Early CD4(+) T cell responses induced by the BNT162b2 SARS-CoV-2 mRNA vaccine predict immunological memory

Longitudinal studies have revealed large interindividual differences in antibody responses induced by SARS-CoV-2 mRNA vaccines. Thus, we performed a comprehensive analysis of adaptive immune responses induced by three doses of the BNT162b2 SARS-CoV-2 mRNA vaccines. The responses of spike-specific CD4(+) T cells, CD8(+) T cells and serum IgG, and the serum neutralization capacities induced by the two vaccines declined 6 months later. The 3(rd) dose increased serum spike IgG and neutralizing capacities against the wild-type and Omicron spikes to higher levels than the 2(nd) dose, and this was supported by memory B cell responses, which gradually increased after the 2(nd) dose and were further enhanced by the 3(rd) dose. The 3(rd) dose moderately increased the frequencies of spike-specific CD4(+) T cells, but the frequencies of spike-specific CD8(+) T cells remained unchanged. T cells reactive against the Omicron spike were 1.3-fold fewer than those against the wild-type spike. The early responsiveness of spike-specific CD4(+) T, circulating T follicular helper cells and circulating T peripheral helper cells correlated with memory B cell responses to the booster vaccination, and early spike-specific CD4(+) T cell responses were also associated with spike-specific CD8(+) T cell responses. These findings highlight the importance of evaluating cellular responses to optimize future vaccine strategies.