ABSTRACT
COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, factors associated with this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we find that baseline expression of AP-1 transcription factors, FOS and ATF3, is inversely correlated with BNT162b2 mRNA vaccine-induced T-cell responses. FOS expression is associated with transcription modules related to baseline immunity, but it is negatively associated with those related to T-cell activation upon BNT162b2 mRNA stimulation. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with FOS and ATF3 expression and inversely correlated with BNT162b2-induced T-cell responses. Taken together, these results demonstrate that baseline expression of AP-1 genes, which is associated with the gut microbial fucose/rhamnose degradation pathway, is a key negative correlate of BNT162b2-induced T-cell responses.
ABSTRACT
Pre-existing SARS-CoV-2-specific T cells, but not antibodies, have been detected in some unexposed individuals. This may account for some of the diversity in clinical outcomes ranging from asymptomatic infection to severe COVID-19. Although age is a risk factor for COVID-19, how age affects SARS-CoV-2-specific T cell responses remains unknown. We found that some pre-existing T cell responses to specific SARS-CoV-2 proteins, Spike (S) and Nucleoprotein (N), were significantly lower in elderly donors (>70 years old) who were seronegative for S than in young donors. However, substantial pre-existing T cell responses to the viral membrane (M) protein were detected in some elderly donors. These responses likely compensate for loss of T cell responses specific to S and N. In contrast, young and elderly donors exhibited comparable T cell responses to S, N, and M proteins after infection with SARS-CoV-2. M-specific responses were mediated by CD4 T cells producing interferon-{gamma} in both seronegative and seropositive individuals. T cells in seronegative elderly donors responded to various M-derived peptides, while the response after SARS-CoV-2 infection was apparently focused on a single peptide. These data suggest that diversity of target antigen repertoire for pre-existing SARS-CoV-2-specific T cells declines with age, but the magnitude of pre-existing T cell responses is maintained by T cells reactive to specific viral proteins such as M. A better understanding of the role of pre-existing SARS-CoV-2-specific T cells that are less susceptible to age-related loss may contribute to development of more effective vaccines for elderly people.
