Systemic SARS-CoV-2-specific antibody responses to infection and to COVID-19 and BCG vaccination (preprint)

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-naive 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 randomized 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.

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))

BCG vaccination of healthcare workers does not reduce SARS-CoV-2 infections nor infection severity or duration: a randomised placebo-controlled trial (preprint)

Background. Bacillus Calmette-Guerin (BCG) vaccination has been hypothesised to reduce SARS-CoV-2 infection, severity, and/or duration via trained immunity induction. Methods. Healthcare workers (HCWs) in 9 Dutch hospitals were randomised to BCG or placebo vaccination (1:1) in March/April 2020 and followed for one year. They reported daily symptoms, SARS-CoV-2 test results, and healthcare-seeking behaviour via a smartphone application, and donated blood for SARS-CoV-2 serology at two time points. Results. 1,511 HCWs were randomised and 1,309 analysed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio=0.95; 95% confidence interval 0.76-1.21; p=0.732). Only three participants required hospitalisation for COVID-19. The proportions of participants with asymptomatic, mild, or mild-to-moderate infections, and the mean infection durations, did not differ between randomisation groups. Unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes either. The percentage of participants with seroconversion (7.8% versus 2.8%; p=0.006) and mean anti-S1 antibody concentration (13.1 versus 4.3 IU/ml; p=0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months post-vaccination. Conclusions. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (on a scale from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection.

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.

Tolerability, safety and immunogenicity of intradermal delivery of a fractional dose mRNA -1273 SARS-CoV-2 vaccine in healthy adults as a dose sparing strategy (preprint)

Background There is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy. Methods We conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 g mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 g mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals. Findings Thirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 g and the 20 g group. In the higher dose group, systemic adverse reactions were more common, but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 g intradermal group, 1,406 (953.5-2,074) BAU/mL for the 20 g intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 g intradermal group. Anti-S1 was 107.2 (63-182.2) BAU/mL for the convalescent plasma control group and 1,558 (547.8-4,433) BAU/mL for the individuals vaccinated with 100 g mRNA-1273. Interpretation Intradermal administration of 10 g and 20 g mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.

Associations between measures of social distancing and SARS-CoV-2 seropositivity: a nationwide population-based study in the Netherlands (preprint)

ABSTRACT This large nationwide population-based seroepidemiological study provides evidence on the effectiveness of physical distancing (>1.5m) and indoor group size reductions on SARS-CoV-2 infection. Additionally, young adults seem to play a significant role in viral spread, opposed to children up until the primary school age with whom close contact is permitted.