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

Abstract

The functional relevance of pre-existing cross-immunity to 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 pre-existing 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 mRNA vaccination displaying kinetics similar to secondary immune responses. Our results highlight the functional contribution of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity following primary SARS-CoV-2 immunization and the high rate of asymptomatic/mild COVID-19 disease courses.

Cellular and Antibody Immunity after COVID-19 Vaccination at >4-Month Follow Up in Immunocompetent and Immunocompromised Subjects

“…We have avoided co-stimulation or the use of immunodominant peptides in our cell-based assays, to reduce any likelihood of overinterpreting the T-cell response to SARS-CoV-2 after vaccination of immunocompromised patients (Braun, Grifoni, Sekine, Ashokkumar) (6,(13)(14)(15). It is possible that if used in our subject population, these assay modifications may also confirm vaccine-induced reinforcement of pre-existing T-cell immunity to SARS-CoV-2, as has been reported recently (Loyal) (16).…”

Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive elderly

“…Thirdly, some elderly had high frequencies of responding CD4 T cells before vaccination (Fig. 1B, day 0), likely re ecting cross-reactive activities gained during previous encounters with other corona viruses, as demonstrated before 5,6 .…”

The way of SARS-CoV-2 vaccine development: success and challenges

“…In addition, cross-reactive CD4 + T cells with a predominantly Th1 memory phenotype from unexposed individuals mainly recognized the C-terminal epitopes in the S protein 139 . The frequency of pre-existing T cells especially against S816-830 correlated well with titers of anti-SARS-CoV-2 IgG antibodies especially against S1 subunit, highlighting the importance of the spike-cross-reactive T cells in COVID-19 142 . Moreover, the pre-existing memory CD4 + T cells cross-reacted with comparable affinity to SARS-CoV-2 and the common cold coronaviruses 139 , 140 .…”