Proliferative Receptor Binding Domain (RBD)-specific CD4+ T cells correlate with neutralizing antibody levels after natural SARS-CoV-2 infection and are induced following vaccination

Long-term immunity to SARS-CoV-2 infection, comprising neutralizing antibodies and T cell-mediated immunity, in a very large majority of the population, is required to reduce the current pandemic. We have investigated in detail the association between memory CD4 and CD8 T cells in recovered COVID-19 subjects, and their levels of neutralizing antibodies.The results show that RBD-specific memory CD4 T cells were particularly variable, and up to half of recovered individuals lacked these CD4 T cells and had much lower neutralizing antibody titres. Conversely, study of additional subjects identified as having low neutralizing antibody titres had very low levels of RBD-specific CD4 T cells. Furthermore, at both the protein and transcriptomic levels, these low antibody subjects had spike-specific CD4 T cells with a higher proportion of an inhibitory phenotype, including Foxp3 and CTLA-4, and less effector phenotype with T-bet and cytotoxic granzymes and perforin. Vaccination led to an improvement in RBD-specific memory CD4 T cells and neutralizing antibody titres in these at-risk subjects. Our results suggest that epitopes within the RBD-region should be the particular target of booster vaccines. scRNA seq of PBMC collected from 4 convalescent donor samples at 3 months post SARS-CoV-2 infection