% CI 1.3-9.0). CONCLUSIONS: The incidence rate of oral high-risk HPV infection was higher in HIV-infected MSM and in those with a higher number of recent oral sex partners. Just over half of the oral high-risk HPV infections at baseline were cleared after 12 months, with a higher likelihood of clearance among MSM reporting higher numbers of recent oral sex partners, but no difference by HIV status.

Prevalence and risk factors for HPV seropositivity and anogenital DNA positivity among men who have sex with men: a repeated cross-sectional study.

OBJECTIVES: This study aimed to assess associations of potential risk factors with human papillomavirus (HPV) seropositivity among men who have sex with men (MSM) and compare these to risk factors for anal and penile (HPV) deoxyribonucleic acid (DNA)-positivity in the same study population. METHODS: Seropositivity and anal and penile HPV DNA-positivity were determined for seven high-risk HPV genotypes for MSM aged 16-24 years participating in Papillomavirus Surveillance among STI clinic Youngsters in the Netherlands (PASSYON) 2009-2021. Logistic regression models were conducted to assess risk factors for seropositivity, anal and penile HPV DNA-positivity. RESULTS: Overall, 1019 MSM were included. HPV-16 and -18 were most common for serology, and anal and penile HPV DNA-positivity. Although no clear similarities were observed for most risk factors for HPV seropositivity and anal or penile DNA positivity, receptive anal intercourse (RAI) was the strongest associated risk factor for both seropositivity ('RAI ever' adjusted odds ratio [aOR] 3.50, 95% confidence interval [CI] 1.56-7.88; 'RAI previous 6 months' aOR 2.17, 95% CI 1.44-3.26) and anal DNA-positivity ('RAI previous 6 months' aOR 1.67, 95% CI 1.09-2.56). CONCLUSIONS: Our study is suggestive of site-specific immune response after HPV infection; RAI might lead to anal HPV infections and consequently to seroconversion. Finally, as the two genotypes that are most oncogenic and preventable by all HPV vaccines were most common, our results underline the importance of gender-neutral vaccination.

High vaccine effectiveness persists for ten years after HPV16/18 vaccination among young Dutch women.

The current study describes the long-term effectiveness of three-dose HPV16/18 vaccination among Dutch women who were eligible for vaccination during a catch-up campaign and were followed in an observational cohort study. Ten years post vaccination, vaccine effectiveness (VE) was estimated using generalized estimating equation models. VE against persistent infections with vaccine type infections (HPV16/18) was high at 95.8%. For cross protective type persistent infections (HPV31/33/45) this was 64.6%. There were no indications of waning of protection over time. This indicates solid long-term protection is provided by the vaccine and is promising with regard to the future clinical impact.

The association between viral load and concurrent human papillomavirus infection at the genital and anal sites of young women and the impact of vaccination.

Concurrent genital-anal human papillomavirus (HPV) infections may impose an increased anal cancer risk in women with HPV-related genital lesions. High viral load may facilitate genital-anal HPV concurrence. Genital and anal HPV is reduced by a bivalent HPV16/18 vaccine, yet the effect on concurrent genital-anal HPV remains unclear. This study analyzed viral load in concurrent genital-anal HPV infections, relative to genital-only and anal-only HPV infections and the impact of vaccination in young women. We included 1074 women, who provided both genital and anal swabs. HPV detection and genotyping was performed using the SPF10-DEIA-LiPA25. HPV copy numbers were measured with type-specific qPCRs and corrected for cellular content to obtain the viral load. Concurrent genital-anal HPV often had significantly higher genital viral load (0.09-371 c/cell) than genital-only HPV (3.17E-04-15.9 c/cell, p < 0.0001 to p < 0.05). Moreover, nearly all concurrent genital-anal HPV types had higher genital copy numbers per PCR reaction (157-416E04 c/rxn) than anal copy numbers (0.90-884E01 c/rxn, p < 0.0001 to p < 0.001). Vaccinated women had significantly less infections with HPV16/18 vaccine-types (2.8% vs 13.7%, p < 0.0001) and HPV31/35/45 cross-protective types (7.4% vs 21.1%, p < 0.0001) than unvaccinated women. In conclusion, particularly high genital viral load is found in concurrent genital-anal HPV infections, which are effectively reduced by vaccination.

Changes in the genomic content of circulating Bordetella pertussis strains isolated from the Netherlands, Sweden, Japan and Australia: adaptive evolution or drift?

BACKGROUND: Bordetella pertussis is the causative agent of human whooping cough (pertussis) and is particularly severe in infants. Despite worldwide vaccinations, whooping cough remains a public health problem. A significant increase in the incidence of whooping cough has been observed in many countries since the 1990s. Several reasons for the re-emergence of this highly contagious disease have been suggested. A particularly intriguing possibility is based on evidence indicating that pathogen adaptation may play a role in this process. In an attempt to gain insight into the genomic make-up of B. pertussis over the last 60 years, we used an oligonucleotide DNA microarray to compare the genomic contents of a collection of 171 strains of B. pertussis isolates from different countries. RESULTS: The CGH microarray analysis estimated the core genome of B. pertussis, to consist of 3,281 CDSs that are conserved among all B. pertussis strains, and represent 84.8% of all CDSs found in the 171 B. pertussis strains. A total of 64 regions of difference consisting of one or more contiguous CDSs were identified among the variable genes. CGH data also revealed that the genome size of B. pertussis strains is decreasing progressively over the past 60 years. Phylogenetic analysis of microarray data generated a minimum spanning tree that depicted the phylogenetic structure of the strains. B. pertussis strains with the same gene content were found in several different countries. However, geographic specificity of the B. pertussis strains was not observed. The gene content was determined to highly correlate with the ptxP-type of the strains. CONCLUSIONS: An overview of genomic contents of a large collection of isolates from different countries allowed us to derive a core genome and a phylogenetic structure of B. pertussis. Our results show that B. pertussis is a dynamic organism that continues to evolve.

HPV infections among young MSM visiting sexual health centers in the Netherlands: Opportunities for targeted HPV vaccination.

INTRODUCTION: In 2009, girls-only HPV16/18 vaccination was introduced in the Netherlands which has achieved 46-61% uptake. Heterosexual men have benefitted from herd protection, but it is unknown whether men who have sex with men (MSM) also benefit from herd effects of the girls-only HPV16/18 vaccination program. Because MSM bear a high HPV-related disease burden, countries might consider targeted vaccination for MSM. To study possible herd effects and prior HPV exposure at a potential moment of vaccination, we assessed trends in the HPV prevalence and proportions (sero)negative for the various vaccine types among young MSM visiting sexual health centers (SHCs). METHODS: We used data from MSM included in PASSYON study years 2009-2017. In this biennial cross-sectional study among visitors of SHCs aged 16-24 years, MSM provided a penile and anal swab for HPV DNA testing (including vaccine types HPV6/11/16/18/31/33/45/52/58) and blood for HPV antibody testing (HPV16/18/31/33/45/52/58). RESULTS: In total 575 MSM were included, with a median of 22 years of age and 15 lifetime sex partners and 3.5% HIV positive. Trends in penile or anal HPV prevalence during 2009-2017 were statistically non-significant for all vaccine types. Of the 455 MSM with a penile and anal swab, 360 (79%), 283 (62%) and 242 (53%) were HPV DNA negative at both anatomical sites for HPV16/18, HPV6/11/16/18 and HPV6/11/16/18/31/33/45/52/58 respectively. Among MSM who were HPV16/18 and HPV16/18/31/33/45/52/58 DNA negative and were tested for serology (n = 335 and 279 respectively), 82% and 71% were also seronegative for the respective types. DISCUSSION: There were no significant declines in the HPV prevalence among MSM up to eight years after introduction of girls-only HPV16/18 vaccination, indicating that MSM are unlikely to benefit largely from herd effects from girls-only vaccination. Most MSM were vaccine-type DNA negative and seronegative, suggesting that vaccination of young MSM visiting SHCs could still be beneficial.