Abstract
Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4–11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.
Highlights
This is a PDF file of a peer-reviewed paper that has been accepted for publication
We measured SARS-CoVL 2-reactive T-cells, including those against the early transcribed replication transcription complex (RTC)[12,13], in intensively monitored healthcare workers (HCW)
Having previously reported a range of neutralising antibody (nAb) L titres at wk[16] in laboratory-confirmed infection, we examined nAb in SN-HCW
Summary
Having found the SN-HCW group to be enriched for SARS-CoV-2-specific T-cells, against RTC, we investigated the possibility that some of these represented expansions of pre-existing cross-reactive responses to the HKU1 sequence than to other seasonal HCoV or SARS-CoV-2 (Extended Data Fig. 6d-e). This suggested prior HKU1 infection primed these NSP7 responses that are able to cross-recognise. Aregion between coronaviridae, suggesting exposure to HCoV is one to those with weak or absent RTC-specific responses (Extended Data Fig. 7), making it unlikely that HCoV infection itself accounted for the SARS-CoV-2-reactive T-cells we detected in SN-HCW. A d,e, Mann-Whitney test and Fisher’s exact test. a, Contact cohort, Extended ACCELER Data Table 5. b-e, COVIDsortium HCW cohort, Extended Data Table 1)
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