Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials

Abstract

Background: Several candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known.

Methods: Following vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the benefit of vaccination over time has the same profile for the original vaccine recipients and the placebo crossovers. This reconstruction allows estimation of both vaccine durability and potential vaccine-associated enhanced disease.

Results: Post-crossover estimates of vaccine efficacy can provide insights about durability, identify waning efficacy, and identify late enhancement of disease, but are less reliable estimates than those obtained by a standard trial where the placebo cohort is maintained. As vaccine efficacy estimates for post-crossover periods depend on prior vaccine efficacy estimates, longer pre-crossover periods with higher case counts provide better estimates of late vaccine efficacy. Further, open-label crossover may lead to riskier behavior in the immediate crossover period for the unblinded vaccine arm, confounding vaccine efficacy estimates for all post-crossover periods.

Conclusions: We advocate blinded crossover and continued follow-up of trial participants to best assess vaccine durability and potential delayed enhancement of disease. This approach allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain participants on placebo, yet still allows important insights about immunological and clinical effectiveness over time.

Figure 1.

Schematic of a standard trial of vaccine vs placebo that pivots to a blinded crossover trial of immediate vs deferred vaccination. The tapering and fading blue wedge following vaccination evokes a potential waning of efficacy. At some point following a positive primary efficacy signal, placebo volunteers receive the vaccine and vaccine volunteers receive placebo. A balanced case split between arms 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.

Figure 2.

Schematic of how crossover allows imputation of the case counts for an inferred placebo group. Following crossover, we assume the vaccine efficacy in Period 2 for the newly vaccinated (Deferred Vaccine Arm) is the same 80% that was observed in the newly vaccinated (Immediate Vaccine Arm) in Period 1. This logic implies that a counterfactual placebo group of 20 volunteers would have about 5 cases. Thus the vaccine efficacy for the original vaccine arm in Period 2 has waned to 100% (1 – 3/5) = 60%.

Figure 3.

Following crossover, the period-specific vaccine efficacy estimates depend on all previous periods. A period with few cases makes subsequent efficacy estimates unstable but paradoxically does not preclude evaluation of subsequent waning efficacy. A bigger and stronger chain is achieved with a long first (and thus subsequent) period and more cases within each period.