National Institute of Allergy and Infectious Diseases, Bethesda, Maryland (D.F., J.F., M.P.F., M.N.).
Fred Hutchinson Cancer Research Center, Seattle, Washington (H.E.J., L.N.C., M.J., D.D., Y.F., Y.H., Y.H., O.H., J.G.K.).
Ann Intern Med. 2021 Aug;174(8):1118-1125. doi: 10.7326/M20-8149. Epub 2021 Apr 13.
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.
多种候选疫苗已进入大规模 3 期安慰剂对照随机临床试验，其中几种已显示出显著的短期疗效。在显示出显著疗效后，安慰剂组应获得其临床试验中有效的疫苗，而此时还不知道疫苗的长期疗效和安全性。没有安慰剂组可能会影响对长期疫苗效果的评估。然而，通过继续对安慰剂组进行接种后的随访，本研究表明，通过假设随着时间的推移，疫苗接种的益处对于原始疫苗接种者和原始安慰剂接种者在接种后具有相同的特征，可以通过数学方法推导出安慰剂对照疫苗的疗效。虽然这种推导方法提供的估计值不如标准试验中未接种安慰剂组的估计值准确，但这种方法可以估计长期效果，包括疫苗效果的持久性以及疫苗最终是否对某些人有害。如果延迟接种是开放标签的，则可能会导致未设盲的原始疫苗组的风险行为增加，从而影响对长期疫苗疗效的估计。因此，通过盲法交叉设计延迟接种，即疫苗组接受安慰剂，反之亦然，是评估疫苗持久性和潜在延迟危害的首选方法。延迟接种使安慰剂组能够及时获得疫苗，因为不再适合让他们继续接受安慰剂，但仍能随着时间的推移对免疫和临床效果有重要的了解。
