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expert reaction to study looking at memory T-cells and the immune response to SARS-CoV-2

A study published in Nature looks at cross-reactive T-cells and the immune response to SARS-CoV-2.

This Roundup accompanied an SMC Briefing.


Prof Peter Openshaw, Professor of Experimental Medicine, Imperial College London, said:

“In this novel and interesting study, the authors note that many of those exposed to SARS-CoV-2 resist infection. They set out to test the idea that T-cells assist clearance of viruses, and that memory T cells (Tmem) to other coronaviruses (CoV) might cross-protect, aborting infection.

“In a prospective study of healthcare workers (HCWs) apparently resistant to infection, they found Tmem directed against the a set of viral proteins called the replication-transcription complex (RTC, including RNA-polymerase and helicase ); this is unusual, in that most T cells that arise after infection recognise structural proteins. These RTC-specific T-cells had evidence of activation, and recognise sequences that are shared with seasonal human CoVs that cause some common colds. Moreover, they found that RNA-polymerase was of the recognised by Tmem from pre-pandemic blood samples.

“The authors speculate that vaccines designed to induce RTC-specific T-cells might have broad protective effects against endemic and emerging coronaviruses and might prevent disease from occurring. The findings open up future avenues for research and raise the profile of T cells as an additional limb of protective immunity that might not only eliminate virus late in disease but also abort infection before symptoms develop, presumably by acting within the mucosa. The findings strengthen the argument for developing live attenuated mucosal vaccines that might be developed as nose drops or sprays.”


Dr Andrew Freedman, Reader in Infectious Diseases and Honorary Consultant Physician, Cardiff University School of Medicine, said:

“This is an important study which may help to explain why some people who were repeatedly exposed to COVID-19 before the vaccine rollout apparently did not catch it.  It appears that some of them had pre-existing memory T cell immunity to a protein involved in replication of the virus, probably induced by previous infection with other seasonal coronaviruses. This, the authors suggest, may have resulted in a transient, abortive infection after exposure to SARS-CoV-2. The immune system was able to clear the virus rapidly before it could cause symptoms or be detected either by PCR or antibody production.

“As the authors point out, this finding could lead to the development of novel vaccines which might confer long lasting protection against SARS-CoV-2 and other coronaviruses, including ones that might emerge and pose a threat in the future. The existing vaccines, which mainly target the spike protein on the envelope of the virus, have proven remarkably effective. We know, however, that immunity does wane over time and there is concern that we may see new variants resistant to these vaccines”


Dr Alexander Edwards, Associate Professor in Biomedical Technology, University of Reading, said:

“Once again a detailed immunological study sheds more light into our complex relationship with viruses. T cells, white blood cells that play a central role in out immune system, can “sniff out” coronavirus proteins even when buried within the virus particle, in contrast to antibodies that “grab hold” of shapes on the surface (these are made by B cells, often with help from T cells). This excellent and thorough study identifies a group of people who are likely to have been exposed to the covid-19 virus but didn’t appear outwardly to have experienced an infection. It found activation of particular T cells that can detect core components inside the coronavirus, in health care workers who in spite of regular testing, never tested positive for virus by swabs. In spite of this detectable immune activation, antibody against virus was also not seen.

“This provides hard evidence for what might be expected from virus-host biology – different people can expect different outcomes after being exposed to a virus. Sometimes you may be lucky and not get infected; other times you might be fully infected and experience mild or severe disease. However, this study identifies an intermediate outcome- 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.

“Insights from this study could be critical in design of a different type of vaccine. Many of the current very successful Covid-19 vaccines focus on priming antibodies against the vital spike protein that helps SARS-CoV2 enter cells. These neutralising antibodies are very effective at inhibiting viral growth and give excellent protection against severe Covid-19. Their weakness also arises from this tight focus on spike– because there are many different spike proteins out there on different coronaviruses, these vaccines only protect against one specific virus. 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 neutralising antibodies. Because these are components within the virus, antibodies are less effective- instead, T cells come into play.

One positive surprise from our intense response to Covid-19 was showing that there are multiple very different ways to make a vaccine in a hurry. Hopefully this study will lead to further advances in vaccine development, as we need all the types of vaccine we can get.”



‘Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV’ by Leo Swadling et al was published at 16:00 UK time on Wednesday 10th November.

DOI: 10.1038/s41586-021-04186-8



All our previous output on this subject can be seen at this weblink:



Declared interests

Dr Andrew Freedman: “I declare no conflict of interest.”

None others received.


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