Background There is considerable interest in using reduced doses of COVID-19 vaccines when given as booster injections. However, the question of whether the dose used in the primary vaccine series is optimal has been ignored. Methods We reviewed the early-phase dose-finding trials of the eight COVID-19 vaccines approved by World Health Organization, and one additional vaccine which showed partial clinical efficacy. We extracted information on study design and findings on reactogenicity and early humoral immune response. Results The number of doses evaluated per vaccine varied widely: single dose (n=1), two doses (n=4), three doses (n=3), seven doses (n=1), as did the number of subjects studied per dose (range 15-190). The frequency and severity of adverse reactions generally increased at higher doses, although only the highest dose of one vaccine resulted in clinically unacceptable reactogenicity. Immune response also tended to improve at higher doses; however, differences between the maximum dose and the second-highest dose were small, typically less than 1.6-fold for both binding antibody concentration and neutralising antibody titre. Conclusions All of the reviewed early-phase dose-finding trials had at least one major design limitation: too few concentrations evaluated, large gaps between adjacent concentrations, or an inadequate sample size. Thus, there is no certainty that the dose taken into clinical efficacy trials, and subsequently authorised by regulatory agencies, was optimal. Studies of reduced doses are required for the primary vaccines series as well as booster injections. This could stretch the global COVID-19 vaccine supply and help to reduce the global inequity of access to vaccination.Competing Interest Statement
The authors have declared no competing interest.Funding Statement
UK Medical Research Council: salary supportAuthor Declarations
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