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Licenced doses of approved COVID-19 vaccines may not be optimal: A review of the early-phase, dose-finding trials

Dunn, David T; Gilson, Richard; McCormack, Sheena; McCoy, Laura E; (2023) Licenced doses of approved COVID-19 vaccines may not be optimal: A review of the early-phase, dose-finding trials. Vaccine 10.1016/j.vaccine.2023.06.037. (In press). Green open access

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Abstract

Although over 13 billion COVID-19 vaccine doses have been administered globally, the issue of whether the optimal doses are being used has received little attention. 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, extracting information on study design and findings on reactogenicity and early humoral immune response. The number of different doses evaluated for each 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 highest 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 - although this is not a criticism of the study investigators, who were working under intense time pressures at the start of the epidemic. It is therefore open to question whether the single dose taken into clinical efficacy trials, and subsequently authorised by regulatory agencies, was optimal. In particular, our analysis indicates that 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 also merits study. We conclude by suggesting improvements in the design of future vaccine trials, for both next-generation COVID-19 vaccines and for vaccines against other pathogens.

Type: Article
Title: Licenced doses of approved COVID-19 vaccines may not be optimal: A review of the early-phase, dose-finding trials
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.vaccine.2023.06.037
Publisher version: https://doi.org/10.1016/j.vaccine.2023.06.037
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Clinical trials, COVID-19, Early-phase
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10172877
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