Spike Mutations – Potential Implications for Vaccine T Cell Responses
Many countries have initiated COVID-19 vaccination programmes in the belief that herd immunity achieved through widespread vaccination will eventually end the pandemic. The vaccines in use so far solely target the Spike protein from SARS-CoV-2, and the world is now anxiously following the appearance of novel strains of coronavirus that bear mutations in the Spike protein.
Escape Variants Reduce the Immunogenic Footprint of a Virus
For now, it appears that Spike carries sufficient immune reactivity via its T cell epitopes to protect vaccinated individuals from infection. However, the natural occurrence of mutations within the SARS-CoV-2 genome can lead to the disappearance of immunogenic T cell epitopes, yielding so-called escape variants with a lower immunogenic footprint. Such escape variants have the potential to greatly compromise the current Spike-based vaccine strategy (1). One example of such a variant could be the D614G variant first reported in February 2020, which rapidly spread in Europe and the US and now is the most prevalent SARS-CoV-2 strain worldwide (2).
D614G Could Be an A*0201 Escape Variant
Our in vitro analysis revealed that the wild-type (WT) Spike peptide YQDVNCTEV binds strongly to A*0201 (the most common Caucasian HLA I allele) whereas the D614G mutant (YQGVNCTEV) exhibits 100-fold lower binding affinity for the same HLA molecule (7 and 700nM, respectively (Figure 1)). This could conceivably result in a much lower CD8+ T cell response against the D614G variant, and may explain its rapid spread throughout Europe where A*0201 is the most frequent HLA allele.
Figure 1: Affinity assessment of wild-type and D614G Spike variant on A*0201.
The Largest HLA Restriction Study of Spike, Mapping Potential T Cell Epitopes
At Immunitrack we epitope-mapped Spike by measuring all possible 1,200 overlapping 9-mer peptides derived from its amino acid sequence in in vitro peptide-binding assays on 20 frequently-encountered HLA I and II molecules. This work identified a total of around 100 epitopes specific for HLA I and 100 epitopes specific to HLA II. Most reported T cell epitopes derived from Spike were mapped in our dataset.
The UK Variant B1.1.7 Contains 8 Spike Mutations, Most Map to Potential T Cell Epitopes
The much-feared B.1.1.7 variant, popularly referred to as the ‘UK variant’, bears several mutations in the Spike protein: deletion 69-70 and deletion 144, as well as amino acid substitutions N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H. As listed in Table 1, our in vitro analysis shows that most of these mutations map to epitopes that bind to HLA I or HLA II, and therefore are likely to trigger a CD8+ or CD4+ T cell response. CD4+ T cell responses are particularly important for the development of a neutralising antibody response.
Our ongoing work will determine whether or not these mutations abrogate binding of the epitopes to their respective HLA. However, it is plausible to consider that the loss of epitopes that trigger a T cell response could result in reduced viral clearance, increased viral load and increased infectivity.
Interestingly, the South African variant K417N is harboured within a potential T cell epitope (Table 1).
We would be delighted to hear from companies or research groups interested in pursuing studies with these epitopes using HLA class I tetramers derived from our in vitro study of Spike. If you would like to test our reagents or enquire about access to the full Spike HLA restriction report, please reach out to us using the contact information below.
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