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

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; effectiveness; mathematical model; reinfection; test-negative design.

Figure 1

Schematic diagrams of mathematical models used in this study. A) Classic susceptible-exposed-infectious-recovered (SEIR) model extended to allow for reinfections (baseline model). B) Baseline model extended to include vaccination (vaccination model). C) Baseline model extended to include waning in protection of prior infection against reinfection (waning-of-immunity model).

Figure 2

The 2-by-2 tables and equations used to estimate effectiveness of prior infection in preventing reinfection () using the test-negative, case–control study design. A) estimated in absence of bias. B) estimated in presence of misclassification of prior infection. C) estimated in presence of misclassification of latent infection. D) estimated in presence of misclassification of current active infection. E) estimated in presence of vaccination scale-up.

Figure 3

Simulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic through 2 epidemic waves. A) Daily number of new infections. B) Proportion of the population ever infected. C) Scale-up of vaccine coverage.

Figure 4

Estimated effectiveness of prior infection in preventing reinfection using the test-negative study design () compared with the true effectiveness of prior infection in preventing reinfection (). A) versus in presence of no waning of protection (baseline model). B) versus month by month after the prior infection in presence of gradual waning of protection against reinfection (waning-of-immunity model). This figure was generated using the instantaneous prevalence at each time point for each population.

Figure 5

Impact of bias in estimating effectiveness of prior infection in preventing reinfection using the test-negative study design (). A) Impact of misclassification of prior infection. B) Impact of misclassification of latent infection. C) Impact of misclassification of current active infection. D) Impact of scale-up of vaccination in the population. This figure was generated using the instantaneous prevalence at each time point for each population.

Figure 6

Flowchart describing the population selection process to estimate effectiveness of prior infection in preventing reinfection using the test-negative study design, using data from Qatar, March 8 to April 21, 2021. Individuals with a polymerase chain reaction (PCR)-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Alpha or Beta variant were exact matched on a 1:1 ratio by sex, 10-year age group, nationality, and PCR test calendar week to the first eligible PCR-negative individual. Prior infection records were retrieved for all matched individuals.