Early COVID-19 vaccine effectiveness of XBB.1.5 vaccine against hospitalization and ICU admission, the Netherlands, 9 October - 5 December 2023 (preprint)

We present early vaccine effectiveness (VE) estimates of the 2023 seasonal COVID-19 vaccination campaign using XBB.1.5 vaccine against COVID-19 hospitalization and ICU admission in previously vaccinated adults [≥]60 years old in the Netherlands. We compared vaccination status of 2050 hospitalizations including 92 ICU admissions with age group-, sex-, region- and date-specific population vaccination coverage between 9 October and 5 December 2023. VE against hospitalization was 70.7% (95% CI: 66.6; 74.3), VE against ICU admission was 73.3% (95% CI: 42.2; 87.6).

Assessment of hybrid population immunity to SARS-CoV-2 following breakthrough infections of distinct SARS-CoV-2 variants (preprint)

Immunity induced by vaccination and infection, referred to as hybrid immunity, provides better protection against SARS-CoV-2 infections compared to immunity induced by vaccinations alone. To assess the development of hybrid immunity we investigated the induction of Nucleoprotein-specific antibodies in PCR-confirmed infections by Delta or Omicron in vaccinated individuals (n = 520). Eighty-two percent of the participants with a breakthrough infection reached N-seropositivity. N-seropositivity was accompanied by Spike S1 antibody boosting, and independent of vaccination status or virus variant. Following the infection relatively more antibodies to the infecting virus variant were detected. In conclusion, these data show that hybrid immunity through breakthrough infections is hallmarked by Nucleoprotein antibodies and repertoire broadening of Spike antibodies. Exposure to future SARS-CoV-2 variants may therefore continue to maintain and broaden vaccine-induced population immunity.

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))

Higher risk of SARS-CoV-2 Omicron BA.4/5 infection than of BA.2 infection after previous BA.1 infection, the Netherlands, 2 May to 24 July 2022 (preprint)

We investigate differences in protection from previous infection and/or vaccination against infection with Omicron BA.4/5 or BA.2. We observed a higher percentage of registered previous SARS-CoV-2 infections among 19836 persons infected with Omicron BA.4/5 compared to 7052 persons infected with BA.2 (31.3% vs. 20.0%) between 2 May and 24 July 2022 (adjusted odds ratio (aOR) for testing week, age group and sex: 1.4 (95%CI: 1.3-1.5)). No difference was observed in the distribution of vaccination status between BA.2 and BA.4/5 cases (aOR: 1.1 for primary and booster vaccination). Among reinfections, those newly infected with BA4/5 had a shorter interval between infections and the previous infection was more often caused by BA.1, compared to those newly infected with BA.2 (aOR: 1.9 (1.5-2.6). This suggests immunity induced by BA.1 is less effective against a BA.4/5 infection than against a BA.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.

Pathogen- and type-specific changes in invasive bacterial disease epidemiology during the first year of the COVID-19 pandemic in the Netherlands (preprint)

The COVID-19 control measures have resulted in a decline in several invasive bacterial disease caused by Neisseria meningitidis (IMD), Streptococcus pneumoniae (IPD) and Haemophilus influenzae (Hi-D). Since these species comprise different serogroups and serotypes that impact transmissibility and virulence, we evaluated type- and pathogen-specific changes in invasive bacterial disease epidemiology in the Netherlands during the first year of the SARS-CoV-2 pandemic. Cases were based on nationwide surveillance for five bacterial species with either respiratory (IMD, IPD, Hi-D) or non-respiratory (controls) transmission routes. Cases and type-distribution were compared between the pre-COVID period (2015-March 2020) and the first COVID-19 year (April 2020-March 2021). Overall, IMD, IPD, and Hi-D cases decreased by 78%, 67%, and 35%, respectively, in the first COVID-19 year compared to the pre-COVID period although effects differed per age group. Invasive bacterial disease in infants caused by Streptococcus agalactiae and Escherichia coli did not decrease, suggesting stable isolate submission. Serogroup B-IMD declined by 61%, while serogroup W and Y-IMD decreased >90%. Changes in IPD were dependent on pneumococcal serotypes, with 7F, 15A, 12F, 33F, and 8 showing the most pronounced decline ([≥]76%). In contrast to an overall decrease in Hi-D cases, vaccine-preventable serotype b (Hib) increased by 51%. In summary, the implementation of COVID-19 control measures had pathogen- and type-specific effects related to bacterial infections, likely reflecting intrinsic differences in transmissibility and age-related differences in (adherence to) control measures. Continued surveillance is critical to monitor potential rebound effects once restriction measures are lifted and transmission is resumed.

Protection of COVID-19 vaccination and previous infection against Omicron BA.1 and Delta SARS-CoV-2 infections, the Netherlands, 22 November 2021- 19 January 2022 (preprint)

Given the emergence of the SARS-CoV-2 Omicron BA.1 variant and the roll-out of booster COVID-19 vaccination, evidence is needed on protection conferred by primary vaccination, booster vaccination and previous SARS-CoV-2 infection against Omicron BA.1 compared with Delta infection. We employed a test-negative design and used multinomial logistic regression on data from community PCR testing in the Netherlands, from 22 November 2021 to 19 January 2022. S-gene target failure (SGTF) was used as proxy for Omicron BA.1 infection versus Delta. A total of 528,488 tests were included, of which 38,975 SGTF and 41,245 non-SGTF infections. Protection from primary vaccination was 25% (95% confidence interval (CI): 21-29) and from previous infection 33% (95% CI: 31-35) against Omicron BA.1 infection. Protection against Delta infection was higher with 76% (95% CI: 75-76) for primary vaccination and 78% (95% CI: 76-80) for previous infection. Higher protection was observed in individuals with both primary vaccination and earlier infection compared with either one. Waning of vaccine- or infection-induced protection over time was observed against both variants. Booster vaccination considerably increased vaccine effectiveness against Omicron BA.1 to 76% (95% CI: 72-79) and 68% (95% CI: 67-69) with and without previous infection, respectively. Primary vaccination with current COVID-19 vaccines and pre-Omicron SARS-CoV-2 infections offer low protection against Omicron BA.1 infection. Booster vaccination considerably increases protection against Omicron BA.1, although protection remains lower than against Delta.

Increased risk of infection with SARS-CoV-2 Omicron compared to Delta in vaccinated and previously infected individuals, the Netherlands, 22 November to 19 December 2021 (preprint)

Infections by the Omicron SARS-CoV-2 variant are rapidly increasing worldwide. Among 70,983 infected individuals (age [≥] 12 years), we observed an increased risk of S-gene target failure, predictive of the Omicron variant, in fully vaccinated (odds ratio: 5.0; 95% confidence interval: 4.0-6.1) and previously infected individuals (OR: 4.9: 95% CI: 3.1-7.7) compared with infected naive individuals. This suggests a substantial decrease in protection from vaccine- or infection-induced immunity against SARS-CoV-2 infections caused by the Omicron variant compared with the Delta variant.

Increased risk of infection with SARS-CoV-2 Beta, Gamma, and Delta variant compared to Alpha variant in vaccinated individuals (preprint)

The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) break through infection- or vaccine-induced immunity is not well understood. Here, we analyze 28,578 sequenced SARS-CoV-2 samples from individuals with known immune status obtained through national community testing in the Netherlands from March to August 2021. We find evidence for an increased risk of infection by the Beta (B.1.351), Gamma (P.1), or Delta (B.1.617.2) variants compared to the Alpha (B.1.1.7) variant after vaccination. No clear differences were found between vaccines. However, the effect was larger in the first 14-59 days after complete vaccination compared to 60 days and longer. In contrast to vaccine-induced immunity, no increased risk for reinfection with Beta, Gamma or Delta variants relative to Alpha variant was found in individuals with infection-induced immunity.

Vaccine effectiveness against COVID-19 related hospital admission in the Netherlands: a test-negative case-control study (preprint)

Introduction: Real-world vaccine effectiveness (VE) estimates are essential to identify potential groups at higher risk of break-through infections and to guide policy. We assessed the VE of COVID-19 vaccination against COVID-19 hospitalization, while adjusting and stratifying for patient characteristics. Methods: We performed a test-negative case-control study in six Dutch hospitals. The study population consisted of adults eligible for COVID-19 vaccination hospitalized between May 1 and June 28 2021 with respiratory symptoms. Cases were defined as patients who tested positive for SARS-CoV-2 by PCR during the first 48 hours of admission or within 14 days prior to hospital admission. Controls were patients tested negative at admission and did not have a positive test during the 2 weeks prior to hospitalization. VE was calculated using multivariable logistic regression, adjusting for calendar week, sex, age, comorbidity and nursing home residency. Subgroup analysis was performed for age, sex and different comorbidities. Secondary endpoints were ICU-admission and mortality. Results: 379 cases and 255 controls were included of whom 157 (18%) were vaccinated prior to admission. Five cases (1%) and 40 controls (16%) were fully vaccinated (VE: 93%; 95% CI: 81-98), and 40 cases (11%) and 70 controls (27%) were partially vaccinated (VE: 70%; 95% CI: 50-82). A strongly protective effect of vaccination was found in all comorbidity subgroups. No ICU-admission or mortality were reported among fully vaccinated cases. Of unvaccinated cases, mortality was 10% and 19% was admitted at the ICU Conclusion: COVID-19 vaccination provides a strong protective effect against COVID-19 related hospital admission, in patients with and without comorbidity.

Vaccine effectiveness against SARS-CoV-2 transmission to household contacts during dominanceof Delta variant (B.1.617.2), August-September 2021, the Netherlands (preprint)

We estimated vaccine effectiveness against onward transmission by comparing secondary attack rates among household members between vaccinated and unvaccinated index cases, based on source and contact tracing data collected when Delta variant was dominant. Effectiveness of full vaccination of the index against transmission to fully vaccinated household contacts was 40% (95% confidence interval (CI) 20-54%), which is in addition to the direct protection of vaccination of contacts against infection. Effectiveness of full vaccination of the index against transmission to unvaccinated household contacts was 63% (95%CI 46-75%). We previously reported effectiveness of 73% (95%CI 65-79%) against transmission to unvaccinated household contacts for the Alpha variant.

COVID-19 vaccine effectiveness against hospitalizations and ICU admissions in the Netherlands, April- August 2021 (preprint)

The objective of this study was to estimate vaccine effectiveness (VE) against COVID-19 hospitalization and ICU admission, per period according to dominating SARS-CoV-2 variant (Alpha and Delta), per vaccine and per time since vaccination. To this end, data from the national COVID-19 vaccination register was added to the national register of COVID-19 hospitalizations. For the study period 4 April - 29 August 2021, 15,571 hospitalized people with COVID-19 were included in the analysis, of whom 887 (5.7%) were fully vaccinated. Incidence rates of hospitalizations and ICU admissions per age group and vaccination status were calculated, and VE was estimated as 1-incidence rate ratio, adjusted for calendar date and age group in a negative binomial regression model. VE against hospitalization for full vaccination was 94% (95%CI 93-95%) in the Alpha period and 95% (95%CI 94-95%) in the Delta period. The VE for full vaccination against ICU admission was 93% (95%CI 87-96%) in the Alpha period and 97% (95%CI 97-98%) in the Delta period. VE was high in all age groups and did not show waning with time since vaccination up to 20 weeks after full vaccination.

High SARS-CoV-2 attack rates following exposure during singing events in the Netherlands, September-October 2020 (preprint)

Previous reports indicate that there may be an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during singing events. We describe SARS-CoV-2 transmission in six singing events from September-October 2020, across the Netherlands, with attack rates from 25-74%. We investigated potential routes of SARS-CoV-2 transmission for each event. Events included 9-21 persons, aged 20-79 years. SARS-CoV-2 transmission likely took place during five out of six events; a possible index case could be identified in four out of five clusters. Limited sequencing data was available, hampering interpretation of results. Indirect contact and droplet transmission (<1.5m) may have caused some cases, but are unlikely to explain the high attack rates. The previously published AirCoV2 model indicated that airborne transmission (via infectious droplets/ aerosols over longer distances (>1.5m)) due to singing is possible in case of supershedder presence ([≥]1010 RNA copies/mL). Also, airflow expelling respiratory droplets over longer distances (>1.5m) may have influenced transmission. In conclusion, a combination of transmission routes probably caused these five clusters. Proportions attributable to each route cannot be deduced. It is possible that airborne transmission of SARS-CoV-2 due to singing (partly) led to the high attack rates observed in these clusters.