Early effect of bivalent human papillomavirus vaccination on cytology outcomes in cervical samples among young women in the Netherlands.

BACKGROUND: The first HPV-vaccine eligible cohorts in the Netherlands will enter the cervical screening program in 2023. However, a substantial number of young women already have had a cervical sample taken before entry into the regular screening program. This study was initiated to explore early effects of HPV vaccination on detection of cytological abnormalities in cervical samples of women younger than the screening age. METHODS: Results of cervical samples were obtained from the Dutch National Pathology Databank (PALGA) and were linked to the women's HPV vaccination status from the national vaccination registry (Praeventis) (N = 42,171). Occurrence of low-grade and high-grade squamous intraepithelial lesions or worse (LSIL and HSIL+) and high-risk HPV positive tests (hrHPV) in the first cervical sample were compared between vaccinated and unvaccinated women by multivariable logistic regression analysis, corrected for age at cervical sampling and age of vaccination (12/13 years, ≥ = 14 years). RESULTS: For fully vaccinated women (three- or two-dose schedule), statistically significant reductions were seen for all outcomes compared to unvaccinated women (hrHPV: adjusted OR, 0.70, 95% CI, 0.63-0.79; LSIL: 0.70, 0.61-0.80; HSIL+: 0.39, 0.30-0.51). CONCLUSIONS: By linking nation-wide registries on pathology and vaccination, we show significant beneficial early effects of HPV-vaccination on LSIL, HSIL+, CIN3/AIS/carcinoma and hrHPV detection in young women upto 24 years of age who have a cervical sample taken before entry into the cervical cancer screening program.

Partial Protective Effect of Bivalent Human Papillomavirus 16/18 Vaccination Against Anogenital Warts in a Large Cohort of Dutch Primary Care Patients.

BACKGROUND: There is ongoing debate about the possible protective effect of the bivalent human papillomavirus (2vHPV) vaccine, targeting oncogenic types HPV-16/18, against anogenital warts (AGWs), commonly attributed to HPV-6/11. We performed a retrospective registry-based open cohort study to assess the effect of 2vHPV vaccination on AGWs. METHODS: We linked general practice (ie, primary care) data from women born between 1993 and 2002, who had been eligible for HPV vaccination in the Netherlands, to the Dutch national immunization registry on an individual level. Women were followed until their first AGW diagnosis or end of follow-up. Adjusted incidence rate ratios (aIRRs) were estimated using Poisson regression with vaccination status as a time-dependent exposure. RESULTS: We linked data of 96 468 women with a total of 328 019 years observation time and 613 AGW diagnoses (incidence: 1.87/1000 person-years). At the end of follow-up, 61% were 2vHPV vaccinated (≥ 1 dose) of whom 91% were fully vaccinated. The AGW incidence was lower among those with ≥ 1 dose vs 0 doses (aIRR, 0.75 [95% confidence interval {CI}, .64-.88]). The effect of vaccination was stronger after full vaccination (aIRR, 0.72 [95% CI, .61-.86]) and for women who were offered vaccination at 12-13 years of age (aIRR, 0.69 [95% CI, .51-.93]) vs those at 13-16 years of age (aIRR, 0.77 [95% CI, .64-.93]). CONCLUSIONS: This is the largest population-based study so far to examine the effect of 2vHPV vaccination on AGWs, with reliable individual information on AGW diagnoses and vaccination status. The results indicate that 2vHPV vaccination partially protects against AGWs, especially when administered in early adolescence.

Long-term HPV-specific immune response after one versus two and three doses of bivalent HPV vaccination in Dutch girls.

BACKGROUND: In view of further reduction of HPV vaccination schedules, gaining more insight into humoral and cellular immune responses after a single HPV vaccine is of great interest. Therefore, these responses were evaluated after different doses of the bivalent (2v) HPV-vaccine in girls. METHODS: Blood was collected yearly up to seven years post-vaccination with one-, two- or three-doses of the 2vHPV vaccine (N = 890). HPV-type-specific IgG and IgA-antibody levels, IgG-isotypes and avidity indexes were measured by a virus-like-particle-based multiplex-immuno-assay for two vaccine and five non-vaccine HPV types. HPV-type-specific memory B-cell numbers- and T-cell cytokine responses were determined in a subpopulation. RESULTS: HPV-type-specific antibody concentrations were significantly lower in one- than in two- and three-dose vaccinated girls but remained stable over seven years. The lower antibody response coincided with reduced HPV-type-specific B- and T-cell responses. There were no differences in both the IgG subtypes and the avidity of the HPV16-specific antibodies between the groups. CONCLUSIONS: One-dose of the 2vHPV vaccine is immunogenic, but results in less B- and T-cell memory and considerable lower antibody responses when compared with more doses. Therefore, at least of some of girls receiving the one-dose of the vaccination might be at higher risk for waning immunity to HPV in the long-term.

Persistence of immune response following bivalent HPV vaccination: A follow-up study among girls routinely vaccinated with a two-dose schedule.

BACKGROUND: In this cohort study, we examined antibody levels and avidity after a two-dose schedule (0, 6 months) of the bivalent HPV-vaccine in girls routinely vaccinated in the Dutch HPV-vaccination program, up to 2 years following vaccination. METHODS: A blood sample at 7, 12 and 24 months after the first dose and questionnaire data were collected (n = 56). HPV type-specific antibody concentrations (lU/ml) against seven types (HPV16/18/31/33/45/52/58) were assessed using a validated virus-like particles (VLP) multiplex immunoassay. Avidity was tested using a modification of this assay. RESULTS: Seropositivity for vaccine types HPV 16 and 18 was 100% up to month 24, but declined for HPV-types 31/33/45/52/58, although not statistically significant for HPV45. All Geometric Mean Concentrations (GMCs) declined by months 12 and 24, but remained high for HPV16/18. Between month 7 and 12, GMCs declined more for other types. High avidity antibodies were induced up to 24 months for vaccine types (75%, 76-78% and 81-82% at months 7, 12 and 24, respectively), but for other types antibody avidity was 16-29% at month 7, 20-32% at month 12 and 19-32% at month 24. CONCLUSIONS: GMCs declined over time for HPV-types 16/18/31/33/45/52/58, but remained high for vaccine-types HPV16/18 up to 24 months of follow-up. Antibody avidity was >75% for vaccine types but <35% for other HPV-types. Further follow-up of this cohort will provide insight into antibody and avidity kinetics over time.

Immune Responses After 2 Versus 3 Doses of HPV Vaccination up to 4½ Years After Vaccination: An Observational Study Among Dutch Routinely Vaccinated Girls.

BACKGROUND: In 2014 the Netherlands switched from 3 to 2 doses for routine vaccination with the prophylactic bivalent human papillomavirus (HPV) vaccine. The current study explored whether antibody responses are noninferior after 2 versus 3 doses in girls. METHODS: Girls vaccinated at 12 years of age with 2 (at 0 and 6 months) or 3 doses (at 0, 1, and 6 months) of the bivalent HPV vaccine were identified in the vaccination registration system. Type-specific antibody concentrations and avidity against HPV-16/18/31/33/45/52/58 were assessed. Analyses were stratified for time since the first dose (0-2, 2-3, 3-4, or 4-4½ years). Noninferiority (margin, 0.5) of the 2- versus the 3-dose schedule in girls was examined. RESULTS: Geometric mean concentrations (GMCs) for vaccine types were only noninferior for 2 versus 3 doses for HPV-18 (at 2-3 years after the first dose; GMC ratio, 0.89; 95% confidence interval, .57-1.38) For vaccine types and cross-protective types (HPV-16/18/31/33/45), the avidity index was noninferior for the 2-dose compared with the 3-dose schedule, except for HPV-31 at 4-4½ years after the first dose and HPV-33 at 3-4 and 4-4½ years. CONCLUSIONS: GMCs for HPV-16/18 were not noninferior for 2 versus 3 doses, except for HPV-18 (at 2-3 years after first dose). However, antibody avidity for these types showed noninferiority, independent of concentrations.

Mumps-specific cross-neutralization by MMR vaccine-induced antibodies predicts protection against mumps virus infection.

BACKGROUND: Similar to other recent mumps genotype G outbreaks worldwide, most mumps patients during the recent mumps genotype G outbreaks in the Netherlands had received 2 doses of measles, mumps and rubella (MMR) vaccine during childhood. Here, we investigate the capacity of vaccine-induced antibodies to neutralize wild type mumps virus strains, including mumps virus genotype G. METHODS: In this study, we tested 105 pre-outbreak serum samples from students who had received 2 MMR vaccine doses and who had no mumps virus infection (n=76), symptomatic mumps virus infection (n=10) or asymptomatic mumps virus infection (n=19) during the mumps outbreaks. In all samples, mumps-specific IgG concentrations were measured by multiplex immunoassay and neutralization titers were measured against the Jeryl Lynn vaccine strain and against wild type genotype G and genotype D mumps virus strains. RESULTS: The correlation between mumps-specific IgG concentrations and neutralization titers against Jeryl Lynn was poor, which suggests that IgG concentrations do not adequately represent immunological protection against mumps virus infection by antibody neutralization. Pre-outbreak neutralization titers in infected persons were significantly lower against genotype G than against the vaccine strain. Furthermore, antibody neutralization of wild type mumps virus genotype G and genotype D was significantly reduced in pre-outbreak samples from infected persons as compared with non-infected persons. No statistically significant difference was found for the vaccine strain. The sensitivity/specificity ratio was largest for neutralization of the genotype G strain as compared with the genotype D strain and the vaccine strain. CONCLUSIONS: The reduced neutralization of wild type mumps virus strains in MMR vaccinated persons prior to infection indicates that pre-outbreak mumps virus neutralization is partly strain-specific and that neutralization differs between infected and non-infected persons. Therefore, we recommend the use of wild type mumps virus neutralization assays as preferred tool for surveillance of protection against mumps virus infection.

Gender-specific mortality in DTP-IPV- and MMR±MenC-eligible age groups to determine possible sex-differential effects of vaccination: an observational study.

BACKGROUND: Several studies suggested that vaccines could have non-specific effects on mortality depending on the type of vaccine. Non-specific effects seem to be different in boys and girls. In this study we want to investigate whether there are differences in gender-specific mortality among Dutch children according to the last vaccination received. We tested the hypothesis that the mortality rate ratio for girls versus boys is more favourable for girls following MMR±MenC vaccination (from 14 months of age) compared with the ratio following DTP-IPV vaccination (2-13 months of age). Secondarily, we investigated whether there were gender-specific changes in mortality following booster vaccination at 4 years of age. METHODS: This observational study included all Dutch children aged 0-11 years from 2000 until 2011. Age groups were classified according to the last vaccination offered. The mortality rates for all natural causes of death were calculated by gender and age group. Incidence rate ratios (IRRs) were computed using a multivariable Poisson analysis to compare mortality in boys and girls across different age groups. RESULTS: The study population consisted of 6,261,472 children. During the study period, 14,038 children (0.22%) died, 91% of which were attributed to a known natural cause of death. The mortality rate for natural causes was higher among boys than girls in all age groups. Adjusted IRRs for girls compared with boys ranged between 0.81 (95% CI 0.74-0.89) and 0.91 (95% CI 0.77-1.07) over the age groups. The IRR did not significantly differ between all vaccine-related age groups (p=0.723), between children 2-13 months (following DTP-IPV vaccination) and 14 months-3 years (following MMR±MenC vaccination) (p=0.493) and between children 14 months-3 years and 4-8 years old (following DTP-IPV vaccination) (p=0.868). CONCLUSIONS: In the Netherlands, a high income country, no differences in gender-specific mortality related to the type of last vaccination received were observed in DTP-IPV- and MMR ± MenC eligible age groups. The inability to detect this effect indicates that when non-specific effects were present the effects were not reflected in changes in the differences in mortality between boys and girls. The findings in this large population-based study are reassuring for the continued trust in the safety of the national vaccination programme.

Mumps serum antibody levels before and after an outbreak to assess infection and immunity in vaccinated students.

BACKGROUND: Since 2009, various mumps outbreaks have occurred in the Netherlands, affecting mostly young adults vaccinated against mumps. In this retrospective study, we estimated attack rates for symptomatic and asymptomatic mumps virus infection based on mumps-specific immunoglobulin (Ig)G concentrations in paired blood samples obtained before and after the mumps outbreaks, collected in 2 university cities. We aimed to identify a serological correlate of immune protection and risk factors for mumps virus infection. METHODS: Mumps-specific IgG levels were measured by Luminex technology in paired pre- and post-outbreak samples from students from Leiden (n = 135) and Utrecht (n = 619). Persons with a 4-fold increase in mumps IgG concentrations or mumps IgG concentrations >1500 RU/mL were assumed to have had a mumps virus infection. RESULTS: Attack rates for symptomatic and asymptomatic mumps virus infection were 2.0% and 3.8%, respectively. Pre-outbreak mumps-specific IgG concentrations were lower among cases than among noncases (P = .005) despite vaccination history, but no serological cutoff for immune protection could be established. Mumps among housemates was significantly associated with serological evidence for mumps virus infection (odds ratio, 7.25 [95% confidence interval, 3.20-16.40]; P < .001). CONCLUSIONS: Symptomatic and asymptomatic mumps virus infections in vaccinated persons can be identified by retrospective assessment of mumps-specific IgG antibodies in blood samples.