Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination

Science. 2021 Oct 8;374(6564):eabh1823. doi: 10.1126/science.abh1823. Epub 2021 Oct 8.


The functional relevance of preexisting cross-immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a subject of intense debate. Here, we show that human endemic coronavirus (HCoV)–reactive and SARS-CoV-2–cross-reactive CD4+ T cells are ubiquitous but decrease with age. We identified a universal immunodominant coronavirus-specific spike peptide (S816-830) and demonstrate that preexisting spike- and S816-830–reactive T cells were recruited into immune responses to SARS-CoV-2 infection and their frequency correlated with anti–SARS-CoV-2-S1-IgG antibodies. Spike–cross-reactive T cells were also activated after primary BNT162b2 COVID-19 messenger RNA vaccination and displayed kinetics similar to those of secondary immune responses. Our results highlight the functional contribution of preexisting spike–cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity after primary SARS-CoV-2 immunization and the high rate of asymptomatic or mild COVID-19 disease courses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Asymptomatic Diseases
  • BNT162 Vaccine
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • COVID-19 / immunology*
  • COVID-19 Vaccines / immunology
  • Cross Reactions
  • Female
  • Humans
  • Immunity
  • Immunodominant Epitopes / immunology
  • Male
  • Middle Aged
  • Open Reading Frames
  • Peptide Fragments / immunology
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / immunology
  • Vaccination
  • Young Adult


  • CD3 Complex
  • COVID-19 Vaccines
  • Immunodominant Epitopes
  • Peptide Fragments
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • BNT162 Vaccine