ABSTRACTAlthough over 12 billion COVID-19 vaccine doses have been administered globally, the important issue of whether the optimal doses are being used has been relatively neglected. To address this question, we reviewed the reports of early-phase dose-finding trials of the nine COVID-19 vaccines approved by World Health Organization (and one additional vaccine which showed partial clinical efficacy), extracting information on study design and findings on reactogenicity and early humoral

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... response. The number of different doses evaluated per vaccine varied widely (range 1-7), as did the number of subjects studied per dose (range 15-190). As expected, the frequency and severity of adverse reactions generally increased at higher doses, although most were clinically tolerable. Higher doses also tended to elicit better immune responses, but differences between the maximum dose and the second-highest dose evaluated were small, typically less than 1.6-fold for both binding antibody concentration and neutralising antibody titre. All of the trials had at least one important design limitation: few doses evaluated, large gaps between adjacent doses, or an inadequate sample size. In general, it is therefore uncertain whether the single dose taken into clinical efficacy trials, and subsequently authorised by regulatory agencies, was optimal. In particular, the recommended doses for some vaccines appear to be unnecessarily high. Although reduced dosing for booster injections is an active area of research, the priming dose is equally deserving of study. We conclude by suggesting some ways in which the design of future trials of candidate COVID-19 vaccines could be improved.