People testing negative for Covid-19 despite exposure may have ‘immune memory’ – The Guardian

We all know that person who, despite their entire household catching Covid-19, has never tested positive for the disease. Now scientists have found an explanation, showing that a proportion of people 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.

About 15% of healthcare workers who were tracked during the first wave of the pandemic in London, England, appeared to fit this scenario.

The discovery could pave the way for a new generation of vaccines targeting the T-cell response, which could produce much longer lasting immunity, scientists said.

Leo Swadling, an immunologist at University College London and lead author of the paper, said: “Everyone has anecdotal evidence of people 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.”

The latest study intensively monitored healthcare workers for signs of infection and immune responses during the first wave of the pandemic. Despite a high risk of exposure 58 participants did not test positive for Covid-19 at any point. However, blood samples taken from these people 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 people who had not been exposed to the virus at all. They also had increases in another blood marker of viral infection.

The work suggests that a subset of people already had memory T-cells from previous infections from other seasonal coronaviruses causing common colds, which protected them from Covid-19.

These immune cells “sniff out” proteins in the replication machinery – a region of Covid-19 shared with seasonal coronaviruses – and in some people 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 recognise SARS-CoV-2,” said Swadling.

The study adds to the known spectrum of possibilities after exposure to Covid-19, ranging from escaping infection entirely to severe disease.

Alexander Edwards, associate professor in biomedical technology at the University of Reading, said: “This study identifies [a new] 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.”

The finding is 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. Nearly all existing Covid-19 vaccines focus on priming antibodies against the vital spike protein that helps SARS-CoV-2 enter cells. These neutralising 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.

By contrast, 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.

“Insights from this study could be critical in design of a different type of vaccine,” said Andrew Freedman, reader in infectious diseases at Cardiff University School of Medicine. “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.”