Test-negative Study Research Articles

Factors associated with testing positive for SARS-CoV-2 and evaluation of a recruitment protocol among healthcare personnel in a COVID-19 vaccine effectiveness study.

The objective of this study was to determine factors associated with testing positive for SARS-CoV-2 among healthcare personnel. Secondary objectives were to assess representativeness of recruited participants and the effectiveness of a multiple-contact protocol for recruiting healthcare personnel in this COVID-19 study. Survey study, conducted as part of an observational test-negative study of COVID-19 vaccine effectiveness. University of Utah Health system, including both inpatient and outpatient facilities. Clinical and non-clinical healthcare personnel at University of Utah Health. 1456 were contacted and 503 (34.5%) completed the survey. Cases were all eligible employees testing positive for COVID-19, with 3:1 randomly selected, matched controls (test negative) selected weekly. Online survey. Significant differences in the demographics of participants and the source population were observed; e.g., nursing staff comprised 31.6% of participants but only 23.3% of the source population. The multiple-contact recruitment protocol increased participation by ten percentage points and ensured equal representation of controls. Potential exposure to illness outside of work was strongly predictive of testing positive for SARS-CoV-2 (OR = 3.74; 95% CI: 2.29, 6.11) whereas potential exposure at work was protective against testing positive (OR: 0.51, 95% CI: 0.29, 0.88). Carefully designed recruitment protocols increase participation and representation of controls, but bias in participant demographics still exists. The negative association between potential workplace exposure and positive test suggests testing bias in the test-negative design. Healthcare personnel's potential exposures to COVID-19 outside of the workplace are important predictors of SARS-CoV-2 seropositivity.

Estimating protection afforded by prior infection in preventing reinfection: applying the test-negative study design.

The COVID-19 pandemic has highlighted the need to use infection testing databases to rapidly estimate effectiveness of prior infection in preventing reinfection ($P{E}_S$) by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Mathematical modeling was used to demonstrate a theoretical foundation for applicability of the test-negative, case-control study design to derive $P{E}_S$. Apart from the very early phase of an epidemic, the difference between the test-negative estimate for $P{E}_S$ and true value of $P{E}_S$ was minimal and became negligible as the epidemic progressed. The test-negative design provided robust estimation of $P{E}_S$ and its waning. Assuming that only 25% of prior infections are documented, misclassification of prior infection status underestimated $P{E}_S$, but the underestimate was considerable only when > 50% of the population was ever infected. Misclassification of latent infection, misclassification of current active infection, and scale-up of vaccination all resulted in negligible bias in estimated $P{E}_S$. The test-negative design was applied to national-level testing data in Qatar to estimate $P{E}_S$ for SARS-CoV-2. $P{E}_S$ against SARS-CoV-2 Alpha and Beta variants was estimated at 97.0% (95% CI, 93.6-98.6) and 85.5% (95% CI, 82.4-88.1), respectively. These estimates were validated using a cohort study design. The test-negative design offers a feasible, robust method to estimate protection from prior infection in preventing reinfection.

Effectiveness of Influenza Vaccination During Pregnancy Against Laboratory-Confirmed Seasonal Influenza Among Infants Under 6 Months of Age in Ontario, Canada.

Randomized trials conducted in low- and middle-income settings demonstrated efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age. However, vaccine effectiveness (VE) estimates from settings with different population characteristics and influenza seasonality remain limited. We conducted a test-negative study in Ontario, Canada. All influenza virus tests among infants <6 months from 2010 to 2019 were identified and linked with health databases to ascertain information on maternal-infant dyads. VE was estimated from the odds ratio for influenza vaccination during pregnancy among cases versus controls, computed using logistic regression with adjustment for potential confounders. Among 23 806 infants tested for influenza, 1783 (7.5%) were positive and 1708 (7.2%) were born to mothers vaccinated against influenza during pregnancy. VE against laboratory-confirmed infant influenza infection was 64% (95% confidence interval [CI], 50%-74%). VE was similar by trimester of vaccination (first/second, 66% [95% CI, 40%-80%]; third, 63% [95% CI, 46%-74%]), infant age at testing (0 to <2 months, 63% [95% CI, 46%-75%]; 2 to <6 months, 64% [95% CI, 36%-79%]), and gestational age at birth (≥37 weeks, 64% [95% CI, 50%-75%]; < 37 weeks, 61% [95% CI, 4%-86%]). VE against influenza hospitalization was 67% (95% CI, 50%-78%). Influenza vaccination during pregnancy offers effective protection to infants <6 months, for whom vaccines are not currently available.

Effectiveness of COVID-19 vaccines in Ecuador: A test-negative design

BackgroundThe COVID-19 pandemic poses a significant global health threat, characterized by high morbidity, severity, and the emergence of concerning variants. Latin America has been greatly affected, with high infection and mortality rates. Vaccination plays a crucial role in mitigating severe disease and controlling the pandemic. This study aims to assess the effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 severe acute respiratory infections (SARI) in hospitalized vaccination target groups in Ecuador. MethodsThis is a test-negative design study. We used data reported through sentinel surveillance of SARI between May 2021 and March 2022 in Ecuador. Patients with case criteria of SARI and hospitalized for a minimum of 24 hours were included in the study. Cases were defined as patients with SARI with a positive RT-qPCR test for SARS-CoV-2 and controls were those with a negative result. Information on vaccination status was obtained from the national vaccination registry, a valid dose of vaccination was considered when it was administered at least 14 days prior to symptom onset. Vaccine effectiveness (VE) (1-OR/OR) was calculated using a logistic regression. ResultsA total of 1,277 patients were included in the analysis of VE. The adjusted vaccine effectiveness (aVE) in preventing hospitalization, adjusted for sex, age group, presence of one or more comorbidities, and period of the predominance of the omicron variant, was 44.5% for the partial primary schedule, 74.7% for the complete primary schedule, and 79.9% for the complete primary schedule plus booster doses. The aVE in avoiding ICU admissions was close to 80% with both the complete primary schedule and the booster doses, and in avoiding deaths, the aVE was 89% and 98%, respectively. ConclusionsIn Ecuador, COVID-19 vaccination prevents hospitalizations, ICU admissions, and deaths. The effectiveness of the vaccines improves with more doses, offering increased protection across all age groups.

Estimation of waning vaccine effectiveness from population-level surveillance data in multi-variant epidemics

Monitoring time-varying vaccine effectiveness (e.g., due to waning of immunity and the emergence of novel variants) provides crucial information for outbreak control. Existing studies of time-varying vaccine effectiveness have used individual-level data, most importantly dates of vaccination and variant classification, which are often not available in a timely manner or from a wide range of population groups. We present a novel Bayesian framework for estimating the waning of variant-specific vaccine effectiveness in the presence of multi-variant circulation from population-level surveillance data. Applications to simulated outbreaks and the COVID-19 epidemic in Japan are also presented. Our results show that variant-specific waning vaccine effectiveness estimated from population-level surveillance data could approximately reproduce the estimates from previous test-negative design studies, allowing for rapid, if crude, assessment of the epidemic situation before fine-scale studies are made available.

Effectiveness of Immunization Products Against Medically Attended Respiratory Syncytial Virus Infection: Generic Protocol for a Test-Negative Case-Control Study.

Monitoring the real-life effectiveness of respiratory syncytial virus (RSV) products is of major public health importance. This generic protocol for a test-negative design study aims to address currently envisioned approaches for RSV prevention (monoclonal antibodies and vaccines) to study effectiveness of these products among target groups: children, older adults, and pregnant women. The generic protocol approach was chosen to allow for flexibility in adapting the protocol to a specific setting. This protocol includes severe acute respiratory infection (SARI) and acute respiratory infection (ARI), both due to RSV, as end points. These end points can be applied to studies in hospitals, primarily targeting patients with more severe disease, but also to studies in general practitioner clinics targeting ARI.

Effectiveness of BNT162b2 BA.4/5 Bivalent mRNA Vaccine Against Symptomatic COVID-19 Among Immunocompetent Individuals Testing at a Large US Retail Pharmacy.

Data on the effectiveness of BA.4/5 bivalent vaccine stratified by age and prior infection are lacking. This test-negative study used data from individuals ≥5 years of age testing for SARS-CoV-2 with symptoms (15 September 2022 to 31 January 2023) at a large national retail pharmacy chain. The exposure was receipt of 2-4 wild-type doses and a BNT162b2 BA.4/5 bivalent vaccine (>2 months since last wild-type dose). The outcome was a positive SARS-CoV-2 test. Absolute (vs unvaccinated) and relative (vs 2-4 wild-type doses) vaccine effectiveness (VE) were calculated as (1 - adjusted odds ratio from logistic regression) × 100. VE was stratified by age and self-reported prior infection. Overall, 307 885 SARS-CoV-2 tests were included (7916 aged 5-11, 16 329 aged 12-17, and 283 640 aged ≥18 years). SARS-CoV-2 positivity was 39%; 21% were unvaccinated, 70% received 2-4 wild-type doses with no bivalent vaccine, and 9% received a BNT162b2 BA.4/5 bivalent dose. At a median of 1-2 months after BNT162b2 BA.4/5 bivalent vaccination, depending on age group, absolute VE was 22%-60% and was significantly higher among those reporting prior infection (range, 55%-79%) than not (range, no protection to 50%). Relative VE was 31%-64%. BNT162b2 BA.4/5 bivalent showed early additional protection against Omicron-related symptomatic COVID-19, with hybrid immunity offering greater protection.

Assessing the real-world effectiveness of five SARS-CoV-2 vaccines in a cohort of Mexican pensioners: a nationwide nested test-negative design study

Despite the extensive distribution of COVID-19 vaccines across Latin America, research on their real-world performance remains limited. We aimed to evaluate the effectiveness of five vaccines (BNT162b2, AZD1222, CoronaVac, Gam-COVID-Vac, and Ad5-nCoV) in a cohort of 2,559,792 pensioners covered by the Mexican Institute of Social Security. We conducted a nested test-negative design study on 28,271 individuals tested for SARS-CoV-2 infection between April and November 2021, accounting for 29,226 separate episodes. We used mixed-effects logistic regression models to estimate the vaccine effectiveness (VE) in fully vaccinated individuals for symptomatic infection, hospitalization, severe disease, and death. The median age of the study population was 70 years (interquartile range 65-76) and 76.4% (21,598/28,271) were male. VE rates were 56.3%, 75.3%, 79.7%, and 79.8% against symptomatic infection (95% confidence interval [CI]: 53.5-59.0), hospitalization (95% CI: 73.4-77.0), severe disease (95% CI: 78.0-81.3), and death (95% CI: 78.1-81.4), respectively. When evaluating vaccines individually, all showed moderate to high VE, with the best being BNT162b2 (symptomatic infection, 69.8%, 95% CI: 67.3-72.0; hospitalization, 84.1%, 95% CI: 82.5-85.6; severe disease, 88.2%, 95% CI: 86.7-89.5; and death, 88.3%, 95% CI: 86.9-89.6) and Gam-COVID-Vac (symptomatic infection, 70.0%, 95% CI: 64.8-74.4; hospitalization, 86.8%, 95% CI: 83.7-89.3; severe disease, 91.9%, 95% CI: 89.4-93.9; and death, 92.0%, 95% CI: 89.5-93.9). All five SARS-CoV-2 vaccines available for this population showed moderate to high levels of protection against COVID-19 and its progression to severe outcomes. Fundación IMSS, México.

Influenza Vaccine Effectiveness Against Influenza-Associated Hospitalization in Hong Kong Children Aged 9 Months to 17 Years, March-June 2023.

In March-June 2023, we conducted a test-negative study in 1671 children who were hospitalized with acute respiratory illness in Hong Kong. Two hundred and eighty-six children (17.2%) were tested positive for influenza virus including 188 with A(H1N1). We estimated influenza vaccine effectiveness against influenza-associated hospitalization as 69.6% (95% confidence interval: 49.3%, 81.7%).

The role of occupation in SARS-CoV-2 infection within a Brazilian municipality: A test-negative case-control study.

To investigate the association between occupation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections within a Brazilian municipality. In this test-negative study, cases and controls were randomly selected among individuals aged 18-65 years that were registered in a primary health care program in São Caetano do Sul, Brazil. Those who had collected samples for RT-PCR testing between April 2020 and May 2021 were randomly selected to compose the case (positive for SARS-CoV-2) and control (negative for SARS-CoV-2) groups, frequency-matched by sex, age group, and month of sample collection. Complementary data were collected through phone interviews. We estimated the residual effect of occupation on SARS-CoV-2 infection using multiple conditional logistic regression models incrementally adjusted for confounding variables. 1724 cases and 1741 controls who reported being at work at the time of RT-PCR collection were included. Cases were mainly females (52.9%), Whites/Asians (73.3%), and unvaccinated against COVID-19 (46.6%). Compared to other university-level professionals, the highest odds of having COVID-19 were found for workers in police and protective services (odds ratio [OR] 2.21; 95% confidence interval [CI] 1.27-3.84), healthcare and caregiving (OR 1.90; 95% CI 1.34-2.68), and food retail and production (OR 1.88; 95% CI = 1.14-3.11), after adjustment for age, sex, education, means of transport, household crowding, and COVID-19 vaccination. Occupation played an important role in SARS-CoV-2 infection. Food retail and production, health care and caregiving, and police and protective services showed the highest odds of SARS-CoV-2 infection.

COVID-19 vaccine effectiveness in children by age groups. Apopulation-based study in Galicia, Spain.

Studies on vaccine effectiveness (VE) against COVID-19 in the pediatric population are outgoing. We aimed to quantify VE against SARS-CoV-2 in two pediatric age groups, 5-11 and 12-17-year-old, while considering vaccine type, SARS-CoV-2 variant, and duration of protection. A population-based test-negative control study was undertaken in Galicia, Spain. Children 5-11-year-old received the Comirnaty® (Pfizer, US) vaccine, while those aged 12-17-year-old received the Comirnaty® (Pfizer, US) or SpikeVax® (ModernaTX, Inc) vaccine. Participants were categorized into unvaccinated (0 doses or one dose with <14 days since vaccination), partially vaccinated (only one dose with ≥14 days, or two doses with <14 days after the second dose administration), and fully vaccinated (two doses with ≥14 days after the second injection). Adjusted odds ratios (OR) and their 95% confidence intervals (CI) were estimated using multiple logistic regression models. VE was calculated as (1-OR) * 100. Stratified and sensitivity analyses were performed. In the fully vaccinated 5-11-year-old children, VE against the Omicron variant was 44.1% (95% CI: 38.2%-49.4%). In the fully vaccinated 12-17-year-old individuals, VE was 83.4% (95% CI: 81.2%-85.3%) against Delta and 74.8% (95% CI: 58.5%-84.9%) against Omicron. Comirnaty® and SpikeVax® vaccines showed a similar magnitude of VE against Delta [Comirnaty® VE: 81.9% (95% CI: 79.3%-84.1%) and SpikeVax® VE: 85.3% (95% CI: 81.9%-88.1%)]. Comirnaty® (Pfizer, US; VE: 79.7%; 95% CI: 50.7%-92.4%) showed a slightly higher magnitude of protection against Omicron than SpikeVax® (ModernaTX, Inc), yet with an overlapping CI (VE: 74.3%; 95% CI: 56.6%-84.9%). VE was maintained in all age subgroups in both pediatric populations, but it declined over time. In Galicia, mRNA VE was moderate against SARS-CoV-2 infections in the 5-11-year-old populations, but high in older children. VE declined over time, suggesting a potential need for booster dose schedules.

COVID-19 vaccine effectiveness by HIV status and history of injection drug use: a test-negative analysis.

People living with HIV (PLWH) and/or who inject drugs may experience lower vaccine effectiveness (VE) against SARS-CoV-2 infection. A validated algorithm was applied to population-based, linked administrative datasets in the British Columbia COVID-19 Cohort (BCC19C) to ascertain HIV status and create a population of PLWH and matched HIV-negative individuals. The study population was limited to individuals who received an RT-PCR laboratory test for SARS-CoV-2 between 15 December 2020 and 21 November 2021 in BC, Canada. Any history of injection drug use (IDU) was ascertained using a validated administrative algorithm. We used a test-negative study design (modified case-control analysis) and multivariable logistic regression to estimate adjusted VE by HIV status and history of IDU. Our analysis included 2700 PLWH and a matched population of 375,043 HIV-negative individuals, among whom there were 351 and 103,049 SARS-CoV-2 cases, respectively. The proportion of people with IDU history was much higher among PLWH compared to HIV-negative individuals (40.7% vs. 4.3%). Overall VE during the first 6 months after second dose was lower among PLWH with IDU history (65.8%, 95% CI = 43.5-79.3) than PLWH with no IDU history (80.3%, 95% CI = 62.7-89.6), and VE was particularly low at 4-6 months (42.4%, 95% CI = -17.8 to 71.8 with IDU history vs. 64.0%; 95% CI = 15.7-84.7 without), although confidence intervals were wide. In contrast, overall VE was 88.6% (95% CI = 88.2-89.0) in the matched HIV-negative population with no history of IDU and remained relatively high at 4-6 months after second dose (84.6%, 95% CI = 83.8-85.4). Despite different patterns of vaccine protection by HIV status and IDU history, peak estimates were similar (≥88%) across all populations. PLWH with a history of IDU may experience lower VE against COVID-19 infection, although findings were limited by a small sample size. The lower VE at 4-6 months may have implications for booster dose prioritization for PLWH and people who inject drugs. The immunocompromising effect of HIV, substance use and/or co-occurring comorbidities may partly explain these findings.

Vaccine Effectiveness of non-adjuvanted and adjuvanted trivalent inactivated influenza vaccines in the prevention of influenza-related hospitalization in older adults: A pooled analysis from the Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN)

BackgroundInfluenza vaccines prevent influenza-related morbidity and mortality; however, suboptimal vaccine effectiveness (VE) of non-adjuvanted trivalent inactivated influenza vaccine (naTIV) or quadrivalent formulations in older adults prompted the use of enhanced products such as adjuvanted TIV (aTIV). Here, the VE of aTIV is compared to naTIV for preventing influenza-associated hospitalization among older adults. MethodsA test-negative design study was used with pooled data from the 2012 to 2015 influenza seasons. An inverse probability of treatment (IPT)-weighted logistic regression estimated the Odds Ratio (OR) for laboratory-confirmed influenza-associated hospitalization. VE was calculated as (1-OR)*100% with accompanying 95% confidence intervals (CI). ResultsOf 7,101 adults aged ≥ 65, 3,364 received naTIV and 526 received aTIV. The overall VE against influenza hospitalization was 45.9% (95% CI: 40.2%–51.1%) for naTIV and 53.5% (42.8%–62.3%) for aTIV. No statistically significant differences in VE were found between aTIV and naTIV by age group or influenza season, though a trend favoring aTIV over naTIV was noted. Frailty may have impacted VE in aTIV recipients compared to those receiving naTIV, according to an exploratory analysis; VE adjusted by frailty was 59.1% (49.6%–66.8%) for aTIV and 44.8% (39.1%–50.0%) for naTIV. The overall relative VE of aTIV to naTIV against laboratory-confirmed influenza hospital admission was 25% (OR 0.75; 0.61–0.92), demonstrating statistically significant benefit favoring aTIV. ConclusionsAdjusting for frailty, aTIV showed statistically significantly better protection than naTIV against influenza-associated hospitalizations in older adults. In future studies, it is important to consider frailty as a significant confounder of VE.

Influenza Vaccine Effectiveness against Hospitalization, Season 2021/22: A Test-Negative Design Study in Barcelona.

Vaccination is considered the most effective measure for preventing influenza and its complications. The influenza vaccine effectiveness (IVE) varies annually due to the evolution of influenza viruses and the update of vaccine composition. Assessing the IVE is crucial to facilitate decision making in public health policies. to estimate the IVE against hospitalization and its determinants in the 2021/22 season in a Spanish tertiary hospital. We conducted a prospective observational test-negative design study within the Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project. Hospitalized patients with severe acute respiratory infection (SARI) and an available influenza reverse transcription polymerase chain reaction (RT-PCR) were selected and classified as cases (positive influenza RT-PCR) or controls (negative influenza RT-PCR). Vaccine information was obtained from electronic clinical records shared by public healthcare providers. Information about potential confounders was obtained from hospital clinical registries. The IVE was calculated by subtracting the ratio of the odds of vaccination in cases and controls from one, as a percentage (IVE = (1 - odds ratio (OR)) × 100). Multivariate IVE estimates were calculated using logistic regression. In total, 260 severe acute respiratory infections (SARI) were identified, of which 34 were positive for influenza, and all were subtype A(H3N2). Fifty-three percent were vaccinated. Adjusted IVE against hospitalization was 26.4% (95% CI -69% to 112%). IVE determinants could not be explored due to sample size limitations. Our data revealed non-significant moderate vaccine effectiveness against hospitalization for the 2021/2022 season.

Effectiveness of Mix-and-Match Vaccination in Preventing SARS-CoV-2 Omicron Variant Infection in Taiwan: A Test-Negative Control Study.

This study aimed to evaluate the effectiveness (VE) of mix-and-match vaccination against SARS-CoV-2 Omicron variant infection and severe outcomes. An SARS-CoV-2 PCR-confirmed retrospective cohort from Chang Gung Medical System in Taiwan was constructed. Vaccination records were tracked from the National Immunization Information System and categorized by different regimens or unvaccinated status. The main outcomes are VE against PCR-confirmed infection and COVID-19-associated moderate to severe disease. Participants were observed during the Omicron wave from March to August 2022. Of 298,737 PCR testing results available, 162,219 were eligible for analysis. VE against infection was modest, ranging from 38.3% to 49.0%, while mRNA-based vaccine regimens revealed better protection against moderate to severe disease, ranging from 80.8% to 90.3%. Subgroup analysis revealed lower VE among persons with major illness in preventing moderate to severe disease. For young adults, the VE of protein-based vaccine regimens showed a comparable protection with other mixed vaccine regimens. The mix-and-match vaccination strategy provided modest clinical effectiveness in preventing Omicron variant infection. mRNA vaccine-based regimens were superior to other regimens against moderate to severe disease especially in older adults. The mix-and-match vaccination strategy could be an alternative to prevent COVID-19 in unstable vaccine supply regions.

The need for a clinical case definition in test-negative design studies estimating vaccine effectiveness

Test negative studies have been used extensively for the estimation of COVID-19 vaccine effectiveness (VE). Such studies are able to estimate VE against medically-attended illness under certain assumptions. Selection bias may be present if the probability of participation is associated with vaccination or COVID-19, but this can be mitigated through use of a clinical case definition to screen patients for eligibility, which increases the likelihood that cases and non-cases come from the same source population. We examined the extent to which this type of bias could harm COVID-19 VE through systematic review and simulation. A systematic review of test-negative studies was re-analysed to identify studies ignoring the need for clinical criteria. Studies using a clinical case definition had a lower pooled VE estimate compared with studies that did not. Simulations varied the probability of selection by case and vaccination status. Positive bias away from the null (i.e., inflated VE consistent with the systematic review) was observed when there was a higher proportion of healthy, vaccinated non-cases, which may occur if a dataset contains many results from asymptomatic screening in settings where vaccination coverage is high. We provide an html tool for researchers to explore site-specific sources of selection bias in their own studies. We recommend all groups consider the potential for selection bias in their vaccine effectiveness studies, particularly when using administrative data.

BNT162b2 mRNA COVID-19 against symptomatic Omicron infection following a mass vaccination campaign in southern Brazil: A prospective test-negative design study

BackgroundEvidence regarding effectiveness of BNT162b2 mRNA COVID-19 vaccine against Omicron in Latin America is limited. We estimated BNT162b2 effectiveness against symptomatic COVID-19 in Brazil when Omicron was predominant. MethodsThis prospective test-negative, case-control study was conducted in Toledo, Brazil, following a mass COVID-19 vaccination with BNT162b2. Patients were included if they were aged ≥12 years, sought care for acute respiratory symptoms in the public health system between November 3, 2021 and June 20, 2022, and were tested for SARS-CoV-2 using RT-PCR. In the primary analysis, we determined the effectiveness of two doses of BNT162b2 against symptomatic COVID-19. ResultsA total of 4,574 were enrolled; of these, 1,758 patients (586 cases and 1,172 controls) were included in the primary analysis. Mean age was 27.7 years, 53.8 % were women, and 90.1 % had a Charlson comorbidity index of zero. Omicron accounted for >97 % of all identified SARS-CoV-2 variants, with BA.1 and BA.2 accounting for 84.3 % and 12.6 %, respectively. Overall adjusted estimate of two-dose vaccine effectiveness against symptomatic COVID-19 was 46.7 % (95 %CI, 19.9 %–64.6 %) after a median time between the second dose and the beginning of COVID-19 symptoms of 94 days (IQR, 60–139 days). Effectiveness waned from 77.7 % at 7–29 days after receipt of a second dose to <30 % (non-significant) after ≥120 days. ConclusionIn a relatively young and healthy Brazilian population, two doses of BNT162b2 provided protection against symptomatic Omicron infection. However, this protection waned significantly over time, underscoring the need for boosting with variant-adapted vaccines in this population prior to waves of disease activity.Trial registration number:ClinicalTrials.gov number, NCT05052307 (https://clinicaltrials.gov/ct2/show/NCT05052307).

Effectiveness of COVID-19 vaccines against infection in Japan: A test-negative study from the VENUS study

BackgroundAlthough the effectiveness of coronavirus disease 2019 (COVID-19) vaccines is a crucial public health concern, evidence from Western Pacific countries is limited, including Japan. This study aimed to estimate the COVID-19 vaccines effectiveness (VE) against infection during the Delta variant predominance (July–September 2021) in Japan. MethodsWe performed a test-negative study using COVID-19 test data of ≥20-year-old residents in four municipalities who were tested in medical institutions between July 1 and September 30, 2021. We extracted COVID-19 test data from healthcare claims data, and the vaccination status at the testing date was ascertained using the Vaccination Record System data. Confirmed positive cases were identified using data from the national system for COVID-19, Health Center Real-time Information-sharing System on COVID-19. Logistic regression analyses were conducted to estimate the odds of testing positive according to vaccination status. VE was calculated as (1 − odds ratio) × 100%. ResultsThis study included 530 positive and 15,650 negative results. Adjusted manufacturer-unspecified VE was 4.1% (95% confidence interval [CI], −36.5–32.6) at 0–13 days after the first dose, 45.2% (95% CI, 13.4–65.3) at ≥14 days after the first dose, 85.2% (95% CI, 69.9–92.7) at 0–13 days after the second dose, and 79.6% (95% CI, 72.6–84.8) at ≥14 days after the second dose. In addition, the VE after the second dose was highest at 14–34 days after the dose (VE, 89.1%; 95% CI, 80.5–93.9). ConclusionsHigh real-world effectiveness of COVID-19 vaccines, especially two doses, against infection during the Delta variant predominance in Japan was confirmed.

Identifiability of causal effects in test-negative design studies.

Causal directed acyclic graphs (DAGs) are often used to select variables in a regression model to identify causal effects. Outcome-based sampling studies, such as the 'test-negative design' used to assess vaccine effectiveness, present unique challenges that are not addressed by the common back-door criterion. Here we discuss intuitive, graphical approaches to explain why the common back-door criterion cannot be used for identification of population average causal effects with outcome-based sampling studies. We also describe graphical rules that can be used instead in outcome-based sampling studies when the objective is limited to determining if the causal odds ratio is identifiable, and illustrate recent changes to the free online software Dagitty which incorporate these principles.

The test-negative design: Opportunities, limitations and biases.

The purpose of this paper is to investigate how to interpret the outcome of a test-negative design study. We does so by systematically reviewing the properties of the design in relation to its potential applications. We first argue that the application of the design does not depend on certain assumptions (as is sometimes articulated in the literature), which may open new opportunities for using the design. Then, we relate a number of limitations of the design. The design cannot be used for studying the mortality effects of vaccines and is problematic for studies into the effect on hospitalization. The vaccine's effectiveness on the transmission of viruses is also potentially problematic, depending very much on the characteristics of the tests. The implication of our findings is that the test-negative designs can, at best, be seen as an indication of effectiveness in highly idealized situations that are often far away from reality.