Effectiveness of Omicron XBB.1.5 vaccine against SARS-CoV-2 Omicron XBB and JN.1 infection in a prospective cohort study in the Netherlands, October 2023 to January 2024 (preprint)

We estimated vaccine effectiveness (VE) of SARS-CoV-2 Omicron XBB.1.5 vaccination against self-reported infection between 9 October 2023 and 9 January 2024 in 23,895 XBB.1.5 vaccine-eligible adults who had previously received at least one booster. VE was 41% (95%CI:23-55) in 18-59-year-olds and 50% (95%CI:44-56) in 60-85-year-olds. Sequencing data in a subset of infections suggests immune escape of the emerging BA.2.86 (JN.1) variant from recent prior infection (OR:2.6; 95%CI:1.1-6.3) and, although not statistically significant, from XBB.1.5 vaccination (OR:1.6; 95%CI:0.9-2.9). 

COVID-19 vaccination-induced antibody responses and waning by age and comorbidity status in a large population-based prospective cohort study (preprint)

Background Information on the magnitude and duration of antibody levels after COVID-19 vaccination in different groups may be useful for prioritizing of additional vaccinations. Methods Serum samples were collected every six months in a prospective cohort study among adults in the Netherlands. Geometric mean concentrations (GMCs) of antibodies against the receptor binding domain of the SARS-CoV-2 spike protein were calculated after the primary series, first, and second booster vaccinations. Effects of age (18-59 vs 60-85 years) and medical risk conditions on GMC 2-6 weeks and 21-25 weeks after each vaccination, and on waning during 3-25 weeks after each vaccination, were estimated by linear regression. Results We included 20,816, 16,820 and 5,879 samples collected after primary, first and second booster vaccination, respectively. GMCs at 2-6 and 21-25 weeks after primary series were lower in participants with older age or medical risk conditions. After the first booster, older age was associated with lower GMC at 2-6 weeks, higher GMC at 21-25 weeks, and slower waning. GMCs or waning after the first and second boosters (only 60-85) were not associated with medical risk conditions. Conclusions Since antibody differences by age and medical risk groups have become small with increasing number of doses, other factors such as disease severity rather than antibody levels are useful for prioritization of additional vaccinations.

Association between common adverse events after COVID-19 vaccination and anti-SARS-CoV-2 antibody concentrations in a population-based prospective cohort study in the Netherlands (preprint)

INTRODUCTION: Adverse events (AE) such as pain at injection site or fever are common after COVID-19 vaccination. We aimed to describe determinants of AE after COVID-19 vaccination and investigate the association between AE and pre- and post-vaccination antibody concentrations. METHODS: Participants of an ongoing prospective cohort study (VASCO) completed a questionnaire on AE within two months after COVID-19 vaccination and provided 6-monthly serum samples. Data from May 2021 to November 2022 were included. Logistic regression analyses were performed to investigate determinants of AE after mRNA vaccination, including pre-vaccination Ig antibody concentrations against the receptor binding domain. Multivariable linear regression was performed in SARS-CoV-2 naive participants to assess the association between AE and log-transformed antibody concentrations 3-8 weeks after mRNA vaccination. RESULTS: 47,947 AE questionnaires were completed by 28,032 participants. In 42% and 34% of questionnaires, injection site and systemic AE were reported, respectively. In 2.2% of questionnaires, participants sought medical attention due to AE. AE were reported significantly more frequently by women, younger participants (<60 years), participants with medical risk conditions and Spikevax recipients (versus Comirnaty). Higher pre-vaccination antibody concentrations were associated with higher incidence of systemic AE after the second and third dose, but not with injection site AE or AE for which medical attention was sought. Any AE after the third dose was associated with higher post-vaccination antibody concentrations (geometric mean concentration ratio: 1.38, 95%CI 1.23-1.54). CONCLUSION: Our study suggests that high pre-vaccination antibody levels induce AE, and that experiencing AE may be a marker for a good antibody response to vaccination.

Information bias of vaccine effectiveness estimation due to informed consent for national registration of COVID-19 vaccination: estimation and correction using a data augmentation model (preprint)

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 iterative data augmentation. 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.

Number of COVID-19 hospitalisations averted by vaccination: Estimates for the Netherlands, August 2, 2021 through August 30, 2022 (preprint)

Background: Vaccines against COVID-19 have proven effective in preventing COVID-19 hospitalisation. In this study, we aimed to quantify one aspect of the public health impact of COVID-19 vaccination by estimating the number of averted hospitalisations. We present results from the beginning of the vaccination campaign (period 1, January 6, 2021) and a period starting at August 2, 2021 (period 2) when all adults had the opportunity to complete their primary series, until August 30, 2022. Methods Using calendar-time specific vaccine effectiveness (VE) estimates and vaccine coverage (VC) by round (primary series, first booster and second booster) and the observed number of COVID-19 associated hospitalisations, we estimated the number of averted hospitalisations per age group for the two study periods. From January 25, 2022, when the indication of hospitalisation was registered, hospitalisations not causally related to COVID-19 were excluded. Results In period 1, there were an estimated 98,170 (95% confidence interval (CI) 96,123-99,928) averted hospitalisations, of which 90,753 (95% CI 88,790-92,531) in period 2, equalling 57.0% and 67.9% of all hospital admissions. Estimated averted hospitalisations were lowest for 12-49-year-olds and highest for 70-79-year-olds. More admissions were averted in the Delta period (72.2%) than in the Omicron period (64.0%). Conclusion COVID-19 vaccination prevented a large number of hospitalisations. Although the estimated number of hospitalisations during the study period could not have occurred realistically due to limits on health care, these findings underline the public health importance of the vaccination campaign to policy makers and the public.

COVID-19 vaccine effectiveness against mortality and risk of death from other causes after COVID-19 vaccination, the Netherlands, January 2021- January 2022 (preprint)

Background: We aimed to estimate vaccine effectiveness (VE) against COVID-19 mortality, and to explore whether an increased risk in non-COVID-19 mortality exists in the weeks following a COVID-19 vaccine dose. Methods: National registries of causes of death, COVID-19 vaccination and long-term care reimbursements were linked by a unique identifier using data from 1 January 2021 to 31 January 2022. We used Cox regression with calendar time as underlying time scale to, firstly, estimate VE against COVID-19 mortality after primary and first booster vaccination, per month since vaccination and, secondly, estimate risk of non-COVID-19 mortality in the 8 weeks following a first, second or booster dose, adjusting for birth year, sex and country of origin. Results: VE against COVID-19 mortality was >90% for all age groups two months after completion of the primary series. VE gradually decreased thereafter, to around 80% at 7-8 months post-primary series for most groups, and around 60% for elderly receiving a high level of long-term care and for people aged 90+ years. The risk of non-COVID-19 mortality was lower or similar in the 8 weeks following a first booster dose compared to no vaccination, first or second dose, respectively, for all age and long-term care groups. Conclusion: COVID-19 vaccination greatly reduced the risk of COVID-19 mortality and no increased risk of death from other causes was seen at the population level.

Sex Differences In COVID-19 Mortality In The Netherlands (preprint)

Introduction: Since the first reports of COVID-19 cases, sex-discrepancies have been reported in COVID-19 mortality. We provide a detailed description of these sex differences in relation to age and comorbidities among notified cases as well as in relation to age and sex specific mortality in the general Dutch population. Methods: Data on COVID-19 cases and mortality until May 31st was extracted from the national surveillance database with exclusion of healthcare workers. Association between sex and case fatality was analyzed with multivariable logistic regression. Subsequently, male-female ratio in standardized mortality ratios and population mortality rates relative to all-cause and infectious diseases-specific mortality were computed stratified by age.Results: Male-female odds ratio for case fatality was 1.33 [95% CI 1.26-1.41] and among hospitalized cases 1.27 [95% CI 1.16-1.40]. This remained significant after adjustment for age and comorbidities. The male-female ratio of the standardized mortality ratio was 1.70 [95%CI 1.62-1.78]. The population mortality rate was 35.1 per 100.000, with a male-female rate ratio of 1.25 (95% CI 1.18-1.31) which was higher than in all-cause and infectious disease mortality.Conclusion: Our study confirms male sex is a predisposing factor for severe outcomes of COVID-19, independent of age and comorbidities. The underlying mechanisms are likely to be COVID-19 specific.