Cardiff University And University of Oxford Discover P272L SARS-CoV-2 Spike Mutation Found On Several Lineages Escape Vaccine And Infection-Induced CD8 T-Cell Responses

SARS-CoV-2 variants: A new research by British researchers from Cardiff University And University of Oxford has alarmingly found that the SARS-CoV-2 spike mutation P272L that is found on several lineages is able to escape vaccine and infection-induced CD8 T-cell responses.

The human adaptive immune system protects against infection via selection of specific antigen receptors on B cells and T-cells.
 
The study team analyzed the prevalent CD8 ‘killer’ T-cell response mounted against SARS-CoV-2 Spike 269-277 epitope YLQPRTFLL via the most frequent Human Leukocyte Antigen (HLA) class I worldwide, HLA A*02.
 
This widespread Spike P272L mutation has arisen in five different SARS-CoV-2 lineages to date and was common in the B.1.177 lineage associated with establishing the ‘second wave’ in Europe. The large CD8 T-cell response seen across a cohort of HLA A*02+ convalescent patients, comprising of over 120 different TCRs, failed to respond to the P272L variant suggesting that proline 272 dominates TCR contacts with this epitope.
 
Furthermore, sizable populations (0.01%-0.2%) of total CD8 T-cells from individuals vaccinated against SARS-CoV-2 stained with HLA A*02-YLQPRTFLL multimers but failed to bind to the P272L reagent. Viral escape at prevalent T-cell epitopes restricted by high frequency HLA may be particularly problematic when vaccine immunity is focused on a single protein such as SARS-CoV-2 Spike and provides a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlights the urgent need for monitoring T-cell escape in new SARS-CoV-2 variants.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.06.21.21259010v1
 
The study team warns that a widespread mutation that has arisen in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to escape recognition by CD8 T-cell responses in both convalescent patients and recipients of the current coronavirus disease 2019 (COVID-19) vaccines.
 
It should be noted that the spike protein mediates the initial stage of the SARS-CoV-2 infection process and is the structure that currently-approved COVID-19 vaccines have been based on.  
 
Alarmingly the spike mutation-P272L-has so far arisen in five different SARS-CoV-2 lineages, including the B.1.177 lineage that was associated with a second pandemic wave in Europe.
 
The study team showed that CD8 T-cells from a cohort of convalescent patients that comprised more than 120 different T cell receptors (TCRs) failed to respond to the P272L variant.
Also a sizeable population of CD8 T-cells from individuals immunized with the currently approved COVID-19 vaccines failed to bind to a P272L reagent.
 
Corresponding author Dr Andrew Sewell from the Division of Infection and Immunity, Cardiff University School of Medicine, said that viral escape at prevalent T-cell epitopes may be particularly problematic when vaccine immunity is focu sed on a single protein such as the SARS-CoV-2 spike.
 
He said that the viral escape observed here provides a strong argument for the inclusion of multiple viral proteins in next-generation vaccines and highlights the urgent need for monitoring T-cell escape in new SARS-CoV-2 variants.
 
The human host adaptive immune system protects against viral infection by selecting specific antigen receptors present on B-cells and T-cells.
 
Though the mechanisms SARS-CoV-2 uses to escape adaptive immunity are not yet well understood, they are now firmly in the spotlight according to the study team.
 
However most research into the immune responses generated by SARS-CoV-2 infection has so far focused on antibody-mediated immunity, some evidence suggests that antibodies may play a secondary role to T-cells in clearing the virus.
 
Dr Sewell told Thailand Medical News, “There are also many reports of healthy individuals successfully controlling SARS-CoV-2 infection without having detectable neutralizing, or receptor-binding domain (RBD) antibodies, while having prominent SARS-CoV-2-specific T-cell memory. Indeed, the relative scarcity of naïve T-cells in individuals over 65 years old and the connection between aging and impaired adaptive immune responses to SARS-CoV-2 has been suggested as a major cause of severe disease.”
 
Interestingly a growing body of evidence also indicates that Human Leukocyte Antigen class I (HLA-I)-restricted CD8 killer T-cells contribute to the immunity provided by currently approved COVID-19 vaccines.
 
Considering  the potential importance of CD8 T-cells in adaptive immune protection against COVID-19, the study team set out to examine dominant T-cell responses to SARS-CoV-2 infection via the most prevalent major histocompatibility complex (MHC) allele in humans – HLA A*02. This HLA MHC class I molecule presents processed intracellular viral protein antigens at the cell surface for inspection by CD8 T-cells.
 
An earlier study using overlapping peptides from the entire SARS-CoV-2 proteome identified that the most common HLA A*02-restricted responses among convalescent patients were to epitopes contained within residues 3881 to 3900 of the open reading frame 1ab (ORF1ab) and residues 261 to 280 of the spike protein. The spike epitope was then narrowed down to residues 269-277 (sequence YLQPRTFLL).
 
Dr Sewell further added, “We, therefore, focused our attention on residues 269-277 of the SARS-CoV-2 spike protein.”
The study findings showed that the most prevalent mutation-P272L-in this T-cell epitope (sequence YLQLRTFLL) was not recognized by more than 120 TCRs that responded to the founder epitope (YLQPRTFLL) across a cohort of nine HLA A*02+ convalescent patients.
 
The study team also found that sizeable populations (0.01-0.02%) of CD8 T-cells that were stained with peptide-HLA A*02 multimers bearing the YLQPRTFLL peptide in a cohort of individuals vaccinated against SARS-CoV-2 could not be stained by reagents manufactured using the P272L variant.
 
Dr Sewell added, “We conclude that the YLQPRTFLL-specific T-cells induced by current COVID vaccines fail to engage to the P272L variant sequence.”
 
The study team says the findings show that SARS-CoV-2 can readily alter its spike protein via a single amino acid substitution so that it is no longer recognized by CD8 T-cells targeting the most prevalent spike epitope restricted by the most common HLA-I across the population.
 
Dr Sewell said, “The specific focusing of immune protection on a single protein (e.g., SARS-CoV-2 spike favored by all currently approved vaccines) is likely to enhance any tendency for escape at predominant T-cell epitopes like YLQPRTFLL. Our demonstration that mutations that evade immunodominant T-cell responses through population-frequent HLA can readily arise and disseminate strongly suggests that it will be prudent to monitor such occurrences and to increase the breadth of next-generation SARS-CoV-2 vaccines to incorporate other viral proteins.”
 
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