SARS-CoV-2 mRNA vaccination elicits robust and persistent T follicular helper cell response in humans

SARS-CoV-2 mRNA vaccines generate high and persistent levels of circulating anti-spike (S) antibodies and S-specific CD4+ T cells following prime-boost vaccination. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses in the draining lymph nodes contribute to this outstanding immunogenicity. Using fine needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we show that frequency of TFH correlates with that of S-binding germinal center B cells. Mining of of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1*04-restricted response to S167-180 in individuals with this allele, which is itself among the most common HLA alleles in humans. Analysis of paired blood and lymph node specimens show that circulating S-specific TFH cells peak one week after the second immunization while S-specific lymph node TFH persist at nearly constant frequencies for at least six months following mRNA vaccination. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this very efficacious human vaccine.