Imperial College Study Shows That Non-Spike Cross-Reactive Memory T Cells Produced As A Result Of Common Colds Also Cross-Protect Against SARS-CoV-2

T-Cells-COVID-19: A new study by researchers from Imperial College London has shown that non-spike cross-reactive memory t cells produced as a result of common colds also cross-protect against infections by the SARS-CoV-2 coronavirus. The study findings also lead to the proposal to include non-spike antigens in second generation COVID-19 vaccines to enhance the vaccine’s efficacy.

 
The study team assessed 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure.

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Utilizing a dual cytokine FLISpot assay on peripheral blood mononuclear cells, the study team enumerated 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 study findings showed higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells.
 
The study findings are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.
 
The study findings were published in the peer reviewed journal: Nature Communication. https://www.nature.com/articles/s41467-021-27674-x
 
The study findings provide first hand evidence of a protective role for these T cells.
 
Although past studies have shown that T cells induced by other coronaviruses can recognize SARS-CoV-2, the new study 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 T-Cells-COVID-19 study team also says their findings provide a blueprint for a second-generation, universal vaccine that could prevent infection from current and future SARS-CoV-2 variants, including Omicron.
 
First author of the study, Dr Rhia Kundu, from Imperial's National Heart & Lung Institute told Thailand Medical News, "Being exposed to the SARS-CoV-2 virus doesn't always result in infection, and we've been keen to understand why. We foun d 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. While this is an important discovery, it is only one form of protection, and I would stress that no one should rely on this alone. Instead, the best way to protect yourself against COVID-19 is to be fully vaccinated, including getting your booster dose."
 
The T cell research began in September 2020 when most people in the UK had neither been infected nor vaccinated against SARS-CoV-2. It included 52 people who lived with someone with PCR-confirmed SARS-CoV-2 infection and who had therefore been exposed to the virus.
 
The research participants did PCR tests at the outset and 4 and 7 days later, to determine if they developed an infection.
 
Blood specimens from the 52 participants were taken within 1-6 days of them being exposed to the virus. This enabled the researchers to analyze 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.


Serum sampled from COVID-19 contacts at the baseline, D7 and D28 visit were assayed for RBD-specific antibody, represented as sample/control ratios (a). PBMCs from these visits were rested overnight at high density prior to stimulation with 1 µg/ml cross-reactive peptide pool cultured for 20 h in a FLISpot assay to detect IL-2- (b) and IFNγ (c) secreting T cells. Serum from these visits were assayed for RBD-specific antibody, represented as sample/control ratios (c). Left-hand panels and blue circles represent PCR-negative contacts whilst right-hand panels and red circle represent PCR-positive contacts.

The study team 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 become infected.
 
These T cells targeted internal proteins within the SARS-CoV-2 virus, rather than the spike protein on the surface of the virus, to protect against infection.
 
It should be noted that current vaccines do not induce an immune response to these internal proteins.
 
The study team says 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.
 
Senior author of the study and Director of the NIHR Respiratory Infections Health Protection Research Unit at Imperial, Professor Dr Ajit Lalvani commented, "Our research findings provide the clearest evidence to date that T cells induced by common cold coronaviruses play a protective role against SARS-CoV-2 infection. These T cells provide protection by attacking proteins within the virus, rather than the spike protein on its surface.”
 
He further added, "The spike protein is under intense immune pressure from vaccine-induced antibody which drives evolution of vaccine escape mutants. 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."
 
The study team noted some limitations to their study, including that, because it is small and 88% of participants were of white European ethnicity, it is not possible for them to model demographic factors.
 
The study team concluded, “The emergence of novel variants with potential to escape naturally acquired or vaccine-induced humoral immunity, along with the recent elucidation of immune-mediated antigenic drift in huCoVs brings the long-term utility of spike-only based vaccines into question. We demonstrate the importance of non-spike targets, in particular ORF1 and nucleocapsid, for T cell-mediated protection in the absence of neutralizing antibodies, consistent with the wide spectrum of antigen-specific T cells induced by SARS-CoV-2 infection and cross-reactive T cells in pre-pandemic cohorts. In light of this, inclusion of these targets alongside the major antibody target of S-protein could be critical in maintaining the benefit of vaccination in the case of vaccine-strain mismatch, as could occur with the emergence of novel variants. Our study complements the small but growing body of evidence that T cells may protect against SARS-CoV-2 infection and supports the potential utility of second-generation vaccines targeting core proteins.”
 
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