• Dean Follmann, Jonathan Fintzi, Michael P Fay, Holly E Janes, Lindsey R Baden, Hana M 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, and Kathleen M Neuzil.
• National Institute of Allergy and Infectious Diseases, Bethesda, Maryland (D.F., J.F., M.P.F., M.N.).
• Ann. Intern. Med. 2021 Aug 1; 174 (8): 111811251118-1125.

AbstractMultiple 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.

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