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

Mudd PA et al. (BioRxiv) doi:10.1101/2021.09.08.459485



  • T follicular helper (Tfh) cell

  • CD4+ T cell

  • mRNA vaccine


Main Findings

  • T follicular helper (Tfh) cell signals are necessary for forming and sustaining germinal center (GC) reactions in order to promote the development of both long-lived plasma cells and high-affinity memory B cells.


  • Human lymph node tissue was collected by fine needle aspiration. Investigators observed a robust positive correlation between the magnitude of the Spike(S)-specific (GC) B cell population in the lymph node and the total Tfh cell population frequency. TCR sequencing of this Tfh cell population showed a prominent TCRα chain cluster indicating a potential immunodominant epitope region targeted by these T cells


  • The sequence of the immunodominant epitope region was identified using public datasets pairing TCR sequences with the spike peptide they are capable of recognizing. The minimal epitope and its HLA-restriction were determined using the NetMHC epitope prediction platform and patient HLA-typing data from the public datasets


  • MHC Class II tetramers specific for the minimal S epitope (S167-180) and DPB1:04:01 allele were shown to be capable of recognizing T cells from from the convalescent patient peripheral blood and Jurkat cells transduced to express both an NFAT-GFP reporter and the epitope-specific TCRs discovered in the public datasets.


  • The MHC Class II tetramers were used to assess the kinetics and phenotype of CD4+ T cells in the peripheral blood and lymph node following mRNA vaccination with BNT162b2


  • In the periphery, following vaccination, most CD4+ T cells specific for this epitope exhibited an effector memory phenotype (CCR7- CD45RO+) with 5-15% possessing circulating Tfh markers (CXCR5+PD1+) that became difficult to detect 200 days following the second dose


  • In the axillary lymph node, there was a strong antigen-specific Tfh frequency at least 60 days following vaccination even as cTfh contraction was observed in the blood. Between day 28 and day 60 post-vaccination, there was also a strong positive correlation between the frequency of TCRα clonotype sequences.




One limitation of this study is that it was only able to assess the Tfh response in individuals vaccinated with BNT162b2 and did not assess the response in recipients of mRNA-1273 (developed by Moderna). While there are many similarities in the design of these vaccine constructs, recent studies have shown a stronger antibody response and potentially higher degree of protection from symptomatic disease in recipients of the mRNA-1273 vaccine likely due to differences in the lipid nanoparticle and the dose concentration and timeframe between vaccination strategies. Also, this study does not take into account how SARS-CoV-2 variants may impact epitope recognition by Tfh cells following vaccination as well as natural infection which generates antigen-specific T cells to multiple ORFs of SARS-CoV-2 aside from spike.  




This study is highly significant and novel as it is one of the first studies to analyze the phenotype and kinetics of Tfh cells in the lymph nodes following mRNA vaccination. The authors use multiple complementary strategies to validate the immunodominant epitope they selected to track antigen-specific CD4 T cell populations. The major takeaway from this study is that a subset of antigen-specific CD4+ T cells circulating in the peripheral blood following vaccination develop a phenotype consistent with cTfh cells and are capable of contributing to stable germinal center reactions even as the peripheral blood frequency for these CD4+ clonotypes begin to disappear. The ability of lipid-nanoparticle encapsulated mRNA vaccines to generate such robust germinal center reactions is critical to forming high-affinity and long-lasting humoral immunity that is potentially superior to natural infection and other vaccine platforms. This also has important implications for the design of high-performance vaccines for other viral infections. Finally, the methodology used in this study has the potential to inform strategies in immuno-oncology, particularly neoantigen discovery and cancer vaccine immune monitoring.



Reviewed by Matthew Brown as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.