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.

• Authors: Dean Follmann, Jonathan Fintzi, Michael P Fay, Holly E Janes, Lindsey Baden, Hana El Sahly, Thomas R Fleming, Devan V Mehrotra, Lindsay N Carpp, Michal Juraska, David Benkeser, Deborah Donnell, Youyi Fong, Shu Han, Ian Hirsch, Ying Huang, Yunda Huang, Ollivier Hyrien, Alex Luedtke, Marco Carone, Martha Nason, An Vandebosch, Honghong Zhou, Iksung Cho, Erin Gabriel, James G Kublin, Myron S Cohen, Lawrence Corey, Peter B Gilbert, Kathleen M Neuzil
• Journal: medRxiv : the preprint server for health sciences (medRxiv) (Dec 14 2020) United States
• PMID: 33336213 (Publication Type: Preprint)