Intradermal delivery of the third dose of the mRNA-1273 SARS-CoV-2 vaccine: safety and immunogenicity of a fractional booster dose

Objectives The aim of this study was to assess safety and immunogenicity of a dose-sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine. Methods COVID-19 naive adults aged 18-30 years were recruited from a previous study on primary vaccination regimens that compared 20 μg ID vaccinations with 100 μg IM vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 μg) or the standard-of-care intramuscular (IM) booster dose (50 μg) of the mRNA-1273 vaccine, six months after completing their primary series (ID-ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). Additionally, COVID-19 naive individuals aged 18-40 years that had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti-spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored. Results In January 2022, 129 participants were included. Fractional ID boosting was safe and well-tolerated, with fewer systemic adverse events compared to IM boosting. At day 28 post-booster, anti-spike S1 IgG geometric mean concentrations were 9,106 (95% CI: 7,150-11,597) binding antibody units (BAU)/mL in the IM-IM group and 4,357 (3,003-6,322) BAU/mL, 6,629 (4,913-8,946) BAU/mL, and 5,264 (4,032-6,873) BAU/mL in the ID-IM, ID-ID, and IM-ID groups, respectively. Conclusions ID boosting provides robust immune responses and is a viable dose-sparing strategy for mRNA COVID-19 vaccines. The favorable side-effect profile supports its potential in reducing vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness.