Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts

Rhia Kundu,Eleanor Parker,Aleksandra Koycheva,Ryan S Thwaites,Jessica Cutajar,Janakan Sam Narean,Emily Conibear,Mica Tolosa-Wright,Richard S Tedder ,Carolina Rosadas,Sarah Hammett,Eimèar Mcdermott ,Joe Fenn ,Lulu Wang,Timesh D Pillay ,Myra O Mcclure ,Nieves Derqui-Fernández ,Megan Davies,Graham P Taylor,Seran Hakki,Jake Dunning,Robert Varro,Ajit Lalvani

doi:10.1038/s41467-021-27674-x

Abstract

Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.

Highlights

Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection
We compared the frequency of early cross-reactive T cells in SARS-CoV-2 PCR-positive and PCR-negative COVID-19 contacts identified through rapid contract tracing, using a cross-reactive peptide pool defined by a novel bioinformatic approach
peripheral blood mononuclear cells (PBMCs) sampled from the 52 confirmed exposed contacts within the INSTINCT study at 1–6 days post-index symptom-onset were assayed for IFN-γ and IL-2-secreting T cell responses to the SARS-CoV-2 S, M, E and N peptide pools, as well as the cross-reactive pool containing the 28 epitopes we identified and the 14 epitopes from Nelde et al, (Supplementary Table 1)

Summary

Introduction

Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. We assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. Our results are consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines. No study yet describes an association of cross-reactive T cells with outcome after SARS-CoV-2 exposure. The frequency of baseline cross-reactive T cells is correlated with the infection outcome following SARS-CoV-2 exposure, and we observe significantly higher frequencies of cross-reactive memory T cell responses in PCR-negative contacts. The association of circulating SARS-CoV-2-specific T cells at exposure with lack of infection is the first evidence of a protective role for cross-reactive T cells in COVID-19, and establish the potential for secondgeneration T cell-inducing SARS-CoV-2 vaccines that could circumvent spike-antibody immune escape variants

Methods

Results

Conclusion