Widespread SARS-CoV-2 mutation escapes vaccine- and infection-induced CD8 T-cell responses

Researchers in the UK have warned 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.

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.  

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.

Now, a team from Cardiff University, Cardiff University School of Medicine, the University of Oxford, and the COVID-19 Genomics UK consortium have shown 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.

Furthermore, sizeable populations of CD8 T-cells from individuals immunized with the currently approved COVID-19  vaccines failed to bind to a P272L reagent.

Andrew Sewell and colleagues say that viral escape at prevalent T-cell epitopes may be particularly problematic when vaccine immunity is focused on a single protein such as the SARS-CoV-2 spike.

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, says the team.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.

Study: Emergence of immune escape at dominant SARS-CoV-2 killer T-cell epitope. Image Credit: NIAID
Study: Emergence of immune escape at dominant SARS-CoV-2 killer T-cell epitope. Image Credit: NIAID

The role of adaptive immunity in protecting against SARS-CoV-2

The host adaptive immune system protects against viral infection by selecting specific antigen receptors present on B-cells and T-cells.

While the mechanisms SARS-CoV-2 uses to escape adaptive immunity are not yet well understood, they are now firmly in the spotlight, says Sewell and colleagues.

Although 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.

“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,” write the researchers.

“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,” they add.

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.

What did the researchers do?

Given the potential importance of CD8 T-cells in adaptive immune protection against COVID-19, the 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.

A previous 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).

“We, therefore, focused our attention on residues 269-277 of the SARS-CoV-2 spike protein,” says Sewell and colleagues.

What did the study find?

The researchers found 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.

SARS-CoV-2 variation in the immunodominant Wuhan-YLQPRTFLL dominant HLA A*02:01- restricted CD8 T-cell epitope. a, Cumulative frequency of all sequences; sequences in the B.1.177 lineage; and sequences possessing the P272L variant, both in B.1.177 and other lineages across the United Kingdom (left) and worldwide (right). Total number of P272L variants by nation, binned into periods of 10 epidemiological (EPI) weeks is shown in Supplementary Figure 1. b, Top 15 most frequently observed variants observed in worldwide Spike glycoprotein sequence data in lineage B.1.177. Data for all lineages is shown in Supplementary Figure 3. c, Phylogenetic tree showing 1227 taxa with variants at Spike position 272, with colours indicating subtrees representing potential independent mutations, computed by ASR on a larger tree of 200 221 taxa (not shown). d, Total number of sequences possessing P272L variant in England and Wales per administrative region up to and including 31st January 2021.
SARS-CoV-2 variation in the immunodominant Wuhan-YLQPRTFLL dominant HLA A*02:01- restricted CD8 T-cell epitope. a, Cumulative frequency of all sequences; sequences in the B.1.177 lineage; and sequences possessing the P272L variant, both in B.1.177 and other lineages across the United Kingdom (left) and worldwide (right). Total number of P272L variants by nation, binned into periods of 10 epidemiological (EPI) weeks is shown in Supplementary Figure 1. b, Top 15 most frequently observed variants observed in worldwide Spike glycoprotein sequence data in lineage B.1.177. Data for all lineages is shown in Supplementary Figure 3. c, Phylogenetic tree showing 1227 taxa with variants at Spike position 272, with colours indicating subtrees representing potential independent mutations, computed by ASR on a larger tree of 200 221 taxa (not shown). d, Total number of sequences possessing P272L variant in England and Wales per administrative region up to and including 31st January 2021.

The 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.

“We conclude that the YLQPRTFLL-specific T-cells induced by current COVID vaccines fail to engage to the P272L variant sequence,” writes Sewell and colleagues.

Top 15 most frequently observed variants observed in worldwide spike glycoprotein sequence data in all lineages. Those thought to be associated with enhanced viral transmission are shown in green and those listed as potentially escaping from antibody mediated-mediated immunity are shown in light pink (possible) and dark pink (high confidence) ass assigned at http://sars2.cvr.gla.ac.uk/cog-uk/#shiny-tab-immunology. This colour-coding of substitutions is used throughout the figure. Variants of unknown function in grey. N501Y also escapes from antibodies b, Fraction of days per month where five or more P272L variants were sequenced in B.1.177 background. c-d, Mapping of mutants shown in A onto Spike sequence map and prefusion structure (PDB 6VXX; Walls et al. 2020. Cell, 181, 281-291)
Top 15 most frequently observed variants observed in worldwide spike glycoprotein sequence data in all lineages. Those thought to be associated with enhanced viral transmission are shown in green and those listed as potentially escaping from antibody-mediated-mediated immunity are shown in light pink (possible) and dark pink (high confidence) ass assigned at http://sars2.cvr.gla.ac.uk/cog-uk/#shiny-tab-immunology. This color-coding of substitutions is used throughout the figure. Variants of unknown function in grey. N501Y also escapes from antibodies b, Fraction of days per month where five or more P272L variants were sequenced in B.1.177 background. c-d, Mapping of mutants shown in A onto Spike sequence map and prefusion structure (PDB 6VXX; Walls et al. 2020. Cell, 181, 281-291)

Important implication for the development of next-generation vaccines

The researchers say 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.

“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,” says the team.

“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,” concludes Sewell and colleagues.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Robertson, Sally. (2021, June 29). Widespread SARS-CoV-2 mutation escapes vaccine- and infection-induced CD8 T-cell responses. News-Medical. Retrieved on September 18, 2021 from https://www.news-medical.net/news/20210629/Widespread-SARS-CoV-2-mutation-escapes-vaccine-and-infection-induced-CD8-T-cell-responses.aspx.

  • MLA

    Robertson, Sally. "Widespread SARS-CoV-2 mutation escapes vaccine- and infection-induced CD8 T-cell responses". News-Medical. 18 September 2021. <https://www.news-medical.net/news/20210629/Widespread-SARS-CoV-2-mutation-escapes-vaccine-and-infection-induced-CD8-T-cell-responses.aspx>.

  • Chicago

    Robertson, Sally. "Widespread SARS-CoV-2 mutation escapes vaccine- and infection-induced CD8 T-cell responses". News-Medical. https://www.news-medical.net/news/20210629/Widespread-SARS-CoV-2-mutation-escapes-vaccine-and-infection-induced-CD8-T-cell-responses.aspx. (accessed September 18, 2021).

  • Harvard

    Robertson, Sally. 2021. Widespread SARS-CoV-2 mutation escapes vaccine- and infection-induced CD8 T-cell responses. News-Medical, viewed 18 September 2021, https://www.news-medical.net/news/20210629/Widespread-SARS-CoV-2-mutation-escapes-vaccine-and-infection-induced-CD8-T-cell-responses.aspx.

Comments

  1. Nate Klingenstein Nate Klingenstein United States says:

    If P272L is the optimal amino acid change for CD8+ T-cell escape, its failure to emerge thus far in B.1.617.2, B.1.1.7, or other widely circulating strains in a somewhat vaccinated population is vexing.  It might be constrained by protein stability.  Mutations have occurred at sites 273 and 274 as well, and the entire 269-277 epitope is important, so that area bears very close watching.  There may need to be a compensatory reversion or mutation that lowers the binding energy of these variants before a potentially destabilizing P272L or other mutation in the epitope can succeed.

    • Suliban Helix Suliban Helix United Kingdom says:

      B.1.1.7 is pretty much a dinosaur now (like B.1.177 before it). Delta and epsilon will be the ones to watch. The compensatory mutation idea is good and happens in HIV. A222V seems like the most likely candidate if this were the case as it defined B.1.177 where the P227L mutation really took off and appears to be unassigned (no clear function) in figure above. *I should point out that I'm not a viral phylogenetics expert!* 😝

      • Nate Klingenstein Nate Klingenstein United States says:

        I agree with most of what you wrote, but I wouldn't write off Alpha as a dinosaur.  The evolutionary machinery of SARS-CoV-2 is amazing, and 8 new spike mutations just popped out in an Alpha descendant.  We really don't know what any given variant might spit out as long as it's extant.

        The paper does show that P272L escapes a very common dominant CD8+ T-cell response.  A222 is in an immunodominant epitope for CD4+ cells for one HLA allele and an immunodominant epitope for CD8+ cells for many alleles, so mutations there could very well have T-cell evasive effects.  I would imagine your theory is also accurate.

        The two mutations are not mutually exclusive.  There are 1468 known CD4+ and CD8+ epitopes in SARS-CoV-2.  Each T-cell recognizes approximately 35 epitopes.  We should expect to see more evasion.

  2. Nate Klingenstein Nate Klingenstein United States says:

    If syncytia are an effective immune escape strategy, as suggested by an earlier study covered here, then it would seem that emergence of CD8+ T-cell immunity would be particularly important for B.1.617.2, since they're the cells most responsible for cleanup of infected cells, polynucleated or not, no?

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
You might also like... ×
Study reveals Pfizer/BioNTech and Oxford/AstraZeneca COVID-19 vaccine efficacy and immune response in clinically vulnerable individuals