Exposure to SARS-CoV-2 does not, universally, result in infection. A subset of people are spared from COVID-19, despite living in close quarters with others who have tested positive. The reason why some people are more resistant to infection has remained unanswered. A leading theory has been that pre-existing T cells, primed by endemic human coronaviruses, might mediate protection in SARS-CoV-2-naive people.

Indeed, previous studies have shown that T cells induced by other coronaviruses can recognize SARS-CoV-2. Now, a new study from the Imperial College London examines—for the first time—how the presence of these T cells at the time of SARS-CoV-2 exposure influences whether someone becomes infected.

The study’s results suggest that pre-existing, non-spike cross-reactive memory T cells, protect SARS-CoV-2-naïve contacts from infection. This work not only provides the first evidence of a protective role for these T cells, it also supports the inclusion of non-spike antigens in second-generation vaccines that could prevent infection from current and future SARS-CoV-2 variants.

The study, entitled “Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts” is published in Nature Communications.

“Being exposed to the SARS-CoV-2 virus doesn’t always result in infection, and we’ve been keen to understand why,” says Rhia Kundu, PhD, postdoctoral associate at Imperial’s National Heart & Lung Institute. “We found that high levels of pre-existing T cells, created by the body when infected with other human coronaviruses like the common cold, can protect against COVID-19 infection.”

The study included 52 people who lived with someone with PCR-confirmed SARS-CoV-2 infection and had therefore been exposed to the virus. The participants were tested by PCR at the outset, and four and seven days later, to determine if they developed an infection. Blood samples from the 52 participants were taken within 1–6 days of them being exposed to the virus.

The study assessed the 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. They also analyzed the levels of pre-existing T cells induced by previous common cold coronavirus infections that also cross-recognize proteins of the SARS-CoV-2 virus. To do this, they used a dual cytokine FLISpot assay on peripheral blood mononuclear cells, measuring the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses.

The researchers found that there were significantly higher levels of these cross-reactive T cells in the 26 people who did not become infected, compared to the 26 people who did. The T cells targeted internal, non-spike proteins, to protect against infection.

Current vaccines do not induce an immune response to these internal proteins. The researchers note that, alongside our existing effective spike protein-targeting vaccines,  these internal proteins offer a new vaccine target that could provide long-lasting protection because T cell responses persist longer than antibody responses which wane within a few months of vaccination.

“The spike protein is under intense immune pressure from vaccine-induced antibody which drives evolution of vaccine escape mutants, says Ajit Lalvani, MD, director of the NIHR Respiratory Infections Health Protection Research Unit at Imperial. “In contrast, the internal proteins targeted by the protective T cells we identified mutate much less. Consequently, they are highly conserved between the various SARS-CoV-2 variants, including omicron. New vaccines that include these conserved, internal proteins would therefore induce broadly protective T cell responses that should protect against current and future SARS-CoV-2 variants.”

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