After relative absence of Bordetella pertussis during the COVID-19 pandemic, notifications in the Netherlands were increased from May 2023 till September 2024. We monitored the largest pertussis outbreak in decades and investigated underlying immunological dynamics based on IgG and IgA antibodies against pertussis antigens (Ptx, FHA & Prn). We analyzed serum from 418 participants (2-87 years) at five timepoints (November 2022-October 2024) from a nationwide prospective serosurveillance study (PIENTER-Corona). Weighted incidence over two years was 6.3% (95% CI: 4.4-8.2) in the Dutch population, and 35% (95% CI: 26.2-44.6) in 6-18y-olds. Children aged 6-12 years, who received a booster vaccination at 4 years, showed lowest anti-Ptx IgG concentrations after the period of reduced circulation. Infected individuals had lower pre-infection anti-FHA IgG and IgA concentrations than matched uninfected individuals. Prolonged coughing was reported by 16% of the infected individuals. Our findings highlight the B. pertussis outbreak was preceded by waning immunity, particularly after acellular pertussis booster vaccination. The small proportion of symptomatic infections implies sufficient protection by the vaccine against disease but not transmission.

Hepatitis B (HBV), hepatitis C (HCV), and HIV remain public health challenges despite effective treatments and preventive options. Infections are often asymptomatic, leading to undiagnosed cases, onward transmission, and preventable morbidity and mortality. In the Netherlands, disease burden is concentrated in specific populations, with many undetected infections. We estimated HBV, HCV, and HIV seroprevalence, identified determinants, and assessed trends over 20 years using data from 14,444 participants aged 15-79 years from three nationwide cross-sectional serosurveys (PIENTER: 1995-1996, 2006-2007, and 2016-2017). Participants completed questionnaires on demographics, behaviour, and socio-economic factors, and serum samples were tested for HBV and HCV in all rounds and HIV in 2017. Seroprevalence estimates were weighted to the Dutch population, trends were analysed using weighted Poisson regression, and determinants were evaluated using multivariable Poisson regression. Weighted HBV seroprevalence remained stable across surveys (3%-5% past or present infection; < 0.4% active infection). HBV prevalence was highest among first-generation migrants, with older age, migration background, and STI history as key determinants. HCV seroprevalence remained low (< 0.4%) and was highest among non-Western migrants. HIV prevalence was 0.1% and highest among non-Western migrants and men who have sex with men. Only 9% of active HBV cases were aware of their status. Overall, HBV, HCV, and HIV seroprevalence remain low in the Netherlands but are concentrated in specific groups with limited awareness. These findings support targeted prevention, screening, and linkage-to-care strategies to achieve the 2030 WHO elimination goals and highlight the importance of continued population-based (sero-)monitoring to guide public health policy.

Biomarkers are essential in drug development and diagnostics, aiding patient selection and disease monitoring. The lack of age-specific protein references complicates tracking patterns related to chronic disease or treatment. This exploratory, proof-of-concept study explores age-related changes in the serum proteome across the full human lifespan. Using proximity extension assays (Olink), we measured the Immuno-oncology panel in serum from 264 healthy individuals, another panel in a subgroup of 109, all without significant disease at blood draw, aged 0 days to 88 years. Cluster analysis of the Immuno-oncology panel revealed two clusters: cluster 1 included samples from children ≤11 days, cluster 2 encompassing samples with an age range from 2 months till 88 years old. Weighted correlation network analysis identified five protein modules, with four showing enrichment in specific pathways. The Organ-Damage panel showed similar age-related protein variations. Finally, we identified four protein patterns over age: constant, increasing, decreasing, or U-shaped and defined age-specific normal expression ranges. Altogether, our findings suggest that healthy aging across the entire lifespan involves alterations in protein expressions and distinct protein profiles exist in newborns, children, adults and older adults. We provide valuable reference data for the different protein patterns observed across the entire lifespan.

OBJECTIVES:In Kilifi, pentavalent coverage remains below the 90% target, with no reported diphtheria or tetanus cases and sporadic pertussis. However, absence of disease does not guarantee immunity. To characterize age-specific gaps and waning protection not captured by routine surveillance, we conducted serial seroprevalence studies of diphtheria, pertussis, and tetanus. METHODS:We analyzed randomly selected participants from multiple cross-sectional surveys within the Kilifi Health and Demographic Surveillance System. Immunoglobulin G antibodies were measured using a fluorescent bead-based multiplex immunoassay applying protective thresholds ≥0.011 IU/ml for diphtheria and tetanus. Pertussis antibodies were grouped by time since infection. Bayesian multilevel regression with post-stratification adjusted estimates for population structure and assay performance; associations with age and year were assessed using logistic regression. RESULTS:Diphtheria seroprotection was low; only 5% of children had long-term seroprotection, with full protection ranging from 11% to 34% and minimal seroprotection from 40% to 52%. Minimal seroprotection increased over time (τ = 0.68, P = 0.04). Tetanus protection was higher, with long-term seroprotection ranging from 10% to 39% and susceptibility <1%; trends were not significant. Older age was associated with lower seroprevalence. Among adults, <1% had long-term diphtheria seroprotection vs 36% for tetanus. Pertussis circulation was minimal, with 5% of children and <1% of adults, with antibody concentrations consistent with recent infection. CONCLUSIONS:Although conventional serological thresholds suggest immunity gaps, particularly, for diphtheria, no diphtheria or tetanus outbreaks have occurred in Kilifi over the past decade. This indicates that antibody concentrations below standard thresholds may not equate to immediate susceptibility, but they do reflect a narrower margin of population immunity. Although this has not yet translated into disease, it could become relevant if transmission conditions change, underscoring the need to sustain high vaccination coverage and sensitive surveillance. Serology should, therefore, be viewed as a complementary tool, useful for tracking emerging vulnerability and informing future booster decisions if susceptibility increases.

While previous population-based studies have assessed post-acute sequelae after coronavirus disease 2019 (COVID-19), none have investigated health-related quality of life (HRQoL) and (extreme) fatigue after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the pre-vaccination era. Using a nationwide seroepidemiological study, we investigated endpoints linked to post-COVID-19 condition in the general Dutch population up to one year after infection, including symptomatic and asymptomatic infections among unvaccinated individuals early in the pandemic. Participants that were not (yet) vaccinated and aged ≥ 15 years were selected from the February 2021 round of the PIENTER Corona cohort study. We assessed associations between time since serologically-identified SARS-CoV-2 infection and health utility, mental health, physical health and fatigue. To enable comparison across the full range of each outcome, we defined cut-off points for multivariable logistic regression models at every 5

BACKGROUND:Measles and rubella have been targeted for elimination by the World Health Organization. Age-specific population immunity to measles and rubella is important to assess progress towards elimination but data are scarce. We conducted seroprevalence surveys to identify disease-specific population immunity profiles in children and adults in Kilifi. METHODS:Sera from cross-sectional surveys in the Kilifi Health Demographic Surveillance System (2009-2021) were analysed using a fluorescent bead-based multiplex immunoassay. Bayesian multilevel regression with post stratification was used to obtain seroprevalence estimates adjusted for the underlying population and assay performance. Associations between seropositivity and age, sex, location and ethnic group were assessed using a mixed effects logistic regression. RESULTS:Measles-adjusted seroprevalence showed a significant increase from 88 % in 2009 to 93 % in 2021 (τ = 0.875, P = 0.01). Seropositivity was significantly higher in all age groups compared to those under 9 months. Seroprevalence among children ineligible for the first measles vaccine dose (MCV1) remained low (10-57 %), whereas MCV1-eligible children (9-17 months) had higher seroprevalence (68-91 %). Adult measles seroprevalence exceeded 96 %. Rubella seroprevalence followed a similar pattern, with adults above 88 %. Following the MR campaign, measles seroprevalence increased from 92 % to 96 % in eligible children, while rubella seroprevalence rose from 45 % to 82 %. CONCLUSION:Population immunity for measles significantly increased over the 12-year period suggesting improvement in immunisation program performance. To reduce reliance on frequent SIAs, efforts should focus on optimizing both the timing and coverage of routine doses, particularly ensuring higher coverage of MCV2. The introduction of rubella vaccination has positively impacted immunity in children. Sustaining this immunity is essential to prevent potential gaps in older age groups, which could increase the risk of Congenital Rubella Syndrome (CRS) in infants.

α-Gal syndrome (AGS) is an emerging tick-borne disease characterised by the development of specific immunoglobulin E (sIgE) antibodies against galactose-α-1,3-galactose (α-gal), a carbohydrate found in most mammalian species, but not in humans. AGS occurs in individuals with a history of tick bites. Currently, no data exist on α-gal sIgE seroprevalence in the Dutch population, including those with tick bites or erythema migrans (EM). Therefore, this study aimed to determine the rate of α-gal sIgE seroprevalence in the Dutch population, to assess α-gal sIgE seroconversion after tick bites, and to determine the relationship between EM and α-gal sIgE in serum. α-Gal sensitisation rates were assessed in individuals with tick bites (TB), EM, and the general population. Blood samples were collected from TB- and EM-cases at baseline and again after 3 months. Single blood samples from controls were selected from a Dutch population survey. In total, 156 TB-cases, 160 EM-cases, and 316 population controls were included. α-Gal sensitisation rates were 1.9% for population controls and 10.3% and 19.1% for TB- and EM-cases at baseline, respectively (cut-off α-gal sIgE:  ≥ 0.10 kUA/L). Rates increased to 17.9% for TB-cases, comparable to the 16.9% for EM-cases 3 months after EM-development. Distinct α-gal sensitisation rates were observed between TB- and EM-cases over a 3-month period. TB-cases showed a rising rate, while EM-cases had elevated rates at both time points. This difference is likely due to timing of the tick bite, with TB-cases having a recent bite and EM-cases developing EM days to weeks post-bite. Both groups had higher sensitisation rates than population controls, corroborating the link between tick bites and α-gal sensitisation.

BackgroundThis longitudinal cohort study describes the kinetics in antibody levels after two doses of the bivalent human papillomavirus (HPV) vaccine in girls (birth cohort 2001) vaccinated in the routine Dutch vaccination program at 12 years of age, up to 7.5 years post-vaccination. Also, the antibody response one month post-vaccination of the first cohort of boys (birth cohort 2012, vaccinated at 10 years of age) eligible for HPV vaccination in the Netherlands is presented.MethodBlood samples and questionnaire data were collected of girls and boys. HPV type-specific antibody concentrations (LU/mL) against HPV16/18/31/33/45/52/58 were assessed using a validated virus-like particle (VLP) multiplex immunoassay. For girls, antibody decays over time were modelled using the modified power-law decay model and the exponential decay model.ResultsThe Geometric Mean Concentrations (GMCs) remained higher for HPV16/18 than for HPV types 31, 33, 45, 52, and 58 among girls up to 7.5 years post-vaccination. The antibody levels of HPV16 and HPV18 reached plateau values of 482 and 159 LU/mL, respectively. Mathematical modelling showed that the half-life values of HPV16/18 were 2.4- to 4.5-fold higher compared with the half-life values of the other HPV types. Among boys (aged 10 years), the GMC for HPV16 was significantly higher than among girls one month post-vaccination (aged 12 years).ConclusionThe GMCs of all HPV types declined over time, although the GMCs of HPV16/18 remained relatively high up to 7.5 years post-vaccination. The GMCs for HPV16/18 among boys were at least equally high as the GMCs among girls at one month post-vaccination. Further follow-up of the cohort of boys is needed to gain knowledge on long-term immune responses of young boys following bivalent HPV vaccination.

BACKGROUND:To inform future response planning we aimed to assess SARS-CoV-2 trends in infection- and/or vaccine-induced immunity, including breakthrough infections, among (sub)groups, professions and regions in the Dutch population during the Variant of Concern (VOC)-era. METHODS:In this prospective population-based cohort, randomly selected participants (n = 9985) aged 1-92 years (recruited early-2020) donated home-collected fingerstick-blood samples at six timepoints in 2021/2022, covering waves dominated by Alpha, Delta, and multiple Omicron (sub-)variants. IgG antibody assessment against Spike-S1 and Nucleoprotein was combined with vaccination- and testing data to estimate infection-induced (inf) and total (infection- and vaccination-induced) seroprevalence. RESULTS:Nationwide inf-seroprevalence rose modestly from 12% (95% CI 11-13) since Alpha to 26% (95% CI 24-28) amidst Delta, while total seroprevalence increased rapidly to 87% (95% CI 85-88), particularly in elderly and those with comorbidities (i.e., vulnerable groups). Interestingly, highest infection rates were noticeable among low/middle educated elderly, non-Western, those in contact professions, adolescents and young adults, and in low-vaccination coverage regions. Following Omicron emergence, inf-seroprevalence elevated sharply to 62% (95% CI 59-65) and further to 86% (95% CI 83-90) in late-2022, with frequent breakthrough infections and decreasing seroprevalence dissimilarities between most groups. Whereas > 90% of < 60-year-olds had been infected at least once, 30% of vaccinated vulnerable individuals had still not acquired hybrid immunity. CONCLUSIONS:Groups identified to have been infected disproportionally during the acute phase of the pandemic require specific attention in evaluation of control measures and future response planning worldwide. Furthermore, ongoing tailored vaccination efforts and (sero-)monitoring of vulnerable groups may remain important.

BackgroundThe first wave of the COVID-19 pandemic in 2020 was largely mitigated by limiting contacts in the general population. In early 2022, most contact-reducing measures were lifted.AimTo assess whether the population has reverted to pre-pandemic contact behaviour and how this would affect transmission potential of a newly emerging pathogen.MethodsWe compared two studies on contact behaviour in the Netherlands: the PIENTER Corona study, conducted during and after the pandemic (held every 2-6 months from April 2020) and the PIENTER3 study (2016-17, as pre-pandemic baseline). In both, participants (ages 1-85 years) reported number and age group of all face-to-face persons contacted on the previous day in a survey. Transmission potential was examined using the next-generation matrix approach.ResultsWe found an average of 15.4 (95% CI: 14.3-16.4) community contacts per person per day after the pandemic in May 2023, 13% lower than baseline (17.8; 95% CI: 17.0-18.5). Among all ages, children (5-9 years) had the highest number of contacts, both pre- and post-pandemic. Mainly adults aged 20-59 years had not reverted to pre-pandemic behaviours, possibly because they more often work from home. Although the number of contacts is lower compared to the pre-pandemic period, the effect on transmission potential of a newly emerging respiratory pathogen is limited if all age groups were equally susceptible.ConclusionContinuous monitoring of contacts can signal changes in contact patterns and can define a 'new normal' baseline. Both aspects are needed to prepare for a future pandemic.

SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in SARS-CoV-2-naïve Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomised to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/mL, 955.0 IU/mL, and 2290.9 IU/mL for one, two, and three immune events, respectively (p < 0.001). In adjusted multivariable linear regression models, anti-S1 and anti-N log10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with long COVID or long-term loss of smell/taste.

Lyme borreliosis (LB) is not notifiable in many European countries, and the patchwork of surveillance strategies in Europe perpetuates knowledge gaps. In the Netherlands, LB incidence has been estimated from recurring general practitioner surveys since the 1990s. To complement the incidence data, this study aimed to estimate the prevalence of antibodies against Borrelia burgdorferi sensu lato in the general population of the Netherlands in 1995/1996, identify risk factors for seropositivity, and compare these findings to data from 2016/2017 to identify temporal trends. Sera from participants (n = 8041, aged 0–80 years) in a cross-sectional nationwide surveillance study were assessed for the presence of antibodies against B. burgdorferi s.l., using a screening ELISA and immunoblot confirmation. Risk factors associated with seropositivity were evaluated using multivariable analysis. A significant difference in weighted seroprevalence was observed between 1995/1996 (2.8%) and 2016/2017 (4.3%). In both cohorts, the seroprevalence was significantly higher among men than among women, and increased with age and tick bite frequency. The upward trend in age-specific seropositivity in individuals over 50 was steeper in 2016/2017 than in 1995/1996, possibly due to improved fitness among contemporary elderly, allowing increased outdoor activities. This study highlights significant trends in the seroprevalence of B. burgdorferi s.l. antibodies in the general population of the Netherlands over 20 years. The doubling of seroprevalence underscores the increasing burden of LB, and the importance of continued surveillance. Targeted interventions, particularly for elderly populations, may help raise awareness to the risks of tick bites and reduce the growing disease burden and societal costs associated with LB.

Defining what constitutes a healthy microbiome throughout our lives remains an ongoing challenge. Understanding to what extent host and environmental factors can influence it has been the primary motivation for large population studies worldwide. Here, we describe the fecal microbiome of 3,746 individuals (0-87 years of age) in a nationwide study in the Netherlands, in association with extensive questionnaires. We validate previous findings, such as infant-adult trajectories, and explore the collective impact of our variables, which explain over 40% of the variation in microbiome composition. We identify associations with less explored factors, particularly those ethnic related, which show the largest impact on the adult microbiome composition, diversity, metabolic profiles, and CAZy (carbohydrate-active enzyme) repertoires. Understanding the sources of microbiome variability is crucial, given its potential as a modifiable target with therapeutic possibilities. With this work, we aim to serve as a foundational element for the design of health interventions and fundamental research.

How human genetic variation contributes to vaccine immunogenicity and effectiveness is unclear, particularly in infants from Africa. We undertook genome-wide association analyses of eight vaccine antibody responses in 2,499 infants from three African countries and identified significant associations across the human leukocyte antigen (HLA) locus for five antigens spanning pertussis, diphtheria and hepatitis B vaccines. Using high-resolution HLA typing in 1,706 individuals from 11 African populations we constructed a continental imputation resource to fine-map signals of association across the class II HLA observing genetic variation explaining up to 10% of the observed variance in antibody responses. Using follicular helper T-cell assays, in silico binding, and immune cell eQTL datasets we find evidence of HLA-DRB1 expression correlating with serological response and inferred protection from pertussis following vaccination. This work improves our understanding of molecular mechanisms underlying HLA associations that should support vaccine design and development across Africa with wider global relevance.

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.

Background Our aim was to assess the relationship between (time since) wild-type SARS-CoV-2 infection and health-related quality of life (HRQoL) and fatigue as endpoints linked to Post COVID-19 condition (PCC).Methods Participants ≥15 years were selected from the February 2021 round of the population-based PIENTER Corona study. We investigated the association between (time since) SARS-COV-2 infection and health outcomes: HRQoL (health utility (SF-6D); physical health and mental health (both SF-12)) and fatigue (CIS-fatigue) using multivariable logistic regression analyses adjusted for age, sex, educational level, number of comorbidities, COVID-19 vaccination status, and the intensity of restrictions. For each outcome, multivariable logistic regression models were fitted at cut-off points selected based on the cumulative distribution of those uninfected.Results Results shown correspond to the cut-off point related to the worst off 15% of each outcome. Significant differences between those uninfected (n=4,614) and cases infected ≤4 months ago (n=368) were observed for health utility (OR [95%CI]: 1.6 [1.2-2.2]), physical health (OR [95%CI]: 1.7 [1.3-2.3]) and fatigue (OR [95%CI]: 1.6 [1.2-2.0]), but not for mental health. There were no significant differences between uninfected and cases infected >4 months ago (n=345) for all outcomes.Conclusions In a Dutch population-based cohort of seroconverted individuals, those infected with wild-type SARS-CoV-2 ≤4 months ago more often reported poor health utility and physical health and were more often severely fatigued compared to those uninfected (at the 15% cut-off). HRQoL and fatigue remained below the detection limit for those infected >4 months ago, suggesting a relatively low prevalence of PCC.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis work was supported by the Ministry of Health, Welfare and Sports (VWS), the Netherlands. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee of the Medical Ethics Committee MEC-U, the Netherlands gave ethical approval for this work.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.Yes

Antibodies to SARS-CoV-2 on the mucosal surfaces of the respiratory tract are understood to contribute to protection against SARS-CoV-2 infection. We aimed to describe the prevalence, levels, and functionality of mucosal antibodies in the general Dutch population. Nasal samples were collected from 778 randomly selected participants, 1-90 years of age, nested within the nationwide prospective SARS-CoV-2 PIENTER corona serosurvey in the Netherlands. Spike-specific immunoglobulin (Ig)G was detected in the nasal samples of 94.6% (in case of the wild-type S1 variant) and 94.9% (Omicron BA.1) of the individuals, whereas 44.2% and 62.7% of the individuals were positive for wild-type and Omicron BA.1 S1 IgA, respectively. The lowest prevalence of mucosal antibodies was observed in children under 12 years of age. The prevalence and levels of IgA and IgG were higher in individuals with a history of SARS-CoV-2 infection. Mucosal antibodies inhibited the binding of Wuhan, Delta, and Omicron BA.1 receptor binding domain to human angiotensin-converting enzyme 2 in 94.4%, 95.4%, and 92.6% of the participants, respectively. Higher levels of mucosal antibodies were associated with a lower risk of future infection.

National Immunisation Programmes (NIPs) develop historically. Its performance (disease incidences, vaccination coverage) is monitored. Reviewing the schedule as a whole could inform on further optimisation of the programme, i.e., providing maximal protection with the lowest number of doses. We systematically evaluated the performance and strategies of the Dutch pathogen-specific NIP schedules through literature review, assessment of surveillance data and expert opinions. Pathogen-specific vaccinations were categorised according to their strategy of protection: I) elimination or eradication, II) herd immunity or III) 'only' individual protection. The schedule of each vaccine-component was evaluated based on fixed criteria: 1. Is the achieved protection adequate? 2. Is the intended protection achieved? 3. Does the programme include too many or too few doses? 4. Is the timing optimal or acceptable? and 5. Are there drawbacks of the NIP for (part of) the population? Identified issues were explored using surveillance data and literature. Using fixed criteria facilitated comparison between pathogens and revealed opportunities to optimise the Dutch NIP by: i. Reducing the number of polio and tetanus vaccinations; ii. prolonging the interval between diphtheria, pertussis, tetanus, polio, hepatitis B, and Hib vaccine doses for improved effectiveness; iii. Expedite the second measles vaccination from 9 to 2-4 years of age to offer unvaccinated children and primary vaccine failures an earlier chance to be protected; and iv. Delaying the second mumps vaccination to enhance protection in adolescents/young adults. No schedule adaptations were deemed necessary for the vaccines against HPV, rubella, pneumococcal disease, and meningococcal disease. Based on this evaluation the NITAG advised to move the DTaP-IPV-HBV-Hib-booster from age 11 to 12 months, the second MMR-dose from 9 to 2-4 years, replace the Tdap-IPV at 4 years with a Tdap at 5-6 years and move the dt-IPV from 9 to 14 years. Implementation of these changes is planned for 2025.

Objectives: Between 2003 and 2019, three trials (randomised controlled trials [RCTs]) in Guinea-Bissau randomised infants to an early 2-dose measles vaccine (MV) schedule at 4 and 9 months vs standard MV at 9 months. The RCTs produced contradictory mortality results; the effect being beneficial in the 2-dose group in the first but tending to have higher mortality in the last two RCTs. We hypothesised that increased frequency of campaigns with oral polio vaccine (C-OPV) explained the pattern. Methods: We performed per-protocol analysis of individual-level survival data from the three RCTs in Cox proportional hazards models yielding hazard ratios (HR) for the 2-dose vs the 1-dose MV group. We examined whether timing of C-OPVs and early administration of OPV0 (birth to day 14) affected the HRs for 2-dose/1-dose MV. Results: The combined HR(2-dose/1-dose) was 0.79 (95% confidence interval: 0.62-1.00) for children receiving no C-OPV-before-enrolment, but 1.39 (0.97-1.99) for those receiving C-OPV-before-enrolment (homogeneity, P = 0.01). C-OPV-before-enrolment had a beneficial effect in the 1-dose group but tended to have a negative effect in the 2-dose group, especially in females. These effects were amplified further by early administration of OPV0. Conclusion: In the absence of C-OPVs, an early 2-dose MV strategy had beneficial effects on mortality, but frequent C-OPVs may have benefitted the 1-dose group more than the 2-dose MV group, leading to varying results depending on the intensity of C-OPVs.

Our understanding of the normal variation in the upper respiratory tract (URT) microbiota across the human lifespan and how these relate to host, environment, and health is limited. We studied the microbiota of 3,104 saliva (<10 year-olds)/oropharynx (≥10 year-olds) and 2,485 nasopharynx samples of 3,160 Dutch individuals 0–87 years of age, participating in a cross-sectional population-wide study (PIENTER-3) using 16S-rRNA sequencing. The microbiota composition was strongly related to age, especially in the nasopharynx, with maturation occurring throughout childhood and adolescence. Clear niche- and age-specific associations were found between the microbiota composition and host/environmental factors and health outcomes. Among others, social interaction, sex, and season were associated with the nasopharyngeal microbial community. By contrast, the oral microbiota was more related to antibiotics, tobacco, and alcohol use. We present an atlas of the URT microbiota across the lifespan in association with environment and health, establishing a baseline for future research.