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.

Age-specific severity of SARS-CoV-2 in February 2020 - June 2021 in the Netherlands (preprint)

Background: Severity of SARS-CoV-2 infection may vary over time. Here, we estimate age-specific risks of hospitalization, ICU admission and death given infection in the Netherlands from February 2020 - June 2021. Methods: A nationwide longitudinal serology study was used to estimate numbers of infections in three epidemic periods (February 2020 - June 2020, July 2020 - February 2021, March 2021 - June 2021). We accounted for reinfections and, as vaccination started in January 2021, breakthrough infections among vaccinated persons. Severity estimates were inferred by combining numbers of infections with aligned numbers of hospitalizations and ICU admissions from a national hospital-based registry, and aligned numbers of deaths based on national excess all-cause mortality estimates. Results: In each period there was a nearly consistent pattern of accelerating, almost exponential, increase in severity of infection with age. The rate of increase with age was highest for death and lowest for hospitalization. In the first period, the overall risk of hospitalization, ICU admission and death were 1.5% (95%-confidence interval [CI] 1.3-1.8%), 0.36% (95%-CI: 0.31-0.42%) and 1.2% (95%-CI: 1.0-1.4), respectively. The risk of hospitalization was higher in the following periods, while the risk of ICU admission remained stable. The risk of death decreased over time, with a substantial drop among [≥]70-years-olds in February 2021 - June 2021. Conclusion: The accelerating increase in severity of SARS-CoV-2 with age remained intact during the first three epidemic periods in the Netherlands. The substantial drop in risk of death among elderly in the third period coincided with the introduction of COVID-19 vaccination.

Determinants of COVID-19 vaccine uptake in the Netherlands: an ecological analysis (preprint)

Background: While overall COVID-19 vaccine uptake is high in the Netherlands, it lags behind in certain subpopulations. Aim: We aimed to identify determinants associated with COVID-19 vaccine uptake at neighbourhood level to inform the strategy to improve uptake and guide research into barriers for vaccination. We focused on those aged 50 years and older, since they are at highest risk of severe disease. Methods: We performed an ecological study using national vaccination register and socio-demographic data at neighbourhood level. Using univariate and multivariable generalized additive models we examined the (potentially non-linear) effect of each determinant on uptake. Results: In those over 50 years of age, a higher proportion of individuals with a non-Western migration background and higher voting proportions for right-wing Christian and conservative political parties were at neighbourhood level univariately associated with lower COVID-19 vaccine uptake. In contrast, higher socioeconomic status and higher voting proportions for right-wing liberal, progressive liberal and Christian middle political parties were associated with higher uptake. Multivariable results differed from univariate results in that a higher voting proportion for progressive left-wing political parties was also associated with higher uptake. In addition, with regard to migration background only a Turkish background remained significant. Conclusion: We identified determinants associated with COVID-19 vaccine uptake at neighbourhood level and observed heterogeneity between different subpopulations. Since the goal of the vaccination campaign is not only to reduce suffering and death by improving the average uptake, but also to reduce health inequity, it is important to focus on these hard-to-reach populations.

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.

Design and baseline description of an observational population-based cohort study on COVID-19 vaccine effectiveness in the Netherlands - The VAccine Study COvid-19 (VASCO) (preprint)

VAccine Study COvid-19 (VASCO) is a cohort study with 5-year follow-up to assess the real-world vaccine effectiveness (VE) of COVID-19 vaccines in the Netherlands. VASCO was initiated when COVID-19 vaccination was introduced in the Netherlands. The primary objective is to estimate vaccine-specific VE against symptomatic SARS-CoV-2 infection, overall and in four subpopulations defined by age and medical risk, at 9 months after study start when most participants would have accumulated at least 6 months of follow-up. Secondary objectives are to estimate VE by time since vaccination and by severity of SARS-CoV-2 infection. Between May and December 2021, 45,271 participants aged 18–85 years have been enrolled in VASCO. Participants were included irrespective of their COVID-19 vaccination status or intention to get vaccinated. At inclusion, at 6, 12, 24, 36, 48 and 60 months after inclusion, and at one month after primary vaccination, participants are asked to take a self-collected fingerprick blood sample at home. In the serum samples, nucleoprotein (N) and spike protein receptor binding domain (RBD)-specific antibody titers are assessed to determine vaccine response and prior SARS-CoV-2 infection(s), including prior asymptomatic infections. 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. The main aim of VASCO is to contribute to policy decision-making regarding future COVID-19 vaccination. Furthermore, VASCO provides an infrastructure to conduct substudies in response to unforeseen developments within the COVID-19 pandemic.

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.

The estimated disease burden of acute COVID-19 in the Netherlands in 2020, in disability-adjusted life-years (preprint)

Background. The impact of COVID-19 on population health is recognised as being substantial, yet few studies have attempted to quantify to what extent infection causes mild or moderate symptoms only, requires hospital and/or ICU admission, results in prolonged and chronic illness, or leads to premature death. We aimed to quantify the total disease burden of acute COVID-19 in the Netherlands in 2020 using the disability-adjusted life-years (DALY) measure, and to investigate how burden varies between age-groups and occupations.Methods. Using standard methods and diverse data sources (mandatory notifications, population-level seroprevalence, hospital and ICU admissions, registered COVID-19 deaths, and the literature), we estimated years of life lost (YLL), years lived with disability, DALY and DALY per 100,000 population due to COVID-19, excluding post-acute sequelae, stratified by 5-year age-group and occupation category.Results. The total disease burden due to acute COVID-19 was 286,100 (95% CI:281,700–290,500) DALY, and the per-capita burden was 1640 (95% CI:1620–1670) DALY/100,000, of which 99.4% consisted of YLL. The per-capita burden increased steeply with age, starting from 60–64 years, with relatively little burden estimated for persons under 50 years old.Conclusions. SARS-CoV-2 infection and associated premature mortality was responsible for a considerable direct health burden in the Netherlands, despite extensive public health measures. DALY were much higher than for other high-burden infectious diseases, but lower than estimated for coronary heart disease. These findings are valuable for informing public health decision-makers regarding the expected COVID-19 health burden among population subgroups, and the possible gains from targeted preventative interventions.

SARS-CoV-2 Spike S1-specific IgG kinetic profiles following mRNA- versus vector-based vaccination in the general Dutch population (preprint)

mRNA- and vector-based vaccines are used at a large scale to prevent COVID-19. We compared Spike S1-specific (S1) IgG antibodies after vaccination with mRNA-based (Comirnaty, Spikevax) or vector-based (Janssen, Vaxzevria) vaccines, using samples from a Dutch nationwide cohort. mRNA vaccines induced faster inclines and higher S1 antibodies compared to vector-based vaccines in adults 18-64 years old (n=2,412). For all vaccines, one dose resulted in boosting of S1 antibodies in adults with a history of SARS-CoV-2 infection. For Comirnaty, two to four months following the second dose (n=196), S1 antibodies in adults aged 18-64 years old (436 BAU/mL, interquartile range: 328-891) were less variable and median concentrations higher compared to those in persons [≥]80 years old (366, 177-743), but differences were not statistically significant (p>0.100). Nearly all participants seroconverted following COVID-19 vaccination, including the aging population. These data confirm results from controlled vaccine trials in a general population, including vulnerable groups.

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.

Seropositivity to Nucleoprotein to detect SARS-CoV-2 infections: a tool to detect breakthrough infections after COVID-19 vaccination (preprint)

BackgroundWith COVID-19 vaccine roll-out ongoing in many countries globally, monitoring of breakthrough infections is of great importance. Antibodies persist in the blood after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Since COVID-19 vaccines induce immune response to the Spike protein of the virus, which is the main serosurveillance target to date, alternative targets should be explored to distinguish infection from vaccination. MethodsMultiplex immunoassay data from 1,513 SARS-CoV-2 RT-qPCR-tested individuals (352 positive and 1,161 negative) with a primary infection and no vaccination history were used to determine the accuracy of Nucleoprotein-specific immunoglobulin G (IgG) in detecting past SARS-CoV-2 infection. We also described Spike S1 and Nucleoprotein-specific IgG responses in 230 COVID-19 vaccinated individuals (Pfizer/BioNTech). ResultsThe sensitivity of Nucleoprotein seropositivity was 85% (95% confidence interval: 80-90%) for mild COVID-19 in the first two months following symptom onset. Sensitivity was lower in asymptomatic individuals (67%, 50-81%). Participants who had experienced a SARS-CoV-2 infection up to 11 months preceding vaccination, as assessed by Spike S1 seropositivity or RT-qPCR, produced 2.7-fold higher median levels of IgG to Spike S1 [≥]14 days after the first dose as compared to those unexposed to SARS-CoV-2 at [≥]7 days after the second dose (p=0.011). Nucleoprotein-specific IgG concentrations were not affected by vaccination in naive participants. ConclusionsSerological responses to Nucleoprotein may prove helpful in identifying SARS-CoV-2 infections after vaccination. Furthermore, it can help interpret IgG to Spike S1 after COVID-19 vaccination as particularly high responses shortly after vaccination could be explained by prior exposure history.

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.

Estimating the asymptomatic proportion of SARS-CoV-2 infection in the general population: Analysis of a nationwide serosurvey in the Netherlands (preprint)

BackgroundThe proportion of SARS-CoV-2 positive persons who are asymptomatic - and whether this proportion is age-dependent - are still open research questions. Because an unknown proportion of reported symptoms among SARS-CoV-2 positives will be attributable to another infection or affliction, the observed, or crude proportion without symptoms may underestimate the proportion of persons without symptoms that are caused by SARS-CoV-2 infection. MethodsBased on a large population-based serological study comprising test results on seropositivity and self-reported symptom history conducted in April/May 2020 in the Netherlands (n=3147), we estimated the proportion of reported symptoms among those persons infected with SARS-CoV-2 that is attributable to this infection, where the set of relevant symptoms fulfills the ECDC case definition of COVID-19, using inferential methods for the attributable risk (AR). Generalised additive regression modelling was used to estimate the age-dependent relative risk (RR) of reported symptoms, and the AR and asymptomatic proportion (AP) were calculated from the fitted RR. ResultsUsing age-aggregated data, the estimated AP was 70% (95% CI: 65-77%). The estimated AP decreased with age, from 80% (95% CI: 67-100%) for the <20 years age-group, to 55% (95% CI: 48-68%) for the 70+ years age-group. ConclusionWhereas the crude AP represents a lower bound for the proportion of persons infected with SARS-CoV-2 without COVID-19 symptoms, the AP as estimated via an attributable risk approach represents an upper bound. Age-specific AP estimates can inform the implementation of public health actions such as targetted virological testing and therefore enhance containment strategies.

The impact of physical distancing measures against COVID-19 transmission on contacts and mixing patterns in the Netherlands: repeated cross-sectional surveys (preprint)

BackgroundDuring the current pandemic of coronavirus (COVID-19) many countries have taken drastic measures to reduce transmission of SARS-CoV2. The measures often include physical distancing that aims to reduce the number of contacts in the population. Little is known about the actual reduction in number of contacts as a consequence of physical distancing measures. MethodsIn the Netherlands, a cross-sectional survey was carried out in 2016/2017 in which 8179 participants retrospectively reported the number, age and gender of different persons they had contacted (spoken to in person or touched) during the previous day. The survey was repeated among 2830 of the original participants, using the same questionnaire, in March and April 2020 after physical distancing measures had been implemented. ResultsThe average number of contacts in the community was reduced from on average 12.5 (interquartile range: 2-17) to 3.7 (interquartile range: 0-4) different persons per participant, a reduction of 71% (95% confidence interval: 71-71). The reduction in the number of community contacts was highest for children and adolescents (between 5 and 20 years) and smallest for elderly persons of 80 years and older. The reduction in the effective number of total contacts, measured as the largest eigenvalue of the matrix with community and household contacts, was 62% (95% confidence interval: 48 - 72). ConclusionThe substantial reduction in contacts has contributed greatly in halting the COVID-19 epidemic. This reduction was unevenly distributed over age groups, household sizes and occupations. These findings offer guidance for the lifting of age-group targeted measures.