Invasive meningococcal B disease (IMD-B) causes morbidity and mortality among infants and adolescents in the Netherlands. While multiple vaccines against IMD-B are licensed by the European Medicines Agency, none of them is currently part of the Dutch National Immunization Program (NIP). We evaluated the clinical impact and cost-effectiveness of different IMD-B vaccination strategies for Dutch infants and adolescents. We developed a static, single-cohort Markov model to estimate the lifetime number of IMD-B cases and deaths prevented, as well as the incremental cost-effectiveness ratio (ICER), of vaccinating infants with 4CMenB (age 0; 2 + 1 schedule) or adolescents with 4CMenB, MenB-fHBp, or MenABCWY + MenB-fHBp (age 15; 1 + 1 schedule), compared with no IMD-B vaccination. The analysis adopted a societal perspective, including costs and quality-adjusted life years (QALYs) related to vaccination, adverse events, acute IMD-B, long-term sequelae, productivity losses of patients and caregivers, special education needs, and out-of-pocket expenses for patients and their families. We also conducted a threshold analysis for the incidence of IMD-B and a systematic uncertainty assessment. For infants, the use of 4CMenB would prevent 11.14 IMD-B cases and 0.85 IMD-B-related deaths in one birth cohort of 166,073 infants over a lifetime. For adolescents, IMD-B vaccination would prevent 7.24–8.57 cases and 0.25–0.29 deaths in a single cohort of 197,782 adolescents, depending on which vaccine is used. The ICER was €594,056/QALY for 4CMenB in infants, while for adolescents the ICER ranged between €717,287/QALY and €890,023/QALY, depending on the vaccine type used. These ICERs exceed the commonly used cost-effectiveness thresholds (€20,000 to €80,000/QALY gained) in the Netherlands, rendering vaccination not cost-effective. This outcome proved robust in deterministic and probabilistic sensitivity analyses, as well as in scenario analyses. The threshold analysis demonstrated that IMD-B vaccination may only become cost-effective at a €80,000/QALY threshold with more than a sixfold increase in incidence. The modelled IMD-B vaccination programs resulted in the prevention of limited morbidity and mortality at a high financial burden. The inclusion of any of the evaluated vaccines in the Dutch NIP for infants or adolescents is not cost-effective in any target group at conventional Dutch cost-effectiveness thresholds given current IMD-B incidence levels.

Estimating COVID-19 vaccine effectiveness (VE) by time since vaccination (TSV) is essential for understanding how protection may change over time and enables meaningful comparisons across studies. This is important for accurate comparisons of VE against different SARS-CoV-2 variants/sublineages, across age groups, during different periods post vaccination campaign, or by vaccine type/brand. We provide recommendations for case-control VE studies on estimating and reporting VE analyses by TSV, with the aim of improving quality of these estimates. Our recommendations cover study design and pre-analysis considerations, descriptive analyses, choice of categories of TSV, categorical and continuous modeling approaches, and best practices for reporting VE by TSV. Using a real-life case-control study, we apply these recommendations and include accompanying statistical scripts in R and Stata. These recommendations will serve as a practical resource for researchers conducting VE analyses by TSV. We encourage ongoing refinement of them through input from other study groups.

Importance:Household contacts of patients with invasive group A streptococcus (iGAS) disease have an increased risk of iGAS. In the Netherlands, the iGAS public health policy was changed in January 2023, offering antibiotic prophylaxis to household contacts of all patients with iGAS rather than only those presenting with necrotizing fasciitis or streptococcal toxic shock syndrome. Objective:To estimate risk of iGAS in the general population and among household and other contacts of primary patients with iGAS, before and after the policy change. Design, Setting, and Participants:This nationwide, population-based, open cohort study, linked population registry data with iGAS laboratory data for the study period (April 2022 to December 2024). The study population consisted of all persons included in the Dutch population registry at any time during the study period. The case definition was an iGAS isolate submitted to the Netherlands Reference Laboratory for Bacterial Meningitis, with disease onset in the study period. Exposure:For contacts of primary patients with iGAS, exposure risk period was defined as the 30 days after culture date of the index patient. Exposure under the new policy was defined as all person-time after January 20, 2023. Main Outcomes and Measures:Incidence rate ratios (IRR) of iGAS during the 30-day risk period compared with unexposed person-time were estimated. Secondary attack rates among household contacts were estimated with an odds ratio (OR) to compare attack rates before and after the policy change. Estimates were adjusted for age group, sex, household socioeconomic status, and year quarter. Results:A total of 19 006 247 persons (9 467 251 male [49.8%]; 6 308 794 [33.2%] aged 20-45 years) contributed 51 067 977 person-years to the analysis. A total of 3644 iGAS isolates from 3630 unique persons were included, of which 14 were household secondary cases. The IRR for household contacts during the risk period was 235.25 (95% CI, 94.35-586.59) before and 74.00 (95% CI, 35.17-155.71) after the policy change, compared with unexposed person-time. The secondary attack rate among household contacts was 0.219% (7 individuals) before and 0.047% (7 individuals) after the policy change (adjusted OR, 0.17; 95% CI, 0.03-0.83). Conclusions and Relevance:In this nationwide cohort study, there was a reduction in secondary iGAS risk among household contacts after implementation of an expanded antibiotic prophylaxis policy, which suggests that antibiotic prophylaxis for household contacts of patients with iGAS prevents secondary iGAS infection.

Since the cessation of real-time monitoring of COVID-19 hospitalizations in early 2024, the burden of and vaccine effectiveness (VE) against severe COVID-19 in the Netherlands was largely unknown. Recently, hospitalization data from 2024 were made available for the purpose of monitoring and evaluating the COVID-19 vaccination campaigns. These data were linked to the population registry, vaccination registry and healthcare use data (for classification into medical risk groups). We analyzed the number and incidence of COVID-19 hospitalizations in 2023 and 2024 by age and medical risk group. VE against hospitalisation of the autumn booster of 2023 (by time since vaccination, 25 September 2023 to 16 September 2024) and of the autumn booster of 2024 (16 September to 31 December 2024) were estimated by medical risk group among persons aged 60 years and older using Cox proportional hazards models with calendar time as underlying time scale and vaccination status as time-varying exposure. Models were adjusted for age, sex, region and household socio-economic status. From around age 60 onward, intermediate and high medical risk groups had a markedly higher incidence than younger age groups, increasing with age. Persons in the low medical risk group had a low incidence up to the age of 80. In 2024, incidence was lower than in 2023. For both autumn booster rounds, estimated VE against hospitalisation was moderate at 55-67% in the first 3 months post-vaccination. In the high medical risk group, 2023 VE decreased fast and was no longer significant at 6 months post-vaccination. For both years, estimates of the number of averted hospitalizations and number needed to vaccinate to prevent one hospitalization indicated that significant health benefit can be achieved by vaccinating the intermediate and high medical risk groups aged 60 years and older. Efforts to increase the moderate vaccine uptake among risk groups could potentially prevent a considerable disease- and healthcare burden. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Dutch Ministry of Health, Welfare and Sports. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The RIVM Centre for Clinical Expertise verified whether this study complies with the Dutch law for Medical Research Involving Human Subjects (WMO) or with the EU Clinical Trial Directive (2001/20/EC), and was of the opinion that review by an ethical research committee or institutional review board is not necessary by current national and European legislation (study number EPI-776). All individual-level data was de-identified (pseudonymized) prior to the analyses. 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. Yes I 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Results based on calculations by the RIVM in project number 9248 using non-public microdata from Statistics Netherlands. Under certain conditions, these microdata are accessible for statistical and scientific research. For further information: https://www.cbs.nl/en-gb/our-services/customised-services-microdata/microdata-conducting-your-own-research

Individual participant data (IPD) meta-analysis provides important opportunities to study interaction and effect modification for which individual studies often lack power. While previous meta-analyses have commonly focused on multiplicative interaction, additive interaction holds greater relevance for public health and may in certain contexts better reflect biological interaction. Methodological literature on interaction in IPD meta-analysis does not cover additive interaction for models including binary or time-to-event outcomes. We aimed to describe how the Relative Excess Risk due to Interaction (RERI) and other measures of additive interaction or effect modification can be validly estimated within 2-stage IPD meta-analysis. First, we explain why direct pooling of study-level RERI estimates may lead to invalid results. Next, we propose a 3-step procedure to estimate additive interaction: (1) estimate effects of both exposures and their product term on the outcome within each individual study; (2) pool study-specific estimates using multivariate meta-analysis; (3) estimate an overall RERI and 95% confidence interval based on the pooled effect estimates. We illustrate this procedure by investigating interaction between depression and smoking and risk of smoking-related cancers using data from the PSYchosocial factors and Cancer (PSY-CA) consortium. We discuss implications of this procedure, including the application in meta-analysis based on published data.

Background:The protective effect of HPV vaccination against cervical cancer has been demonstrated in registry linkage studies. The start age of screening in those studies was lower than 25 years. We estimated the vaccine effectiveness of bivalent HPV16/18 vaccination against invasive cervical cancer and cervical intraepithelial neoplasia grade 3 (CIN3+) in the Netherlands where routine screening starts at age 30 years. Methods:We linked the vaccination status of women born in year 1993 who were eligible for HPV vaccination at age 16 years with histopathological results recorded in the nationwide pathology databank (Palga). Cumulative risks of invasive cervical cancer and CIN3+ were estimated for fully vaccinated (3 doses or 2 doses ≥150 days apart), partially vaccinated, and unvaccinated women. Vaccine effectiveness estimates were adjusted for differences in screening participation between the vaccine groups. Findings:A total of 103,059 women were included, of whom 47,130 were fully vaccinated, 5,098 were partially vaccinated, and 50,831 were unvaccinated. Five (0·011%) cancers were observed in fully vaccinated, two (0·039%) in partially vaccinated, and 42 (0·083%) in unvaccinated women. The vaccine effectiveness in fully vaccinated women was 91·5% (95% CI 78·9, 96·6) against cancer and 81·2% (95% CI 78·4, 83·7) against CIN3+. The vaccine effectiveness in partially vaccinated women was 48·1% (95% CI -56·8, 82·8) against cancer and 58·4% (95% CI 45·3, 68·3) against CIN3+. Interpretation:The high effectiveness of bivalent HPV vaccination against cervical cancer and CIN3+ and the low cancer incidence supports a screening start age of 30 years in vaccinated women. Research in context:Evidence before this study: We searched Pubmed and Google Scholar with the search terms ("Cervical Cancer") AND ("HPV" OR "human papillomavirus") AND ("vaccination"). Articles published in English were searched until January 2, 2025. Studies from Sweden, Denmark, and Scotland were identified linking individual vaccination, screening and cancer registry data. The start age of screening in these studies was 23-25 years. They showed a strong effectiveness in preventing cervical cancer following the introduction of bivalent and quadrivalent HPV vaccination.Added value of this study: We observed a very low absolute incidence of cervical cancer in vaccinated women and a much lower incidence of cervical cancer and CIN3+ in women vaccinated at age 16 compared with unvaccinated women, in a setting where routine screening starts at age 30. By linking the vaccination registry to the nationwide pathology databank, we were able to adjust for screening non-attendance in the incidence of cancer and CIN3+ over a 15 year period.Implications of all the available evidence: Our study supports a start age of screening of at least 30 years in women vaccinated at a young age. Avoiding screening before age 30 in these women is expected to substantially reduce the harms associated with screening and treatment.

In 2022, an increase in invasive group A streptococcal (iGAS) infections was observed in the Netherlands. A particular increase was seen among children; therefore, we aimed to assess risk factors for iGAS infection in children aged 6 months to 5 years. A prospective case-control study was conducted between February and May 2023. We approached parents of notified iGAS cases to complete a questionnaire on exposures during 4 weeks prior to disease onset. Controls were recruited via social media and matched to cases on sex and birthyear. Conditional logistic regression was performed to estimate odds ratios (OR) of exposures. For the analysis, we included 18 cases and 103 controls. Varicella prior to onset of iGAS disease was reported in two (11%) cases and one (1%) control (OR: 12.0, 95% CI: 1.1-139.0). Exposure to group A streptococcal (GAS)-like illnesses such as impetigo, pharyngitis, and scarlet fever was reported in 8 (44%) cases and 15 (15%) controls (OR: 7.1, 95% CI: 1.8-29.0). Our findings are in line with previous studies by identifying varicella as a risk factor for iGAS among young children and highlight the association with non-invasive GAS infections in the community as a possible source of transmission.

Background:The protective effect of HPV vaccination against cervical cancer has been demonstrated in registry linkage studies. The start age of screening in those studies was lower than 25 years. We aimed to estimate the effectiveness of bivalent HPV16/18 vaccination against invasive cervical cancer and cervical intraepithelial neoplasia grade 3 (CIN3+) in the Netherlands, where routine screening starts at age 30 years. Methods:We linked the vaccination status of women born in 1993 who were eligible for HPV vaccination at age 16 years with histopathological results recorded until April 1, 2024, in the nationwide pathology databank (Palga). Cumulative risks of invasive cervical cancer and CIN3+ were estimated for fully vaccinated (3 doses or 2 doses ≥150 days apart), partially vaccinated, and unvaccinated women. Cumulative risk ratios (CRRs) were adjusted for differences in screening participation between vaccine groups. Findings:A total of 103,059 women were included, of whom 47,130 were fully vaccinated, 5098 partially vaccinated, and 50,831 unvaccinated. Five cancers (0·011%) were observed in fully vaccinated, two (0·039%) in partially vaccinated, and 42 (0·083%) in unvaccinated women. The CRR for fully vaccinated women compared with unvaccinated women was 0·085 (95% confidence interval 0·025, 0·24) for cancer and 0·19 (0·16, 0·23) for CIN3+. The CRR for partially vaccinated women was 0·52 (0·12, 1·71) for cancer and 0·42 (0·30, 0·57) for CIN3+. Interpretation:The risk of cervical cancer and CIN3+ was strongly reduced in vaccinated women indicating that vaccine protection extends at least until age 30. Funding:The Dutch Ministry of Health, Welfare, and Sport.

Background: The innate immune response is important for the development of the specific adaptive immunity, however it may also be associated with reactogenicity after vaccination. We explore the association between innate responsiveness, reactogenicity, and antibody response after first COVID-19 vaccination. Methods: We included 146 healthy Dutch individuals aged 12-59 who received their first BNT162b2 (Comirnaty, Pfizer) COVID-19 vaccination. Data on reactogenicity were collected for each individual through daily questionnaires from day 0-5 after vaccination. From 60 participants, serum (adults) and plasma (adolescents) samples were collected before and/or 2 +/- 1 days after vaccination to measure cytokines/chemokines as markers for innate responsiveness. Each individual was categorised into innate low, intermediate and high responder based on above or below the median value for each analyte detected after vaccination. For 137 participants, serum was collected at day 28 after vaccination for Spike S1- and RBD-antibody concentration. The associations between reactogenicity and/or innate responsiveness and/or log-transformed antibody concentration were explored using logistic and linear regressions. Results: Most participants (85 %) reported both local and systemic symptoms after vaccination. Two participants reported no symptoms. More than half (54 %) reported one or more moderate symptoms. Significantly higher levels of pro-inflammatory mediators CXCL9, CXCL10, CXCL11, IFN gamma and CCL20 in adults, and CXCL9, CXCL10 and CXCL11 in adolescents, were found after vaccination. Participants who showed high innate immune responsiveness had higher odds (OR 6.0; 95 % CI 1.4-33) of experiencing one or more moderate symptoms. No association was found between innate responsiveness or having one or more moderate symptoms with Spike S1or RBD-antibody concentration at day 28 after vaccination. Conclusion: Our results suggest an association between the strength of the innate immune response and the severity of reactogenicity to SARS-CoV-2 vaccination. However, more research is needed to understand the relation between reactogenicity and immunogenicity of COVID-19 vaccines.

BACKGROUND:The impact of human papillomavirus (HPV) vaccination programs depends on the degree of indirect protection against new infections achieved among unvaccinated women. We estimated the indirect effect of bivalent HPV vaccination by comparing the HPV-type incidence in unvaccinated female participants between a cohort offered vaccination in 2009/2010 and a cohort of similar-aged women offered vaccination in 2014. METHODS:We compared the incidence rates of HPV types in the HAVANA cohort (follow-up from 2010/2011 until 2015/2016) with those from the HAVANA-2 cohort (2017-2022) using two regression approaches to estimate the indirect effect of HPV vaccination. First, we calculated the incidence ratio (IRR) for a vaccine or cross-protective type in HAVANA-2 versus HAVANA by Poisson regression and compared it to the IRR for a non-cross-protective type. The indirect vaccine effect is defined as 1-ratio of the IRRs. Second, we performed Cox regression with infection by vaccine or cross-protective type as the endpoint and calculated the hazard ratio (HR) for HAVANA-2 versus HAVANA after adjusting for time-varying sociodemographic variables. The indirect effect is defined as 1-HR. RESULTS:We included 661 unvaccinated participants in HAVANA and 927 in HAVANA-2. We observed a significant reduction in incident HPV16 infections of 70.9% (95% CI 48.3-83.7%) with Poisson regression and of 73.1% (95% CI 53.3-84.5%) with Cox regression. For HPV45, significant decreases of 67.3% (95% CI 8.8-88.3%) and 69.8% (95% CI 15.2-89.3%) were observed. For HPV18, HPV31, and HPV33, the indirect effect was not statistically significant. CONCLUSIONS:Large indirect effects of the bivalent HPV vaccination program were observed for HPV16 and HPV45 infections.

We assessed the validity of serum total anti-nucleoprotein Immunoglobulin (N-antibodies) to identify SARS-CoV-2 (re)infections by estimating the persistence of N-antibody seropositivity and boosting following infection. From a prospective Dutch cohort study (VASCO), we included adult participants with ≥2 consecutive self-collected serum samples, 4-8 months apart, between May 2021-May 2023. Sample pairs were stratified by N-seropositivity of the first sample and by self-reported infection within the sampling interval. We calculated the proportions of participants with N-seroconversion and fold-increase (1.5, 2, 3, 4) of N-antibody concentration over time since infection and explored determinants. We included 67,632 sample pairs. Pairs with a seronegative first sample (70%) showed 89% N-seroconversion after reported infection and 11% when no infection was reported. In pairs with a seropositive first sample (30%), 82%-65% showed a 1.5- to 4-fold increase with a reported reinfection, and 19%-10% without a reported reinfection, respectively. After one year, 83% remained N-seropositive post-first infection and 93%-61% showed a 1.5-fold to 4-fold increase post-reinfection. Odds for seroconversion/fold increase were higher for symptomatic infections and Omicron infections. In the current era with limited antigen or PCR testing, N-serology can be validly used to detect SARS-CoV-2 (re)infections at least up to a year after infection, supporting the monitoring of COVID-19 burden and vaccine effectiveness.

Background - Diagnostic (self-)testing for SARS-CoV-2 may lead to selection bias in test-negative case-control designs (TND) for COVID-19 vaccine effectiveness (CVE) at primary care level. We investigated whether after the acute phase of the pandemic, (self-)testing among those with an acute respiratory infection (ARI) was associated with healthcare seeking behaviour at primary care level in the general Dutch population. Methods - We pooled questionnaire data from three study rounds (June 2022, November 2022 & April 2023) of the nationwide PIENTER Corona cohort study. Among participants aged 18-91 years, we selected the first self-reported ARI episode, defined as cough, sore throat, dyspnoea and/or coryza, since March 2022. We performed log-binomial regression analyses adjusted for age, sex, educational level and comorbidities to assess associations between COVID-19 vaccination, SARS-CoV-2 (self-)testing and general practitioner (GP) consultation, and between GP consultation and prior (self-)test result. Results - Among 3152 participants with an ARI episode, vaccinated (vs unvaccinated) participants more often (self-)tested (adjusted RR [95% CI]: 1.07 [1.04-1.11]) or consulted a GP (1.57 [1.21-2.09]). (Self-)test result overall was not associated with GP consultation (0.86 [0.69-1.08]). Vaccination-stratified analyses showed vaccinated individuals were less likely to consult the GP after a positive (self-) test (0.62 [0.49-0.79]), while unvaccinated were more likely to (2.00 [1.08-3.51]). Conclusions - In this Dutch population-based cohort, GP consultation between May 2022 and March 2023 was differential by (self-)test result and vaccination status, indicating potential selection bias in TND CVE estimates from testing before GP consultation. More research to quantify this bias in various settings is needed. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This 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 Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The PICO study was conducted in accordance with the principles of the Declaration of Helsinki and the study protocol was approved by the Medical Ethics Committee MEC-U, the Netherlands (Clinical Trial Registration NTR8473). All participants provided written informed consent. 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. Yes I 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study can be requested via the PICO study website (https://www.rivm.nl/en/pienter-corona-study/information-for-researchers). Restrictions may apply to the availability of these data.

Fatigue is one of the most common persistent symptoms of SARS-CoV-2 infection. We aimed to assess fatigue during and after a SARS-CoV-2 infection by age, sex, presence of a medical risk condition, SARS-CoV-2 variant and vaccination status, accounting for pre-infection fatigue and compared with uninfected individuals. We used data from an ongoing prospective cohort study in the Netherlands (VASCO). We included 22,705 first infections reported between 12 July 2021 and 9 March 2024. Mean fatigue scores increased during infection, declined rapidly in the first 90 days post-infection, but remained elevated until at least 270 days for Delta and 120 days for Omicron infections. Prevalence of severe fatigue was 18.5% before first infection. It increased to 24.4% and 22.5% during acute infection and decreased to 21.2% and 18.9% at 90 days after Delta and Omicron infection, respectively. The prevalence among uninfected participants was lower than among matched Delta-infected participants during the acute phase of the infection and 90 days post-infection. For matched Omicron-infected individuals this was only observed during the acute phase. We observed no differences in mean post- vs pre-infection fatigue scores at 90-270 days post-infection by vaccination status. The impact of SARS-CoV-2 infection on the prevalence of severe fatigue was modest at population level, especially for Omicron.

BACKGROUND:With SARS-CoV-2 self-tests, persons with acute respiratory infections (ARI) can know their COVID-19 status. This may alter their decision to consult a general practitioner (GP), potentially biasing COVID-19 vaccine effectiveness (VE) studies. We explore bias mechanisms, simulate magnitude, and verify control methods. METHODS:We used directed acyclic graphs (DAGs) to illustrate the bias mechanisms. Based on the European primary care VEBIS multicentre test-negative design (TND) study, we simulated populations with varying true VE (20%-60%), proportions of persons with ARI self-testing (10%-30%), effect of COVID-19 vaccination on self-testing (1.5-2.5), and effect of self-test result on GP consultation (0.5-2). We performed 5000 runs per scenario, estimating VE among those consulting a GP. We calculated bias as true VE minus mean simulated VE, unadjusted and adjusted for self-testing, using logistic regression. RESULTS:DAGs suggested collider stratification bias if vaccination had an effect on self-testing and if self-test results affected GP consultation. Bias was -12% to 18% at 20% true VE, with the most extreme associations and 30% self-testing. With 60% true VE and 10%-20% self-testing, bias was lower. Bias was higher (-18% to 45%) if both positive and negative self-test results affected GP consultation. Adjusting for self-testing removed the bias. CONCLUSIONS:Self-testing may bias COVID-19 VE TND studies in primary care if self-testing is high, particularly with low VE. We recommend primary care TND VE studies collect self-testing information to eliminate potential bias. Observational studies are needed to understand the relationship between vaccination, self-testing, and GP consultation, in these studies' source population.

Background Registration in the Dutch national COVID-19 vaccination register requires consent from the vaccinee. This causes misclassification of non-consenting vaccinated persons as being unvaccinated. We quantified and corrected the resulting information bias in the estimation of vaccine effectiveness (VE). Methods National data were used for the period dominated by the SARS-CoV-2 Delta variant (11 July to 15 November 2021). VE ((1-relative risk)*100 %) against COVID-19 hospitalization and ICU admission was estimated for individuals 12-49, 50-69, and ≥70 years of age using negative binomial regression. Anonymous data on vaccinations administered by the Municipal Health Services were used to determine informed consent percentages and estimate corrected VEs by iteratively imputing corrected vaccination status. Absolute bias was calculated as the absolute change in VE; relative bias as uncorrected / corrected relative risk. Results A total of 8,804 COVID-19 hospitalizations and 1,692 COVID-19 ICU admissions were observed. The bias was largest in the 70+ age group where the non-consent proportion was 7.0% and observed vaccination coverage was 87%: VE of primary vaccination against hospitalization changed from 75.5% (95% CI 73.5-77.4) before to 85.9% (95% CI 84.7-87.1) after correction (absolute bias -10.4 percentage point, relative bias 1.74). VE against ICU admission in this group was 88.7% (95% CI 86.2-90.8) before and 93.7% (95% CI 92.2-94.9) after correction (absolute bias -5.0 percentage point, relative bias 1.79). Conclusions VE estimates can be substantially biased with modest non-consent percentages for registration of vaccination. Data on covariate specific non-consent percentages should be available to correct this bias. ### Competing Interest Statement C.H. van Werkhoven declares financial and non-financial research support from DaVolterrra and bioMerieux; financial research support from LimmaTech; consultancy fees from MSD and Sanofi-Pasteur (all payments to the University Medical Centre Utrecht and not related to the current manuscript). All other authors report no conflicts of interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a secondary analysis of another study (<https://doi.org/10.1101/2022.07.21.22277831>) for which the research proposal was assessed by the Centre for Clinical Expertise at the RIVM. They verified whether the work complies with the specific conditions as stated in the law for medical research involving human subjects (WMO), and were of the opinion that the research does not fulfill one or both of these conditions and therefore conclude it is exempted for further approval by the ethical research committee. 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. Yes I 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

We present early vaccine effectiveness (VE) estimates of the 2023 seasonal COVID-19 XBB.1.5 vaccine against COVID-19 hospitalisation and admission to an intensive care unit (ICU) in previously vaccinated adults ≥ 60 years in the Netherlands. We compared vaccination status of 2,050 hospitalisations including 92 ICU admissions with age group-, sex-, region- and date-specific population vaccination coverage between 9 October and 5 December 2023. VE against hospitalisation was 70.7% (95% CI: 66.6–74.3), VE against ICU admission was 73.3% (95% CI: 42.2–87.6).

This study explored the effect of SARS-CoV-2 infection and COVID-19 vaccination during pregnancy on neonatal outcomes among women from the general Dutch population. VASCO is an ongoing prospective cohort study aimed at assessing vaccine effectiveness of COVID-19 vaccination. Pregnancy status was reported at baseline and through regular follow-up questionnaires. As an extension to the main study, all female participants who reported to have been pregnant between enrolment (May-December 2021) and January 2023 were requested to complete an additional questionnaire on neonatal outcomes. Multivariable linear and logistic regression analyses were used to determine the associations between self-reported SARS-CoV-2 infection or COVID-19 vaccination during pregnancy and neonatal outcomes, adjusted for age, educational level, and presence of a medical risk condition. Infection analyses were additionally adjusted for COVID-19 vaccination before and during pregnancy, and vaccination analyses for SARS-CoV-2 infection before and during pregnancy. Of 312 eligible participants, 232 (74%) completed the questionnaire. In total, 196 COVID-19 vaccinations and 115 SARS-CoV-2 infections during pregnancy were reported. Infections were mostly first infections (86; 75%), caused by the Omicron variant (95; 83%), in women who had received ≥1 vaccination prior to infection (101; 88%). SARS-CoV-2 infection during pregnancy was not significantly associated with gestational age (β = 1.7; 95%CI: -1.6-5.0), birth weight (β = 82; -59 to 223), Apgar score <9 (odds ratio (OR): 1.3; 0.6-2.9), postpartum hospital stay (OR: 1.0; 0.6-1.8), or neonatal intensive care unit admission (OR: 0.8; 0.2-3.2). COVID-19 vaccination during pregnancy was not significantly associated with gestational age (β = -0.4; -4.0 to 3.2), birth weight (β = 88; -64 to 240), Apgar score <9 (OR: 0.9; 0.4-2.3), postpartum hospital stay (OR: 0.9; 0.5-1.7), or neonatal intensive care unit admission (OR: 1.6; 0.4-8.6). In conclusion, this study did not find an effect of SARS-CoV-2 infection or COVID-19 vaccination during pregnancy on any of the studied neonatal outcomes among a general Dutch, largely vaccinated, population. Together with data from other studies, this supports the safety of COVID-19 vaccination during pregnancy.

Monitoring the real-life effectiveness of respiratory syncytial virus (RSV) products is of major public health importance. This generic protocol for a test-negative design study aims to address currently envisioned approaches for RSV prevention (monoclonal antibodies and vaccines) to study effectiveness of these products among target groups: children, older adults, and pregnant women. The generic protocol approach was chosen to allow for flexibility in adapting the protocol to a specific setting. This protocol includes severe acute respiratory infection (SARI) and acute respiratory infection (ARI), both due to RSV, as end points. These end points can be applied to studies in hospitals, primarily targeting patients with more severe disease, but also to studies in general practitioner clinics targeting ARI.