Superior antibody and membrane protein-specific T cell responses to CoronaVac by intradermal versus intramuscular routes in adolescents

Strategies to improve the immunogenicity of COVID-19 vaccines are necessary to optimise their protection against disease. Fractional dosing by intradermal administration (ID) has been shown to be equally immunogenic as intramuscular (IM) for several vaccines, but the immunogenicity of ID inactivated whole-virus SARS-CoV-2 at the full dose is unknown. This study (NCT04800133) investigated the superiority of antibody and T cell responses of full-dose CoronaVac by ID over IM in adolescents. Participants aged 11-17 years received 2 doses IM or ID, followed by the 3rd dose 13-42 days later. Humoral and cellular immunogenicity outcomes were measured post-dose 2 (IM-CC versus ID-CC) and post-dose 3 (IM-CCC versus ID-CCC). Doses 2 and 3 were administered to 173 and 104 adolescents, respectively. S IgG, S-RBD IgG, S IgG Fc{gamma}RIIIa-binding, SNM-specific IL-2+CD4+, SNM-specific IL-2+CD8+, S-specific IL-2+CD8+, N-specific IL-2+CD4+, N-specific IL-2+CD8+ and M-specific IL-2+CD4+ responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC, whereas IgG avidity was inferior. For ID-CCC, S-RBD IgG, surrogate virus neutralisation test (sVNT), 90% plaque reduction neutralisation titre (PRNT90), PRNT50, S IgG avidity, S IgG Fc{gamma}RIIIa-binding, M-specific IL-2+CD4+, interferon-{gamma}+CD8+ and IL-2+CD8+ responses were superior and non-inferior to IM-CCC. The estimated vaccine efficacies were 49%, 52%, 66% and 79% for IM-CC, ID-CC, IM-CCC and ID-CCC, respectively. More in the ID groups reported local, mild adverse reactions. This is the first study to demonstrate superior antibody and M-specific T cell responses by ID inactivated SARS-CoV-2 vaccination and serves as the basis for future research to improve immunogenicity of inactivated vaccines.