Evaluating Vaccine Efficacy Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Abstract

Although interim results from several large, placebo-controlled, phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic coronavirus disease 2019 (COVID-19), it is unknown how effective the vaccines are in preventing people from becoming asymptomatically infected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between 2 antibody or reverse-transcription polymerase chain reaction (RT-PCR) tests. Additional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment of participants or crossover of placebo recipients to the vaccine arm before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, staggered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies that mimic the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates.

Keywords: asymptomatic infection; seroconversion; symptomatic COVID-19; viral RNA; waning efficacy.

Figure 1.

Serum sampling schedules in 6 phase 3 coronavirus disease 2019 vaccine trials. The sampling time points are measured from the day of enrollment.

Figure 2.

Estimation of VE_a and VE_hin a clinical trial under blinded priority-dependent (B) and priority-independent (C) crossover and under unblinded priority-dependent (B’) and priority-independent (C’) crossover. The black curve pertains to the true value, the red curve pertains to the proposed estimate, and the green curves pertain to the 95% confidence intervals. Abbreviations: VEa, vaccine efficacy on attack rate; VEh, vaccine efficacy on hazard rate.