BREAKING! Oxford Study Reveals New Omicron Variants And Sub-lineages Causes Impaired T Cell Immunogenicity With Potential For T Cell Immunity Escape!

COVID-19 News: Already with so many of the newly emerged Omicron variants and sub-lineages displaying greater and wider antibody escape, the potential threat of future variants or sub-lineages characterized by T cell evasion is an ongoing concern that is worrying many researchers.


 
As SARSCoV-2 approaches optimal cell entry, other selection advantages, e.g., T cell escape, may be utilized to increase pathogenic fitness. While extensive research has been undertaken to estimate effects of SARS-CoV-2 mutations on antibody recognition, mutational impact on T cell epitopes is poorly understood. Indeed, the ability to rapidly estimate the extent to which mutations impact T cell immunogenicity would reduce uncertainty upon emergence of a novel VOC.
 
A new study by researchers from MRC Weatherall Institute of Molecular Medicine (WIMM) at John Radcliffe Hospital, University of Oxford -UK has worryingly found that the new Omicron variants and sub-lineages are causing impaired T Cell Immunogenicity with potential for T Cell immunity escape.
 
Such COVID-19 News is not only alarming but shows that current complacency in the way that the pandemic is being managed is going to be disastrous for humankind as we are potentially dealing with a virus that could be even far more worse than HIV, with the only difference that besides slowly killing the the majority who are not in the vulnerable groups, there are no known effective antivirals to curtail its powers of damage unlike HIV.
 
In order to assess how the extent emerging mutations, affect T cell immunogenicity, the study team generated ‘immunogenicity’ scores by combining 1) a ‘netMHCpan’ antigen presentation score and 2) the ‘TRAP’ T cell recognition score. By examining immunogenicity scores of 580 paired Wuhan-mutated WT vs. MT pMHC (from any protein), the study team observed that while global predicted T cell immunogenicity is preserved upon Omicron, BA1 epitopes show a subtle reduction when compared with their Wuhan Hu-1 counterparts.
 
When the study team repeated this analysis for Omicron subvariants BA2, BA4 and BA5, the same trend was observed. The study team also examined cross-HLA variation and observed reduced BA1 T cell immunogenicity for HLA-A02 and -C01 ligands.
 
However, for BA2, BA4 and BA5 on the other hand the study team observed significant impairments in T cell immunogenicity for HLA-A02, -A03, -B07 and -C01 ligands.
 
Interestingly, the magnitude of impairment per supertype varied between subvariants, suggesting that different mutations across Omicron-based VOC produce nuanced effects on T cell immunogenicity that appear to be HLA-dependent.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.10.21.513200v1
 
It must be noted that T cell recognition of SARS-CoV-2 antigens after vaccination and/or natural infection has played a central role in resolving SARS-CoV-2 infections and generating adaptive immune memory.
 
/> However, the clinical impact of SARS-CoV-2-specific T cell responses is variable and the mechanisms underlying T cell interaction with target antigens are not fully understood. This is especially true given the virus rapid evolution, which leads to new variants with immune escape capacity.
 
The study team used the Omicron variant as a model organism and took a systems approach to evaluate the impact of mutations on CD8+ T cell immunogenicity.
 
The study team computed an immunogenicity potential score for each SARS-CoV-2 peptide antigen from the ancestral strain and Omicron, capturing both antigen presentation and T cell recognition probabilities.
 
Importantly, by comparing ancestral vs. Omicron immunogenicity scores, the study findings revealed a divergent and heterogeneous landscape of impact for CD8+ T cell recognition of mutated targets in Omicron variants.
 
Although T cell recognition of Omicron peptides is broadly preserved, the study team observed mutated peptides with deteriorated immunogenicity that may assist breakthrough infection in some individuals.
 
The study team then combined their scoring scheme with an in-silico mutagenesis, to characterize the position- and residue-specific theoretical mutational impact on immunogenicity.
 
Although the findings indicated many escape trajectories from the theoretical landscape of substitutions, the study findings suggests that Omicron mutations in T cell epitopes did not develop under cell-mediated pressure.
 
The study findings provide a generalizable platform for fostering a deeper understanding of existing and novel variant impact on antigen-specific vaccine- and/or infection-induced T cell immunity.
 
In the study, the researchers used in silico approaches i) to examine how mutations among Omicron VOCs affect SARS-CoV-2-specific CD8+ T cell responses and ii) to provide a preliminary framework for how theoretical mutations can impact SARS-CoV-2 epitopes.
 
The study is a step toward estimating the impact of mutation(s) on T cell immunogenicity upon the emergence of novel VOC.
 
The study team demonstrated how T cell immunogenicity modelling can be used to not only dissect the impact of existing mutations on T cell responses, but also to forecast theoretical mutations that may be most detrimental for T cell immunity when combined with in silico mutagenesis.
 
The study team envisions that this work can support ongoing surveillance and forecasting efforts and serve as a foundation of a knowledge base for determining how VOC may impact T cell responses upon their emergence.
 
Previous ‘broad brush’ approaches have failed to uncover evidence of T cell escape following key variant mutations.
 
During the early stages of Omicron’s rise to global dominance, the overwhelming consensus argued that Omicron does not significantly impair T cell responses.
 
Unfortunately, due to the diversity of HLA and breadth of epitopes, it had rightly been reasoned that widespread and complete T cell escape is unlikely at this stage of the pandemic.
 
Past in silico studies compared all theoretical HLA ligands across specific VOC and concluded that T cell responses to Omicron were likely to be maintained effectively.
 
It should be noted however that not all HLA ligands can invoke T cell responses.
 
Past studies observed considerable numbers of patients with impaired T cell responses to Omicron infection.
https://pubmed.ncbi.nlm.nih.gov/35018386/
 
https://pubmed.ncbi.nlm.nih.gov/35699621/
 
https://pubmed.ncbi.nlm.nih.gov/35474748/
 
Although widespread and complete escape is unlikely, it is plausible that detrimental mutations could impair certain individuals e.g., with certain HLAs and narrow TCR repertoires targeting impacted pMHC.
 
Hence, the study team hypothesized that some Omicron mutations may be more detrimental than the consensus, affecting the responses of some individuals more than others.
 
Already another past study also supported this hypothesis indicating heterogeneous effects on binding HLA, given mutations among VOCs prior to Omicron.
https://pubmed.ncbi.nlm.nih.gov/35149224/
 
The study team thus investigated CD8+ T cell targets with a mutation in Omicron and used predictive modelling to infer the effects of each mutation on T cell immunogenicity.
 
The study findings support a body of literature that indicates overall, there exists a subtle reduction in T cell immunogenicity with mutated epitopes in Omicron VOCs, compared to Wuhan Hu-1.
 
The study by examining mutated epitopes in detail, extends this paradigm, revealing a divergent landscape for how different CD8+ T cell targets are affected by Omicron-based mutation(s).
 
The study findings showed that this heterogeneous landscape may produce a net impairment on some individuals’ T cell response against Omicron VOC, likely conditioned by bias toward certain epitopes in individual repertoires and patient HLA genotype.
 
The study team speculates that these combined factors may lead to T cell escape in some individuals and perhaps breakthrough infections, although as many epitopes are not mutated in emerging Omicron variants and sub-lineages, the extent to which mutated epitopes contribute to clinical outcome remains to be elucidated.
 
Alarmingly, evidence of SARS-CoV-2-specific T cell escape has begun to emerge.
 
One recent study for example identified two mutations in a non-Hodgkin’s lymphoma patient infected with SARSCoV-2, which escaped CD8+ T cell responses.
https://assets.researchsquare.com/files/rs-750741/v1_covered.pdf?c=1631874979
 
Another study focused on the dominant HLA-A02 epitope YLQ, which was found to evade >175 TCRs due to a PàL mutation.
https://pubmed.ncbi.nlm.nih.gov/35931021/
 
Prior to Omicron’s emergence, another study found that proline removals in Delta and Alpha could damage HLA-B07 pMHC binding.
https://pubmed.ncbi.nlm.nih.gov/34637888/
 
By extending these insights, this new study modelling predicts that PàX Omicron mutations eliminate certain HLA-B07 pMHC.
 
The study findings along with previous published works mentioned above indicates that PàX mutations which are now observed across Omicron variants that have infected large proportions of populations in CD8+ T cell epitopes should be a priority for surveillance regarding T cell escape in HLA-B07 individuals and for associations with breakthrough infections.
 
The study findings combined with recent studies is starting to indicate a more nuanced outlook regarding the impact of newer Omicron mutations on T cell responses, than the consensus.
 
Currently, there are ongoing efforts to characterize disorders that are considered ‘post-COVID’ complications, ranging from so-called long-COVID to broad inflammatory disease.
 
A leading hypothesis underpinning observations of multisystem inflammatory disorder and severe acute hepatitis, is that a theoretical SARS-CoV-2 superantigen promotes aberrant T cell activation.
https://pubmed.ncbi.nlm.nih.gov/35874696/
 
https://pubmed.ncbi.nlm.nih.gov/35576952/
 
Importantly, the ‘PRRA’ motif, part of the hypothesized core of a SARS-CoV-2 superantigen overlays three CD8+ T cell epitopes that have mutations in BA1 Omicron.
https://www.mdpi.com/2076-0817/11/4/390
 
https://pubmed.ncbi.nlm.nih.gov/32989130/
 
The study findings of the current research indicates that after Omicron mutation, 9/15 of the pMHC containing this theoretical superantigen core are removed as HLA ligands.
 
The study team proposes that remaining presenters HLA-A*33:03, -A31:03, -B14:02 be investigated for associations with inflammatory disorders following COVID-19 infection. More generally, the study team have predicted that a set of pMHC are likely to exhibit increased immunogenicity and bind more TCRs following Omicron mutation.
 
Critically, further investigation is warranted to assess these particular CD8+ T cell targets, HLAs and cognate TCRs, for associations with post COVID inflammatory disorders.
 
The study findings with potential exceptions, do not suggest that reductions in T cell immunogenicity observed with Omicron were the result of immune pressure.
 
Many evaluated epitopes were predicted to be escape-prone, albeit with variation, given theoretical single point substitution. This insight could be concerning, given the considerable number of unexplored mutations available for SARS-CoV-2 that the study findings estimate could lead to T cell escape.
 
The study findings would help researchers understand to what extent the loss of immunogenic epitopes due to mutation affects clinical outcomes.
 
The study team concluded, “We have utilized in-silico approaches to assess the impact of existing and theoretical mutations on SARS-CoV-2 CD8+ T cell targets. We reveal a divergent, heterogeneous landscape of impact for Omicron VOC. We proposed a framework for forecasting the effects of theoretical SARS-CoV-2 mutations using immunogenicity modelling and in-silico mutagenesis. We hope that our work provides a gateway toward a comprehensive and publicly available approach for assessing the impact of mutations on T cell immunogenicity upon emergence of novel VOC. In the case of detrimental impacts, we envision this approach, given further development, could rapidly generate a profile of affected epitopes and HLAs to estimate populations that are most likely be affected by novel VOC. Our framework should next be applied to all known SARS-CoV-2 CD8+ T cell epitopes to i) fully characterize escape-prone vs. robust epitopes, ii) identify further theoretical mutations warranting surveillance and iii) further molecular insight into the biology underpinning mutation impact.
 
As the newer emerging Omicron variants and sub-lineages that are more antibody evasive start dominating in circulation and starts causing more surges and also reinfections and coinfections, variants and sub-lineages that start developing advance T Cell escape is not only going to cause more havoc but the long term health and medical issues are also go to be catastrophic for humankind!
 
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