Immunogenicity and Reactogenicity of Fractional vs. Full Booster Doses of COVID-19 Vaccines: A Non-Inferiority, Randomized, 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, randomized Phase IV non-inferiority study, carried out in Campo Grande, Midwest, Brazil. After obtaining consent, eligible participants were randomized to one of 5-6 study arms, depending on their priming vaccine. Participants were followed for the primary outcome for 21-60 days after intervention through in-person visits and remote contact for blood collection and safety evaluation. The primary outcome was the difference in seroresponse rates between the full and fractional doses, with a non-inferiority threshold of 10%.

Results: A total of 1451 participants were randomized and administered booster vaccines between July 5 and October 3, 2022. A half dose of BNT162b2 met the non-inferiority threshold, compared to a full dose in the Sinovac and AZD1222 primed groups. Sinovac showed inferiority compared to AZD1222 and BNT162b2 full or fractional dose boosters in participants primed with Sinovac. Fractional booster doses of BNT162b2 consistently resulted in higher levels of anti-spike binding IgG antibodies (ranging from 35∙4% to 78∙3%) compared to fractional boosters of AZD1222 (ranging from 10∙0% to 44∙7%) or full 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.

Conclusions: Our data show that fractional booster doses generate similar anti-spike antibody levels as full BNT162b2 and AZD1222 doses in second visit, irrespective of the initial vaccine. We advise against Sinovac as a booster. In financially constrained populations primed with Sinovac or AZD1222, opting for fractional BNT162b2 or AZD1222 doses is a practical alternative. Trial registration number: NCT05343871.

Funding: Coalition for Epidemic Preparedness Innovations (CEPI)/Sabin Vaccine Institute