Immunogenicity and reactogenicity of fractional vs. full booster doses of COVID-19 vaccines: a non-inferiority, randomised, double-blind, phase IV clinical trial in Brazil.

Background: Fractional doses of vaccine to protect against COVID-19 offer the potential to expand vaccine availability, reduce side effects, and enhance vaccination campaign efficiency. This study aimed to assess the immune response and safety of fractional doses of SARS-CoV-2 booster vaccines compared to full doses in immunocompetent adults aged 18-60 who had previously received a full series of Sinovac, AZD1222 (AstraZeneca), or BNT162b2 (Pfizer/BioNTech). Methods: This trial was structured as a parallel-group, double-blind, randomised Phase IV non-inferiority study, carried out in Campo Grande, Midwest, Brazil. After obtaining consent, eligible participants were randomised to one of 5-6 study arms, depending on their priming vaccine. Participants were followed for 21-60 days after vaccination through in-person visits and remote contact for blood collection and safety evaluation. Anti-spike binding IgG antibodies were measured by ELISA. The primary outcome was the difference in seroresponse rates between the full and fractional doses, with a non-inferiority threshold of 10%. Findings: A total of 1451 participants were randomised and administered booster vaccines between 5 July and 3 October, 2022. A half dose of BNT162b2 met the non-inferiority threshold, compared to a full dose in the Sinovac and AZD1222 primed groups. Sinovac induced an inferior response compared to AZD1222 and BNT162b2 full or fractional dose boosters in participants primed with Sinovac. Fractional booster doses of BNT162b2 consistently resulted in higher seroresponse rates (ranging from 35.4% to 78.3%) compared to fractional boosters of AZD1222 (ranging from 10.0% to 44.7%) or a full dose of Sinovac (4.2%). Both full and fractional dose vaccines were generally well tolerated. Local and systemic adverse events occurred across all treatment arms in line with expectations, with nine serious adverse events reported, none of which were determined to be related to study vaccination. Interpretation: Our data show that the immunogenicity of booster vaccines depends on the initial vaccine, baseline antibody levels, and the booster vaccine used. Fractional doses of BNT162b2 and AZD1222 were non-inferior to a full Sinovac booster in individuals primed with Sinovac. However, fractional doses of BNT162b2 were not non-inferior in BNT162b2-primed individuals, and AZD1222 fractional doses were only non-inferior in the AZD1222 priming arm. We advise against Sinovac as a booster. Fractional doses of BNT162b2 or AZD1222 remain practical alternatives for Sinovac-primed populations in resource-limited settings. Funding: Coalition for Epidemic Preparedness Innovations (CEPI)/Sabin Vaccine Institute.