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

OBJECTIVES: We estimated vaccine effectiveness (VE) of primary and booster vaccinations against SARS-CoV-2 infection overall and in four risk groups defined by age and medical risk condition during the Delta and Omicron BA.1/BA.2 periods. METHODS: VAccine Study COvid-19 is an ongoing prospective cohort study among Dutch adults. The primary end point was a self-reported positive SARS-CoV-2 test from July 12, 2021 to June 06, 2022. The analyses included only participants without a previous SARS-CoV-2 infection based on a positive test or serology. We used Cox proportional hazard models with vaccination status as the time-varying exposure and adjustment for age, sex, educational level, and medical risk condition. RESULTS: A total of 37,170 participants (mean age 57 years) were included. In the Delta period, VE <6 weeks after the primary vaccination was 80% (95% confidence interval 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. 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. CONCLUSION: Our results show the benefit of booster vaccinations against infection, also in risk groups; although, the additional protection wanes quite rapidly.

BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial.

Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (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 to 1.21; P = 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%; P = 0.006) and mean SARS-CoV-2 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 postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging 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. IMPORTANCE While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.

Diagnostic accuracy of SARS-CoV-2 rapid antigen self-tests in asymptomatic individuals in the omicron period: a cross-sectional study.

OBJECTIVES: To assess the performances of three commonly used antigen rapid diagnostic tests used as self-tests in asymptomatic individuals in the Omicron period. METHODS: We performed a cross-sectional diagnostic test accuracy study in the Omicron period in three public health service COVID-19 test sites in the Netherlands, including 3600 asymptomatic individuals aged ≥ 16 years presenting for SARS-CoV-2 testing for any reason except confirmatory testing after a positive self-test. Participants were sampled for RT-PCR (reference test) and received one self-test (either Acon Flowflex [Flowflex], MP Biomedicals (MPBio), or Siemens-Healthineers CLINITEST [CLINITEST]) to perform unsupervised at home. Diagnostic accuracies of each self-test were calculated. RESULTS: Overall sensitivities were 27.5% (95% CI, 21.3-34.3%) for Flowflex, 20.9% (13.9-29.4%) for MPBio, and 25.6% (19.1-33.1%) for CLINITEST. After applying a viral load cut-off (≥5.2 log10 SARS-CoV-2 E-gene copies/mL), sensitivities increased to 48.3% (37.6-59.2%), 37.8% (22.5-55.2%), and 40.0% (29.5-51.2%), respectively. Specificities were >99% for all tests in most analyses. DISCUSSION: The sensitivities of three commonly used SARS-CoV-2 antigen rapid diagnostic tests when used as self-tests in asymptomatic individuals in the Omicron period were very low. Antigen rapid diagnostic test self-testing in asymptomatic individuals may only detect a minority of infections at that point in time. Repeated self-testing in case of a negative self-test is advocated to improve the diagnostic yield, and individuals should be advised to re-test when symptoms develop.

Head-to-head comparison of the accuracy of saliva and nasal rapid antigen SARS-CoV-2 self-testing: cross-sectional study.

BACKGROUND: The diagnostic accuracy of unsupervised self-testing with rapid antigen diagnostic tests (Ag-RDTs) is mostly unknown. We studied the diagnostic accuracy of a self-performed SARS-CoV-2 saliva and nasal Ag-RDT in the general population. METHODS: This large cross-sectional study consecutively included unselected individuals aged ≥ 16 years presenting for SARS-CoV-2 testing at three public health service test sites. Participants underwent molecular test sampling and received two self-tests (the Hangzhou AllTest Biotech saliva self-test and the SD Biosensor nasal self-test by Roche Diagnostics) to perform themselves at home. Diagnostic accuracy of both self-tests was assessed with molecular testing as reference. RESULTS: Out of 2819 participants, 6.5% had a positive molecular test. Overall sensitivities were 46.7% (39.3-54.2%) for the saliva Ag-RDT and 68.9% (61.6-75.6%) for the nasal Ag-RDT. With a viral load cut-off (≥ 5.2 log10 SARS-CoV-2 E-gene copies/mL) as a proxy of infectiousness, these sensitivities increased to 54.9% (46.4-63.3%) and 83.9% (76.9-89.5%), respectively. For the nasal Ag-RDT, sensitivities were 78.5% (71.1-84.8%) and 22.6% (9.6-41.1%) in those symptomatic and asymptomatic at the time of sampling, which increased to 90.4% (83.8-94.9%) and 38.9% (17.3-64.3%) after applying the viral load cut-off. In those with and without prior SARS-CoV-2 infection, sensitivities were 36.8% (16.3-61.6%) and 72.7% (65.1-79.4%). Specificities were > 99% and > 99%, positive predictive values > 70% and > 90%, and negative predictive values > 95% and > 95%, for the saliva and nasal Ag-RDT, respectively, in most analyses. Most participants considered the self-performing and result interpretation (very) easy for both self-tests. CONCLUSIONS: The Hangzhou AllTest Biotech saliva self Ag-RDT is not reliable for SARS-CoV-2 detection, overall, and in all studied subgroups. The SD Biosensor nasal self Ag-RDT had high sensitivity in individuals with symptoms and in those without prior SARS-CoV-2 infection but low sensitivity in asymptomatic individuals and those with a prior SARS-CoV-2 infection which warrants further investigation.

Diagnostic accuracy of covid-19 rapid antigen tests with unsupervised self-sampling in people with symptoms in the omicron period: cross sectional study.

OBJECTIVE: To assess the performance of rapid antigen tests with unsupervised nasal and combined oropharyngeal and nasal self-sampling during the omicron period. DESIGN: Prospective cross sectional diagnostic test accuracy study. SETTING: Three public health service covid-19 test sites in the Netherlands, 21 December 2021 to 10 February 2022. PARTICIPANTS: 6497 people with covid-19 symptoms aged ≥16 years presenting for testing. INTERVENTIONS: Participants had a swab sample taken for reverse transcription polymerase chain reaction (RT-PCR, reference test) and received one rapid antigen test to perform unsupervised using either nasal self-sampling (during the emergence of omicron, and when omicron accounted for >90% of infections, phase 1) or with combined oropharyngeal and nasal self-sampling in a subsequent (phase 2; when omicron accounted for >99% of infections). The evaluated tests were Flowflex (Acon Laboratories; phase 1 only), MPBio (MP Biomedicals), and Clinitest (Siemens-Healthineers). MAIN OUTCOME MEASURES: The main outcomes were sensitivity, specificity, and positive and negative predictive values of each self-test, with RT-PCR testing as the reference standard. RESULTS: During phase 1, 45.0% (n=279) of participants in the Flowflex group, 29.1% (n=239) in the MPBio group, and 35.4% ((n=257) in the Clinitest group were confirmatory testers (previously tested positive by a self-test at own initiative). Overall sensitivities with nasal self-sampling were 79.0% (95% confidence interval 74.7% to 82.8%) for Flowflex, 69.9% (65.1% to 74.4%) for MPBio, and 70.2% (65.6% to 74.5%) for Clinitest. Sensitivities were substantially higher in confirmatory testers (93.6%, 83.6%, and 85.7%, respectively) than in those who tested for other reasons (52.4%, 51.5%, and 49.5%, respectively). Sensitivities decreased from 87.0% to 80.9% (P=0.16 by χ2 test), 80.0% to 73.0% (P=0.60), and 83.1% to 70.3% (P=0.03), respectively, when transitioning from omicron accounting for 29% of infections to >95% of infections. During phase 2, 53.0% (n=288) of participants in the MPBio group and 44.4% (n=290) in the Clinitest group were confirmatory testers. Overall sensitivities with combined oropharyngeal and nasal self-sampling were 83.0% (78.8% to 86.7%) for MPBio and 77.3% (72.9% to 81.2%) for Clinitest. When combined oropharyngeal and nasal self-sampling was compared with nasal self-sampling, sensitivities were found to be slightly higher in confirmatory testers (87.4% and 86.1%, respectively) and substantially higher in those testing for other reasons (69.3% and 59.9%, respectively). CONCLUSIONS: Sensitivities of three rapid antigen tests with nasal self-sampling decreased during the emergence of omicron but was only statistically significant for Clinitest. Sensitivities appeared to be substantially influenced by the proportion of confirmatory testers. Sensitivities of MPBio and Clinitest improved after the addition of oropharyngeal to nasal self-sampling. A positive self-test result justifies prompt self-isolation without the need for confirmatory testing. Individuals with a negative self-test result should adhere to general preventive measures because a false negative result cannot be ruled out. Manufacturers of MPBio and Clinitest may consider extending their instructions for use to include combined oropharyngeal and nasal self-sampling, and other manufacturers of rapid antigen tests should consider evaluating this as well.

Factors Associated With Using the COVID-19 Mobile Contact-Tracing App Among Individuals Diagnosed With SARS-CoV-2 in Amsterdam, the Netherlands: Observational Study.

BACKGROUND: Worldwide, efforts are being made to stop the COVID-19 pandemic caused by SARS-CoV-2. Contact tracing and quarantining are key in limiting SARS-CoV-2 transmission. Mathematical models have shown that the time between infection, isolation of cases, and quarantining of contacts are the most important components that determine whether the pandemic can be controlled. Mobile contact-tracing apps could accelerate the tracing and quarantining of contacts, including anonymous contacts. However, real-world observational data on the uptake and determinants of contact-tracing apps are limited. OBJECTIVE: The aim of this paper is to assess the use of a national Dutch contact-tracing app among notified cases diagnosed with SARS-CoV-2 infection and investigate which characteristics are associated with the use of the app. METHODS: Due to privacy regulations, data from the app could not be used. Instead, we used anonymized SARS-CoV-2 routine contact-tracing data collected between October 28, 2020, and February 26, 2021, in the region of Amsterdam, the Netherlands. Complete case logistic regression analysis was performed to identify which factors (age, gender, country of birth, municipality, number of close contacts, and employment in either health care or education) were associated with using the app. Age and number of close contacts were modelled as B-splines due to their nonlinear relationship. RESULTS: Of 29,766 SARS-CoV-2 positive cases, 4824 (16.2%) reported app use. Median age of cases was 41 (IQR 29-55) years, and 46.7% (n=13,898) were male. In multivariable analysis, males (adjusted odds ratio [AOR] 1.11, 95% CI 1.04-1.18) and residents of municipalities surrounding Amsterdam were more likely to use the app (Aalsmeer AOR 1.34, 95% CI 1.13-1.58; Ouder-Amstel AOR 1.96, 95% CI 1.54-2.50), while people born outside the Netherlands, particularly those born in non-Western countries (AOR 0.33, 95% CI 0.30-0.36), were less likely to use the app. Odds of app use increased with age until the age of 58 years and decreased sharply thereafter (P<.001). Odds of app use increased with number of contacts, peaked at 8 contacts, and then decreased (P<.001). Individuals working in day care, home care, and elderly nursing homes were less likely to use the app. CONCLUSIONS: Contact-tracing app use among people with confirmed SARS-CoV-2 infection was low in the region of Amsterdam. This diminishes the potential impact of the app by hampering the ability to warn contacts. Use was particularly low among older people, people born outside the Netherlands, and people with many contacts. Use of the app was also relatively low compared to those from some other European countries, some of which had additional features beyond contact tracing, making them potentially more appealing. For the Dutch contact-tracing app to have an impact, uptake needs to be higher; therefore, investing more into promotional efforts and additional features could be considered.

Bacillus Calmette-Guérin vaccine to reduce healthcare worker absenteeism in COVID-19 pandemic, a randomized controlled trial.

OBJECTIVES: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Guérin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic. METHODS: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919). RESULTS: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication. CONCLUSIONS: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19.

Interventions to control nosocomial transmission of SARS-CoV-2: a modelling study.

BACKGROUND: Emergence of more transmissible SARS-CoV-2 variants requires more efficient control measures to limit nosocomial transmission and maintain healthcare capacities during pandemic waves. Yet the relative importance of different strategies is unknown. METHODS: We developed an agent-based model and compared the impact of personal protective equipment (PPE), screening of healthcare workers (HCWs), contact tracing of symptomatic HCWs and restricting HCWs from working in multiple units (HCW cohorting) on nosocomial SARS-CoV-2 transmission. The model was fit on hospital data from the first wave in the Netherlands (February until August 2020) and assumed that HCWs used 90% effective PPE in COVID-19 wards and self-isolated at home for 7 days immediately upon symptom onset. Intervention effects on the effective reproduction number (RE), HCW absenteeism and the proportion of infected individuals among tested individuals (positivity rate) were estimated for a more transmissible variant. RESULTS: Introduction of a variant with 56% higher transmissibility increased - all other variables kept constant - RE from 0.4 to 0.65 (+ 63%) and nosocomial transmissions by 303%, mainly because of more transmissions caused by pre-symptomatic patients and HCWs. Compared to baseline, PPE use in all hospital wards (assuming 90% effectiveness) reduced RE by 85% and absenteeism by 57%. Screening HCWs every 3 days with perfect test sensitivity reduced RE by 67%, yielding a maximum test positivity rate of 5%. Screening HCWs every 3 or 7 days assuming time-varying test sensitivities reduced RE by 9% and 3%, respectively. Contact tracing reduced RE by at least 32% and achieved higher test positivity rates than screening interventions. HCW cohorting reduced RE by 5%. Sensitivity analyses show that our findings do not change significantly for 70% PPE effectiveness. For low PPE effectiveness of 50%, PPE use in all wards is less effective than screening every 3 days with perfect sensitivity but still more effective than all other interventions. CONCLUSIONS: In response to the emergence of more transmissible SARS-CoV-2 variants, PPE use in all hospital wards might still be most effective in preventing nosocomial transmission. Regular screening and contact tracing of HCWs are also effective interventions but critically depend on the sensitivity of the diagnostic test used.

Diagnostic accuracy of rapid antigen tests in asymptomatic and presymptomatic close contacts of individuals with confirmed SARS-CoV-2 infection: cross sectional study.

OBJECTIVE: To assess the diagnostic test accuracy of two rapid antigen tests in asymptomatic and presymptomatic close contacts of people with SARS-CoV-2 infection on day 5 after exposure. DESIGN: Prospective cross sectional study. SETTING: Four public health service covid-19 test sites in the Netherlands. PARTICIPANTS: 4274 consecutively included close contacts (identified through test-and-trace programme or contact tracing app) aged 16 years or older and asymptomatic for covid-19 when requesting a test. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of Veritor System (Beckton Dickinson) and Biosensor (Roche Diagnostics) rapid antigen tests, with reverse-transcriptase polymerase chain reaction (RT-PCR) testing as reference standard. The viral load cut-off above which 95% of people with a positive RT-PCR test result were virus culture positive was used as a proxy of infectiousness. RESULTS: Of 2678 participants tested with Veritor, 233 (8.7%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 149 were also detected by the rapid antigen test (sensitivity 63.9%, 95% confidence interval 57.4% to 70.1%). Of 1596 participants tested with Biosensor, 132 (8.3%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 83 were detected by the rapid antigen test (sensitivity 62.9%, 54.0% to 71.1%). In those who were still asymptomatic at the time of sampling, sensitivity was 58.7% (51.1% to 66.0%) for Veritor (n=2317) and 59.4% (49.2% to 69.1%) for Biosensor (n=1414), and in those who developed symptoms were 84.2% (68.7% to 94.0%; n=219) for Veritor and 73.3% (54.1% to 87.7%; n=158) for Biosensor. When a viral load cut-off was applied for infectiouness (≥5.2 log10 SARS-CoV-2 E gene copies/mL), the overall sensitivity was 90.1% (84.2% to 94.4%) for Veritor and 86.8% (78.1% to 93.0%) for Biosensor, and 88.1% (80.5% to 93.5%) for Veritor and 85.1% (74.3% to 92.6%) for Biosensor, among those who remained asymptomatic throughout. Specificities were >99%, and positive and negative predictive values were >90% and >95%, for both rapid antigen tests in all analyses. CONCLUSIONS: The sensitivities of both rapid antigen tests in asymptomatic and presymptomatic close contacts tested on day 5 onwards after close contact with an index case were more than 60%, increasing to more than 85% after a viral load cut-off was applied as a proxy for infectiousness.

Model-based evaluation of school- and non-school-related measures to control the COVID-19 pandemic.

The role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. We use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures at different time points during the COVID-19 pandemic in the Netherlands. Our analyses suggest that the impact of measures reducing school-based contacts depends on the remaining opportunities to reduce non-school-based contacts. If opportunities to reduce the effective reproduction number (Re) with non-school-based measures are exhausted or undesired and Re is still close to 1, the additional benefit of school-based measures may be considerable, particularly among older school children. As two examples, we demonstrate that keeping schools closed after the summer holidays in 2020, in the absence of other measures, would not have prevented the second pandemic wave in autumn 2020 but closing schools in November 2020 could have reduced Re below 1, with unchanged non-school-based contacts.

Impact of delays on effectiveness of contact tracing strategies for COVID-19: a modelling study.

BACKGROUND: In countries with declining numbers of confirmed cases of COVID-19, lockdown measures are gradually being lifted. However, even if most physical distancing measures are continued, other public health measures will be needed to control the epidemic. Contact tracing via conventional methods or mobile app technology is central to control strategies during de-escalation of physical distancing. We aimed to identify key factors for a contact tracing strategy to be successful. METHODS: We evaluated the impact of timeliness and completeness in various steps of a contact tracing strategy using a stochastic mathematical model with explicit time delays between time of infection and symptom onset, and between symptom onset, diagnosis by testing, and isolation (testing delay). The model also includes tracing of close contacts (eg, household members) and casual contacts, followed by testing regardless of symptoms and isolation if testing positive, with different tracing delays and coverages. We computed effective reproduction numbers of a contact tracing strategy (RCTS) for a population with physical distancing measures and various scenarios for isolation of index cases and tracing and quarantine of their contacts. FINDINGS: For the most optimistic scenario (testing and tracing delays of 0 days and tracing coverage of 100%), and assuming that around 40% of transmissions occur before symptom onset, the model predicts that the estimated effective reproduction number of 1·2 (with physical distancing only) will be reduced to 0·8 (95% CI 0·7-0·9) by adding contact tracing. The model also shows that a similar reduction can be achieved when testing and tracing coverage is reduced to 80% (RCTS 0·8, 95% CI 0·7-1·0). A testing delay of more than 1 day requires the tracing delay to be at most 1 day or tracing coverage to be at least 80% to keep RCTS below 1. With a testing delay of 3 days or longer, even the most efficient strategy cannot reach RCTS values below 1. The effect of minimising tracing delay (eg, with app-based technology) declines with decreasing coverage of app use, but app-based tracing alone remains more effective than conventional tracing alone even with 20% coverage, reducing the reproduction number by 17·6% compared with 2·5%. The proportion of onward transmissions per index case that can be prevented depends on testing and tracing delays, and given a 0-day tracing delay, ranges from up to 79·9% with a 0-day testing delay to 41·8% with a 3-day testing delay and 4·9% with a 7-day testing delay. INTERPRETATION: In our model, minimising testing delay had the largest impact on reducing onward transmissions. Optimising testing and tracing coverage and minimising tracing delays, for instance with app-based technology, further enhanced contact tracing effectiveness, with the potential to prevent up to 80% of all transmissions. Access to testing should therefore be optimised, and mobile app technology might reduce delays in the contact tracing process and optimise contact tracing coverage. FUNDING: ZonMw, Fundação para a Ciência e a Tecnologia, and EU Horizon 2020 RECOVER.