Certain people who test negative for COVID-19 despite being exposed to the SARS-CoV-2 coronavirus might be having an immune memory due to preexisting polymerase-specific T cells

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A new study by led by researchers from University College London (UCL) has found that certain people who test negative for COVID-19 despite being exposed to the SARS-CoV-2 coronavirus might actually be having an “immune memory” due to pre-existing polymerase-specific T cells.

These individuals can clear the virus rapidly due to a strong immune response from existing T-cells, hence resulting in a COVId-19 test being seronegative.

There have been cases of individuals who despite their entire household catching COVID-19, has never tested positive for the disease.
 
The study team from UCL has now found an explanation, showing that a proportion of individuals experience “abortive infection” in which the virus enters the body but is cleared by the immune system’s T-cells at the earliest stage meaning that PCR and antibody tests record a negative result.
 
Hence these individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion
 
Interestingly about 15% of healthcare workers who were tracked during the first wave of the pandemic in London, England, appeared to fit this scenario.
 
According to the study team, “T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections.”
 
The study team hypothesized that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-24–11, would expand in vivo to support rapid viral control, aborting infection.
 
The team measured SARS-CoV-2-reactive T-cells, including those against the early transcribed replication transcription complex (RTC), in intensively monitored healthcare workers (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralization (seronegative HCW, SN-HCW).
 
Interestingly, the seronegative healthcare workers (SN-HCW) had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort).
 
Also, the SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, 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 (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognizing HCoV variants were identified in SN-HCW.

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.
 
The study findings highlight RTC-specific T-cells as targets for vaccines against endemic and emerging Coronaviridae.
 
The study findings were published in the peer reviewed journal: Nature. 

https://www.nature.com/articles/s41586-021-04186-8

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We provide T-cell and innate transcript evidence for abortive, seron- egative SARS-CoV-2 infection. Longitudinal samples from SN-HCW and an additional cohort, showed RTC (particularly polymerase)-specific T-cells were enriched before exposure, expanded in vivo, and prefer- entially accumulated in those in whom SARS-CoV-2 failed to establish infection, compared to those with overt infection.

The differential biasing of T-cells towards early expressed non-structural SARS-CoV-2 proteins in HCW not seroconverting may reflect repetitive occupational exposure to very low viral inocula, reported to drive the induction of non-structural T-cells in HIV, SIV and HBV26,37,38. Such repetitive exposure would be congruent with the observed protracted induction of the innate signal IFI27 and the devel- opment of de novo T-cells in some SN-HCW.

However, we also documented expansion of pre-existing T-cells, with responses capable of cross-recognising epitope variants between sea- sonal HCoV and SARS-CoV-2. Cross-reactive SARS-CoV-2-specifc CD8+ T-cells directed against epitopes highly conserved among HCoV are now well-described, with pre-existing T-cells frequently targeting essential viral proteins with low scope for tolerating mutational variation, such as those in ORF1ab6,18,32.

The abundant SARS-CoV-2-specific CD4+ T-cells may also contribute to protection in SN-HCW by antibody-independent mechanisms, such as antiviral cytokines and chemokines production. HCW have higher frequencies of HCoV-reactive T-cells than the general public19 and recent HCoV infection is associated with reduced risk of severe COVID-19 infection39, likely partly attributable to cross-reactive neutralising antibodies;40,41 however, pre-existing T-cells have also been implicated15,42. The early induction of T-cells, before detectable antibod- ies in mild infection30 and concurrent with mRNA vaccination efficacy, support a role for pre-existing cross-reactive memory T-cells2,31.

Pre-existing RTC-specific T-cells, at higher frequency than naïve T-cells and poised for immediate re-activation on antigen cross-recognition, would be expected to favour early control, explain- ing their enrichment after abortive compared to classical infection.

However, the relative contribution of viral inoculum and cross-reactive T-cells needs to be further dissected in human challenge experiments and animal models. A caveat of this work is that we only analysed peripheral immunity; it is plausible that mucosal-sequestered anti- bodies43 played a role in our seronegative cohort.

It also remains pos- sible that innate immunity mediates control in abortive infections, with RTC-biased T-cell responses being generated as a biomarker of low-grade infection. Interferon-independent induction of RIG-I has been proposed to abort SARS-CoV-2 infection by restraining the viral lifecycle prior to sgRNA production;13 this would favour the presenta- tion of epitopes from ORF1ab, released into the cytoplasm in the first stage of the viral life cycle12, whilst blocking production of structural proteins from pgRNA. This raises the possibility that some SARS-CoV-2 infected cells could be recognised and removed by ORF1ab-reactive T-cells without widespread production of structural proteins and mature virion formation.

We have described induction of innate and cellular immunity with- out seroconversion, highlighting a subset of individuals where risk of SARS-CoV-2 reinfection and immunogenicity of vaccines should be specifically assessed. The HCW we studied were exposed to Wuhan Hu-1 and had partial protection from PPE; it remains to be seen whether abortive infections can occur upon exposure to more infectious vari- ants of concern, or in the presence of vaccine-induced immunity. How- ever, clearance without seroconversion points to T-cells which may be particularly effective vaccine targets.

Cross-protection between coronaviruses is proportional to their sequence homology in mice44, making the highly conserved NSP12 region studied here, as well as less studied NSP3/14/16, top candidates for heterologous immunity. Our data highlight the presence of pre-existing T-cells in a proportion of donors that are able to expand in vivo and target a highly conserved region of SARS-CoV-2 and other Coronaviridae. Boosting of such T-cells may offer durable pan-Coronaviridae reactivity against endemic and emerging viruses, arguing for their inclusion and assessment, as an adjunct to spike-specific antibodies, in next-generation vaccines.

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