A Deferred-Vaccination Design to Assess Durability of COVID-19 Vaccine Effect After the Placebo Group Is Vaccinated

Abstract

Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.

Figure 1.. Schematic of a standard trial of vaccine versus placebo that pivots to a trial of immediate versus deferred vaccination using blinded crossover.

At some point after a positive primary efficacy signal, placebo group participants receive the vaccine and the vaccine group participants receive placebo. A balanced case split between study groups in period 2 supports maintenance of the period 1 vaccine efficacy. A key assumption is that vaccine efficacy for the newly vaccinated is the same whether at the start of period 1 or at the start of period 2. The tapering and fading blue wedge after vaccination indicates a potential waning of efficacy.

Figure 2.. Schematic of how deferred placebo vaccination allows imputation of the case counts for an inferred placebo group.

The vaccine efficacy in period 2 for the newly vaccinated (deferred vaccine group) is assumed to be the same 80% that was observed in the newly vaccinated (immediate vaccine group) in period 1. This logic implies that a counterfactual placebo group of 35 persons would have about 10 cases, because this satisfies 100%[1–(2/35)/(10/35)] = 80%. Thus the vaccine efficacy for the original vaccine group in period 2 has waned 55%, calculated as 100% [1–(5/39)/(10/35)]. The lighter blue shade of the immediate vaccine group participants in period 2 indicates waning immunity.