Diverse BCR usage and T cell activation induced by different COVID-19 sequential vaccinations

Abstract

ABSTRACT Limited knowledge is available on the differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibody breadth and T cell differentiation among different COVID-19 sequential vaccination strategies. In this study, we compared the immunogenicity of the third different dose of COVID-19 vaccines, such as mRNA (I-I-M), adenoviral vector (I-I-A), and recombinant protein (I-I-R) vaccines, in terms of the magnitude and breadth of antibody response and differentiation of SARS-CoV-2-specific T and B cells. These studies were performed in the same clinical trial, and the samples were assessed in the same laboratory. IGHV1-69, IGHV3-9, and IGHV4-34 were the dominant B cell receptor (BCR) usages of the I-I-M, I-I-A, and I-I-R groups, respectively; the RBD + B cell activation capacities were comparable. Additionally, the I-I-R group was characterized by higher numbers of regulatory T cells, circulating T follicular helper cells (cTFH) – cTFH1 (CXRC3 + CCR6 - ), cTFH1-17 (CXRC3 + CCR6 + ), cTFH17 (CXRC3 - CCR6 + ), and cTFH-CM (CD45RA - CCR7 + ), and lower SMNE + T cell proliferative capacity than the other two groups, whereas I-I-A showed a higher proportion and number of virus-specific CD4 + T cells than I-I-R, as determined in ex vivo experiments. Our data confirmed different SARS-CoV-2-specific antibody profiles among the three different vaccination strategies and also provided insights regarding BCR usage and T/B cell activation and differentiation, which will guide a better selection of vaccination strategies in the future. IMPORTANCE Using the same laboratory test to avoid unnecessary interference due to cohort ethnicity, and experimental and statistical errors, we have compared the T/B cell immune response in the same cohort sequential vaccinated by different types of COVID-19 vaccine. We found that different sequential vaccinations can induce different dominant BCR usage with no significant neutralizing titers and RBD + B-cell phenotype. Recombinant protein vaccine can induce higher numbers of regulatory T cells, circulating TFH (CTFH)1, CTFH17, and CTFH-CM, and lower SMNE + T-cell proliferative capacity than the other two groups, whereas I-I-A showed higher proportion and number of virus-specific CD4 + T cells than I-I-R. Overall, our study provides a deep insight about the source of differences in immune protection of different types of COVID-19 vaccines, which further improves our understanding of the mechanisms underlying the immune response to SARS-CoV-2.