Identifying and alleviating bias due to differential depletion of susceptible people in post-marketing evaluations of COVID-19 vaccines

Kahn, R.; Schrag, S. J.; Verani, J. R.; Lipsitch, M.

Recent studies have provided key information about SARS-CoV-2 vaccines' efficacy and effectiveness (VE). One important question that remains is whether the protection conferred by vaccines wanes over time. However, estimates over time are subject to bias from differential depletion of susceptibles between vaccinated and unvaccinated groups. Here we examine the extent to which biases occur under different scenarios and assess whether serologic testing has the potential to correct this bias. By identifying non-vaccine antibodies, these tests could identify individuals with prior infection. We find that the main determinant of bias is the proportion of the population that has been infected since vaccination began, which is influenced by several factors. In scenarios with high baseline VE, differential depletion of susceptibles creates minimal bias in VE estimates. However, if VE is lower, the bias for leaky vaccines (that reduce individual probability of infection given contact) is larger and should be corrected if the mechanism is known to be leaky. Conducting analyses both unadjusted and adjusted for past infection could give lower and upper bounds for the true VE. Studies of VE should therefore enroll individuals regardless of prior infection history but also collect information, ideally through serologic testing, on this critical variable.