Dose of approved COVID-19 vaccines is based on weak evidence: a review of early-phase, dose-finding trials (preprint)

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.

Safety and Immunogenicity of a Self-Amplifying RNA Vaccine Against COVID-19: COVAC1, a Phase I, Dose-Ranging Trial (preprint)

Summary: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0·1-10·0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays.Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0·001), ranging from 8% to 61% in ELISA and 46% to 87% in the immunoblot assay.Concurrent anti-S IgG ranged from GM concentration (95% CI) 74 (45-119) at 0·1mg to 1023 (468-2236) ng/ml at 5·0mg (p<0·001) and was not higher at 10·0mg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15-48% depending on dose level received.Interpretation: Encapsulated saRNA is safe for clinical development and is immunogenic at low dose levels. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.Trial Registration: (ISRCTN17072692, EudraCT 2020-001646-20)Funding Statement: Medical Research Council UKRI (MC_PC_19076 and MC_UU_12023/23), National Institute for Health Research, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust.Declaration of Interests: P.F.M. and R.J.S. are co-inventors on a patent application covering this SARS-CoV-2 saRNA vaccine. All other authors have nothing to declare. Ethics Approval Statement: This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency and the North East - York Research Ethics Committee (reference 20/SC/0145).