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

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4⁺ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4⁺ T (T_FH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node T_FH. Mining of the responding T_FH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1^∗04-restricted response to S_167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific T_FH cells peak one week after the second immunization, S-specific T_FH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust T_FH cell responses play in establishing long-term immunity by this efficacious human vaccine.