UCL Study Shows Individuals Testing Negative For COVID-19 Despite Exposure May Have ‘Immune Memory’ Due To Pre-Existing Polymerase-Specific T Cells

COVID-19 Research: 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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These study findings could pave the way for a new generation of vaccines targeting the T-cell response, which could produce much longer lasting immunity, scientists said.
 
Lead author, Dr Leo Swadling, an immunologist at University College London told Thailand Medical News, “Everyone has anecdotal evidence of individuals being exposed but not succumbing to infection. What we didn’t know is whether these individuals really did manage to completely avoid the virus or whether they naturally cleared the virus before it was detectable by routine tests.”
 
This new research intensively monitored healthcare workers for signs of infection and immune responses during the first wave of the pandemic.
 
Interestingly despite a high risk of exposure 58 participants did not test positive for COVID-19 at any point.
 
However, blood samples taken from these individuals showed they had an increase in T-cells that reacted against COVID-19, compared with samples taken before the pandemic took hold and compared with individuals who had not been exposed to the SARS-CoV-2 coronavirus at all. These individuals also had increases in another blood marker of viral infection.
 
The study findings suggest that a subset of individuals already had memory T-cells from previous infections from other seasonal coronaviruses causing common colds, which protected them from COVID-19.
 
Dr Swadling further commented, “These immune cells ‘sniff out’ proteins in the replication machinery ie a region of COVID-19 shared with seasonal coronaviruses and in some individuals this response was quick and potent enough for the infection to be cleared at the earliest stage. These pre-existing T-cells are poised ready to recognize SARS-CoV-2.”
 
The findings add to the known spectrum of possibilities after exposure to Covid-19, ranging from escaping infection entirely to severe disease.
 
Dr Alexander Edwards, associate professor in biomedical technology at the University of Reading who was not involved with the study commented on the study findings, “This study identifies a new intermediate outcome ie enough virus exposure to activate part of your immune system but not enough to experience symptoms, detect significant levels of virus or mount an antibody response.”
 
This study findings are particularly significant because the T-cell arm of the immune response tends to confer longer lasting immunity, typically of years rather than months, compared with antibodies.
 
Almost all existing COVID-19 vaccines focus on priming antibodies against the vital spike protein that helps SARS-CoV-2 enter cells. These neutralizing antibodies give excellent protection against severe illness.
 
However, the immunity wanes over time and a potential weakness of spike-based vaccines is that this region of the virus is known to mutate.
 
On the other hand, the T-cell response does not tend to fade as quickly and the internal replication machinery that it targets is highly conserved across coronaviruses, meaning a vaccine that also targeted this region would probably protect against new strains and possibly even against entirely new pathogens.
 
Dr Andrew Freedman, a reader in infectious diseases at Cardiff University School of Medicine who was not involved in the study also commented on the findings, “Insights from this study could be critical in design of a different type of vaccine. A vaccine that primes T-cell immunity against different viral protein targets that are shared between many different coronaviruses would complement our spike vaccines that induce neutralizing antibodies. Because these are components within the virus, antibodies are less effective instead, T-cells come into play.”
 
The study team concluded, “We have described induction of innate and cellular immunity without 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 variants of concern, or in the presence of vaccine-induced immunity. However, 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 study findings 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.”
 
The study also involved researchers from Queen Mary University of London-UK, Duke-NUS Medical School-Singapore, Imperial College London NHS Trust-UK, Nottingham University Hospitals-UK and Guy’s and St. Thomas’ NHS Foundation Trust-UK.
 
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