Evaluating COVID-19 vaccine effectiveness across epidemiologic designs: test-negative case-control versus retrospective cohort analyses in a nationwide study.

BACKGROUND: Observational studies are central to assessing vaccine effectiveness and informing public health policy. The two most common designs are test-negative case-control and cohort studies, yet direct comparisons of their performance using the same population, data sources, and analytic strategies remain rare. This study compares these two designs within a national population using harmonized analytic approaches. METHODS: Nationwide, matched test-negative case-control and retrospective cohort studies were conducted in Qatar between 1 January 2021 and 18 December 2021 to assess the effectiveness of the coronavirus disease (COVID-19) primary series of BNT162b2 and mRNA-1273 against any severe acute respiratory syndrome coronavirus 2 infection, symptomatic infection, and severe COVID-19. RESULTS: In the test-negative design, BNT162b2 effectiveness was 71.0% [95% confidence interval (CI): 70.1-71.9] against any infection, 75.6% (95% CI: 74.2-77.0) against symptomatic infection, and 96.3% (95% CI: 95.2-97.2) against severe COVID-19. In the cohort design, after adjustment for testing rate, corresponding effectiveness was 78.0% (95% CI: 77.1-78.9), 81.2% (95% CI: 79.8-82.5), and 98.0% (95% CI: 96.6-98.8), respectively. Both designs demonstrated similar, rapid, and largely linear waning of effectiveness in both magnitude and pattern. Test-negative design estimates lay between cohort estimates with and without adjustment for testing rate. Similar results were observed for mRNA-1273. CONCLUSIONS: Both designs yielded consistent effectiveness estimates across vaccines and clinically relevant outcomes, with only modest differences related to handling of health-seeking behavior. These findings demonstrate that, when rigorously implemented using quality data and harmonized analytic strategies, both designs produce comparable effectiveness estimates.