UK Study Finds That SARS-CoV-2 Spike Mutation P272L Emerged To Evade Killer T-Cells Induced By Infection And Inoculation

A new study by researchers from Cardiff University School of Medicine-UK has found that the SARS-CoV-2 spike mutation P272L emerged to basically evade killer T-Cells generated by infection and vaccination.


 
The study found that the SARS-CoV-2 Spike mutation P272L emerged and transmitted in several viral lineages including in the current Omicron variants.
 
The residue 272 sits centrally in a frequently targeted, dominant killer T cell epitope and the study findings showed that P272L escaped from >175 T cell receptors raised in cohorts of patients and vaccines.
 
The research team studied the prevalent cytotoxic CD8 T cell response mounted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein 269-277 epitope (sequence YLQPRTFLL) via the most frequent human leukocyte antigen (HLA) class I worldwide, HLA A∗02.
 
The Spike P272L mutation that has arisen in at least 112 different SARS-CoV-2 lineages to date, including in lineages classified as “variants of concern,” was not recognized by the large CD8 T cell response seen across cohorts of HLA A∗02+ convalescent patients and individuals vaccinated against SARS-CoV-2, despite these responses comprising of over 175 different individual T cell receptors.
 
Viral escape at prevalent T cell epitopes restricted by high frequency HLAs may be particularly problematic when vaccine immunity is focused on a single protein such as SARS-CoV-2 Spike, providing a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlighting the need for monitoring T cell escape in new SARS-CoV-2 variants.
 
The study findings were published in the peer reviewed journal: Cell.
https://www.cell.com/cell/fulltext/S0092-8674(22)00849-2
 
The SARS-CoV-2 spike mutation P272L first arose during the United Kingdom's second wave of COVID-19, which began in September 2020, and has been pinpointed to the part of the spike protein most frequently recognized by killer T-cells. The SARS spike protein is also the basis for current vaccines.
 
Interestingly, this "escape mutation" has been found in more than 100 viral lineages to date, including those classed as "variants of concern." It has been seen in strains in the U.K. and Europe, and in Australia and the U.S. between September 2020 and March 2022.
 
Typically, when a mutation arises independently multiple times this raises concerns the virus is evolving for a reason such as immune escape.
 
The study findings have shown that the P272L Spike mutation escaped recognition by killer T-cells in a group of health care workers from south Wales infected with SARS-CoV-2 early in the pandemic.
 
Alarmingly, this mutation also evaded all T-cells raised against this part of the virus in donors that had been vaccinated.
 
The study team says monitoring for "viral escape" is important and if mutations like P272L start to dominate then future vaccines may need to be altered to include different viral proteins.
 
Professor Dr Andrew Sewell, from Cardiff University's School of Medicine and Systems Immunity Research Institute who is the lead author of the study to ld Thailand Medical News ,"We studied more than 175 different types of killer T-cells that could see the part of the virus containing the P272L mutation and were surprised to see that this one mutation resulted in escape in all the donors studied.”
 
Professor Sewell further added, "Similar escape mutations have been seen in influenza viruses. It has been estimated the virus that caused the 1968 Hong Kong flu pandemic has mutated to escape from recognition by a type of killer T-cell once every three years."
 
He continued, “Alarmingly, in this study, P272L escaped from more than 175 T-cell receptors, both in the COVID patients and those who had been vaccinated.”
 
It was stated that since this study was completed, the mutation has been observed in the original omicron variant (BA.1) in England.
 
However, this variant was outcompeted by other omicron variants (most recently BA.5) that are more transmissible, but the study team anticipates that the killer T-cell escape mutant may arise and transmit in BA.5 and any subsequent variants.
 
An expert in SARS-CoV-2 genomics from Cardiff University's School of Biosciences and Systems Immunity Research Institute, Professor Dr Tom Connor commented, "The P272L mutation has arisen in many different SARS-CoV-2 lineages since the start of the pandemic. The independent evolution of the same mutation in multiple viral lineages is an example of homoplasy, which may be suggestive of a mutation that could confer a selective advantage.”
 
He added, "I anticipate that we may see more occurrences of the P272L variant over time, as the virus continues its evolution into a human pathogen. Our work emphasizes how much we still have to learn about SARS-CoV-2, and the importance of monitoring T-cell escape in future."
 
Clinical research lead who collected the study samples, Dr Lucy Jones added, "Our study looked at recognition of the virus spike protein by the most common sort of killer T-cell across the population. If the P272L mutation comes to predominate in time, it might be advantageous to provide vaccine boosts with this new sequence or to extend vaccination to include other viral proteins. Current vaccines work well and should still be taken up by people, but our study findings suggest vaccines may need altering as we learn more about the virus."
 
The study team added, It is important to note, however, that as the pandemic progresses, and SARS-CoV-2 reaches an optimal position with regards to ACE2 binding and cell entry, it is likely that other selective advantages (such as T cell escape) will become more important in the mix of potential advantages that the virus could develop to enable it to persist as a human pathogen. It is also instructive that P272L has continued to emerge on a local level since its first emergence in early 2020, including in all variants of concern identified to date. Amongst these, P272L emerged and showed local spread in both B.1.1.7/Alpha and B.1.617.2/Delta, including significant numbers of cases in Australia, Italy, and the US. Based upon these observations, we believe that P272L, and other similar mutations that will impact T cell epitopes, will become increasingly important as a route for SARS-CoV-2 lineages to increase their competitiveness, particularly as global vaccination rates increase. Our study findings suggest that the 269–277 epitope of Spike is one region that should be monitored, and its impact considered as part of the development of next generation vaccines. Furthermore, the potential of T cell escape presented by mutations in this region would argue for the inclusion of mutations in the 269–277 epitope of Spike in risk assessments by public health agencies going forward.”
 
The study team concluded, “In summary, our study findings demonstrated that SARS-CoV-2 can readily alter its Spike protein via a single amino acid substitution so that it is not recognized by CD8 T cells targeting the most prevalent epitope in Spike restricted by the most common HLA-I across the population. While it is not possible to directly attribute the emergence and propagation of the Spike P272L SARS-CoV-2 variant in parts of the world where HLA A∗02:01 is frequently expressed to CD8 T cell-mediated selection pressure, specific focusing of immune protection on a single protein is likely to enhance any tendency for escape at predominant T cell epitopes like YLQPRTFLL. Our study findings demonstrate 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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