Test-Negative Study Designs for Evaluating Vaccine Effectiveness

INTRODUCTION

This JAMA Guide to Statistics and Methods article explains the test-negative study design, an observational study design routinely used to estimate vaccine effectiveness, and examines its use in a study that estimated the performance of messenger RNA boosters against the Omicron variant.

The evaluation of vaccines continues long after initial regulatory approval. Postapproval observational studies are often used to investigate aspects of vaccine effectiveness (VE) that clinical trials cannot feasibly assess. These includes long-term effectiveness, effectiveness within subgroups, effectiveness against rare outcomes, and effectiveness as the circulating pathogen changes.¹ Policymakers rely on these data to guide vaccine recommendations or formulation updates.²

The test-negative design, also known as the test-negative case-control study, is an observational study design routinely used to estimate VE against influenza, rotavirus, and COVID-19.^3,4 In one example, Accorsi et al⁵ leveraged data from a national COVID-19 testing program to provide timely estimates of the performance of messenger RNA (mRNA) boosters against the Omicron variant.

WHAT IS A TEST-NEGATIVE DESIGN?

In a test-negative design, the study population consists of people tested for the disease of interest, typically because they exhibit specific symptoms (Figure 1). Those with positive diagnostic test results are test-positive cases. Test-negative controls meet the criteria for testing but have negative diagnostic test results.⁶ Thus, their symptoms are due to a cause that the vaccine does not target. Test-negative designs can be prospective, in which eligible participants are recruited at the time of the test, allowing additional individual-level information to be collected. Test-negative designs can also be retrospective, in which existing testing data are repurposed, restricting to individuals meeting eligibility criteria (eg, ≥1 self-reported COVID-like symptoms).

Cases and controls are then compared with respect to their vaccination history, which can be ascertained from medical records, immunization registries, or by self-report. Similar to a case-control study, the odds ratio (OR) comparing vaccination status between cases and controls captures whether vaccinated individuals are less likely to be cases. When the vaccine is effective, vaccinated persons are underrepresented among the test-positive cases ...