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.

Effectiveness of bivalent mRNA booster vaccination against SARS-CoV-2 Omicron infection in the Netherlands, September to December 2022 (preprint)

We used data of 32,542 prospective cohort study participants who previously received primary and one or two monovalent booster COVID-19 vaccinations. Between 26 September and 19 December 2022, relative effectiveness of bivalent Original/Omicron BA.1 vaccination against self-reported Omicron SARS-CoV-2 infection was 31% in 18-59-year-olds and 14% in 60-85-year-olds. Protection was higher after prior Omicron infection than after bivalent vaccination without prior infection. Although bivalent booster vaccination increases protection against COVID-19 hospitalizations, we found limited added benefit in preventing SARS-CoV-2 infection.

Vaccine effectiveness against SARS-CoV-2 Delta and Omicron infection and infectiousness within households in the Netherlands between July 2021 and August 2022. (preprint)

Introduction. We aimed to estimate vaccine effectiveness against infection (VE-infection) and infectiousness (VE- infectiousness) in a household setting during Delta and Omicron. Knowing these effects can aid policy makers in deciding which groups to prioritize for vaccination. Methods. Participants with a positive SARS-CoV-2 test were asked about COVID-19 vaccination status and SARS-CoV-2 testing of their household members one month later. VE-infection and VE-infectiousness was estimated using GEE logistic regression adjusting for age and vaccination status, calendar week and household size. Results. 3,409 questionnaires concerning 4,123 household members were included. During the Delta-period, VE-infection of primary series was 47% (95% CI: -27%-78%) and VE-infectiousness of primary series was 70% (95% CI: 28%-87%). During the Omicron-period, VE-infection was -36% (95% CI: -88%-1%) for primary series and -30% (95% CI: -80%-6%) for booster vaccination. The VE-infectiousness was 45% (95% CI: -14%-74%) for primary series and 64% (95% CI: 31%-82%) for booster vaccination. Discussion. Our study shows that COVID-19 vaccination is effective against infection with SARS-CoV-2 Delta and against infectiousness of SARS-CoV-2 Delta and Omicron. Estimation of VE against infection with SARS-CoV-2 Omicron was limited by several factors. Our results support vaccination for those in close contact with vulnerable people to prevent transmission.

Vaccine effectiveness of primary and booster COVID-19 vaccinations against SARS-CoV-2 infection in the Netherlands from 12 July 2021 to 6 June 2022: a prospective cohort study (preprint)

Introduction - Monitoring of COVID-19 vaccine effectiveness (VE) is needed to inform vaccine policy. We estimated VE of primary vaccination, and first and second booster vaccination, against SARS-CoV-2 infection overall, and in four risk groups defined by age and medical risk condition, in the Delta and Omicron BA.1/BA.2 periods. Methods - VASCO is an ongoing prospective cohort study among vaccinated and unvaccinated Dutch adults. The primary endpoint was a self-reported positive SARS-CoV-2 test during 12 July 2021-6 June 2022. Participants with a prior SARS-CoV-2 infection, based on a positive test or serology, were excluded. We used Cox proportional hazard models with vaccination status as time-varying exposure and adjustment for age, sex, educational level, and medical risk condition. We stratified by Delta and Omicron BA.1/BA.2 periods, risk group, and time since vaccination. Results - 37,170 participants (mean age 57 years) were included. In the Delta period, VE <6 weeks after primary vaccination was 80% (95%CI 69-87) and decreased to 71% (65-77) after 6 months. VE increased to 96% (86-99) shortly after the first booster vaccination. In the Omicron period these estimates were 46% (22-63), 25% (8-39) and 57% (52-62), respectively. VE was 50% (34-62) <6 weeks after a second booster vaccination in participants aged [≥]60 years. For the Omicron period, an interaction term between vaccination status and risk group significantly improved the model (p<0.001), with generally lower VEs for those with a medical risk condition. Conclusions - Our results show the benefit of booster vaccinations against infection, also in risk groups, although the additional protection wanes quite rapidly.

The effect of previous SARS-CoV-2 infection and COVID-19 vaccination on SARS-CoV-2 Omicron infection and relation with serological response - a prospective cohort study (preprint)

Objectives: To estimate the protective effect of previous infections and vaccinations on SARS-CoV-2 Omicron infection. Design: Prospective cohort study Setting: Community-based cohort, the Netherlands Participants: 43,257 Community-dwelling adults aged 18-85 years contributed 8,291,966 person-days between 10 January 2022 and 1 September 2022. Main outcome measures: SARS-CoV-2 infection, defined as either a reported positive (self-administered) antigen or PCR test, or seroconversion or 4-fold increase in Nucleoprotein-antibodies, based on 6-monthly serum samples. Cox proportional hazard models were used with SARS-CoV-2 infection and any COVID-19 vaccination as time-varying exposures, calendar time as underlying time scale and adjustment for age, sex, medical risk and educational level. Results: In participants with 2, 3 or 4 prior immunizing events (vaccination or previous infection), we found a relative reduction of 71-85% in Omicron infection in weeks 4-10 post-last event with hybrid immunity compared to vaccine-induced immunity. Differences in risk of infection were partly explained by differences in anti-Spike RBD (S) antibody concentration, which showed a similar pattern but with smaller differences between vaccine-induced and hybrid immunity. Compared to the lowest quartile, participants in subsequent quartiles of S-antibody concentrations had 19%, 35% and 71% reduced risk of infection, respectively. Among participants with hybrid immunity, with one previous pre-Omicron infection, there was no relevant difference in risk of Omicron infection by sequence of vaccination(s) and infection). Regardless of the type of previous immunizing events, additional events increased the protection against infection, but not above the level of the first weeks after the previous event. Conclusions: Our results showed that hybrid immunity is more protective against infection with SARS-CoV-2 Omicron than vaccine-induced immunity, up to at least 30 weeks after the last immunizing event. Among those with hybrid immunity, the sequence and number of immunizing events was not found to be of importance, and its protective effect was partly explained by circulating S-antibodies. In our population with a high level of immunity, additional immunizing events reduced risk of infection with Omicron variants only temporarily. Trial registration: Dutch Trial Register (NTR), registration number NL9279 (available via ICTRP Search Portal (who.int))

Cohort profile: an observational population-based cohort study on COVID-19 vaccine effectiveness in the Netherlands – The VAccine Study COvid-19 (VASCO) (preprint)

Purpose - VAccine Study COvid-19 (VASCO) is a cohort study with 5-year follow-up that was initiated when COVID-19 vaccination was introduced in the Netherlands. The primary objective is to estimate real-world vaccine effectiveness (VE) of COVID-19 vaccines against SARS-CoV-2 infection in the Netherlands, overall and in four subpopulations defined by age and medical risk. Participants - The cohort consists of 45,547 community-dwelling participants aged 18-85 years who were included irrespective of their COVID-19 vaccination status or intention to get vaccinated. A medical risk condition is present in 4,289 (19.8%) of 21,679 18-59 year-olds and in 9,135 (38.3%) of 23,821 60-85 year-olds. After one year of follow-up, 5,502 participants had dropped out of the study. At inclusion, and several times after inclusion, participants are asked to take a self-collected fingerprick blood sample in which nucleoprotein and spike protein receptor binding domain-specific antibody titers are assessed. Participants are also asked to complete monthly digital questionnaires in the first year, and 3-monthly in years 2-5, including questions on sociodemographic factors, health status, COVID-19 vaccination, SARS-CoV-2-related symptoms and testing results, and behavioral responses to COVID-19 measures. Findings to date - VASCO data has been used to describe VE against SARS-CoV-2 infection of primary vaccination, first and second booster and bivalent boosters, the impact of hybrid immunity on SARS-CoV-2 infection and VE against infectiousness. Furthermore, data was used to describe antibody response following vaccination and breakthrough infections and to investigate the relation between antibody response and reactogenicity. Future plans - VASCO will be able to contribute to policy decision-making regarding future COVID-19 vaccination. Furthermore, VASCO provides an infrastructure to conduct further studies and to anticipate on changing vaccination campaigns and testing policy, and new virus variants. Registration - VASCO is registered in the online Dutch clinical trials register (trialsearch.who.int) with registration number NL9279.