Safety and immunogenicity of a reduced dose of the BNT162b2 mRNA COVID-19 vaccine (REDU-VAC): a single blind, randomized, non-inferiority trial

Abstract

Background The use of fractional dose regimens of COVID-19 vaccines has the potential to accelerate vaccination rates in low-income countries. Dose-finding studies of the mRNA vaccine BNT162b2 (Pfizer-BioNTech) have suggested that a fractional dose induces comparable antibody responses to the full, licensed dose in people below 55 years old. Here, we report the safety and immunogenicity of a fractional dose regimen of the BNT162b2 vaccine. Methods REDU-VAC is a participant-blinded, randomised, phase 4, multicentre, non-inferiority study investigating safety, reactogenicity and immunogenicity of BNT162b2. Adults aged between 18 and 55 years, without uncontrolled co-morbidities, either previously infected or infection naive, were eligible and recruited at five sites across Belgium. Participants were randomly assigned to receive 20ug/20ug (fractional dose) or 30ug/30ug (full dose) of BNT162b2, administered intra-muscularly at a three-week interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-RBD IgG titres at 28 days post second dose between the reduced and the full dose regimens. The reduced dose was considered non-inferior to the full dose if the lower limit of the two-sided 95% CI of the GMR was greater than 0.67. The primary analysis was done on the per-protocol population, including infection naive participants only. Findings Between April 19 and April 23, 2021, 145 participants were enrolled in the study and randomized, of whom 141 were vaccinated and reached the primary endpoint. Participants were mostly female (69.5%), of European origin (95%), with a mean age of 40.4 years (SD 7.9). At 28 days post second dose, the geometric mean titre (GMT) of SARS-CoV-2 anti-RBD IgG of the reduced dose regimen (1,705 BAU/mL) was not non-inferior to the full dose regimen (2,387 BAU/mL), with a GMR of 0.714 (two-sided 95% CI 0.540-0.944). No serious adverse events occurred. Conclusions While non-inferiority of the reduced dose regimen was not demonstrated, the SARS-CoV-2 anti-RBD IgG titre was only moderately lower than that of the full dose regimen and, importantly, still markedly higher than the reported antibody response to the licensed adenoviral vector vaccines. These data suggest that reduced doses of the BNT162b2 mRNA vaccine may offer additional benefit as compared to the vaccines currently in use in most low and middle-income countries, warranting larger immunogenicity and effectiveness trials. The trial is registered at ClinicalTrials.gov (NCT04852861).