SARS-CoV-2 variants: Subversion of antibody response and predicted impact on T cell recognition
Authors: Daniel M. Altmann, Catherine J. Reynolds, Rosemary J. Boyton
Journal: Cell Reports Medicine (2021)

COVID-19 variants of concern, including B.1.1.7, B.1.351, and P.1, encompass mutations facilitating immune evasion. Neutralizing antibody recognition and function may be variably impaired. We considered the impact of mutations on T cell responses. Mutations could be neutral or result in either loss or gain of predicted epitopes depending on HLA type. COVID-19 variants of concern, including B.1.1.7, B.1.351, and P.1, encompass mutations facilitating immune evasion. Neutralizing antibody recognition and function may be variably impaired. We considered the impact of mutations on T cell responses. Mutations could be neutral or result in either loss or gain of predicted epitopes depending on HLA type. There have been recent descriptions of an increasingly prevalent SARS-CoV-2 variant phylogenetic cluster and, notably, the B.1.1.7 lineage (sometimes termed VOC 202012/01), which is associated with increased transmission in the United Kingdom. This variant is now described in some 25 countries, as well as additional variants of concern identified in South Africa (B.1.351/501Y.V2) and Brazil (P.1).1Kemp S.A. Meng B. Ferriera I.A.T.M. Datir R. Harvey W.T. Papa G. Lytras S. Collier D.A. Mohamed A. Gallo G. et al.Recurrent emergence and transmission of a SARS-CoV-2 spike deletion DH69/V70.bioRxiv. 2020; https://doi.org/10.1101/2020.12.14.422555Crossref Scopus (0) Google Scholar, 2Rambaut A. Loman N. Pybus O. Barclay W. Barrett J. Carabelli A. Connor T. Peacock T. Robertson D.L. Volz E. et al.Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations.2020https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563Google Scholar, 3Wang Z. Schmidt F. Weisblum Y. Muecksch F. Barnes C.O. Finkin S. Schaefer-Babajew D. Cipolla M. Gaebler C. 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Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies.Cell Host Microbe. 2021; 29: 463-476.e6Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar Preprints are now appearing in which the impact either of individual mutations or of the collective mutations within B.1.1.7, the South African 501Y.V2 or Brazilian B.1.1.28 and P.1 variants, is evaluated with respect to neutralization by convalescent sera (after natural infection with the wild-type variant), vaccinee sera after two boosts, or monoclonal antibodies generated from these immune repertoires.3Wang Z. Schmidt F. Weisblum Y. Muecksch F. Barnes C.O. Finkin S. Schaefer-Babajew D. Cipolla M. Gaebler C. Lieberman J.A. et al.mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.Nature. 2021; 592: 616-622https://doi.org/10.1038/s41586-021-03324-6Crossref PubMed Scopus (841) Google Scholar,4Wibmer C.K. Ayres F. Hermanus T. Madzivhandila M. Kgagudi P. Oosthuysen B. Lambson B.E. de Oliveira T. Vermeulen M. van der Berg K. et al.SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma.Nat. Med. 2021; 27: 622-625https://doi.org/10.1038/s41591-021-01285-xCrossref PubMed Scopus (671) Google Scholar, A report from Pfizer indicates marginal deleterious impact of the B.1.1.7 mutations on neutralization.10Muik A. Wallisch A.K. Sänger B. Swanson K.A. Mühl J. Chen W. Cai H. Maurus D. Sarkar R. Türeci Ö. et al.Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera.Science. 2021; 371: 1152-1153Crossref PubMed Scopus (344) Google Scholar However, reports on neutralization of the other variants suggest a significant ablation of spike recognition.3Wang Z. Schmidt F. Weisblum Y. Muecksch F. Barnes C.O. Finkin S. Schaefer-Babajew D. Cipolla M. Gaebler C. Lieberman J.A. et al.mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.Nature. 2021; 592: 616-622https://doi.org/10.1038/s41586-021-03324-6Crossref PubMed Scopus (841) Google Scholar,4Wibmer C.K. Ayres F. Hermanus T. Madzivhandila M. Kgagudi P. Oosthuysen B. Lambson B.E. de Oliveira T. Vermeulen M. van der Berg K. et al.SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma.Nat. Med. 2021; 27: 622-625https://doi.org/10.1038/s41591-021-01285-xCrossref PubMed Scopus (671) Google Scholar In the study from Wang and colleagues, a quarter of their neutralizing monoclonal panel showed substantially reduced binding to at least one of the mutant RBDs.3Wang Z. Schmidt F. Weisblum Y. Muecksch F. Barnes C.O. Finkin S. Schaefer-Babajew D. Cipolla M. Gaebler C. Lieberman J.A. et al.mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.Nature. 2021; 592: 616-622https://doi.org/10.1038/s41586-021-03324-6Crossref PubMed Scopus (841) Google Scholar Analysis of the impact on T cell recognition is still in progress. The contribution to protective immunity from T cells, with CD4 Th1 immunity having been highlighted in the response to SARS-CoV-2, is broad, targeting epitopes spanning the viral proteome. Hundreds of proposed epitopes have now been described (though in most cases, without defined HLA restriction), these of varying frequency within a given, infected individual and of varying prevalence as shared ("public") epitopes between individuals—those that can bind promiscuously within the peptide-binding grooves of diverse HLA alleles, with several such epitopes having been described.11Altmann D.M. Boyton R.J. SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection.Sci. Immunol. 2020; 5: eabd6160https://doi.org/10.1126/sciimmunol.abd6160Crossref PubMed Scopus (167) Google Scholar, 12Reynolds C.J. Swadling L. Gibbons J.M. Pade C. Jensen M.P. Diniz M.O. Schmidt N.M. Butler D.K. Amin O.E. Bailey S.N.L. et al.COVIDsortium investigatorsCOVIDsortium immune correlates networkDiscordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection.Sci. Immunol. 2020; 5: eabf3698https://doi.org/10.1126/sciimmunol.abf3698Crossref PubMed Scopus (0) Google Scholar, 13Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. et al.Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.Cell Rep Med. 2021; 2: 100204https://doi.org/10.1016/j.xcrm.2021.100204Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 14Nelde A. Bilich T. Heitmann J.S. Maringer Y. Salih H.R. Roerden M. Lübke M. Bauer J. Rieth J. Wacker M. et al.SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition.Nat. Immunol. 2021; 22: 74-85Crossref PubMed Scopus (331) Google Scholar We considered the maximal potential impact on the CD4 T cell SARS-CoV-2 repertoire initially by mapping each of the B.1.1.7 and 501Y.V2 coding changes and asking whether these impinged on predicted epitopes (Tables S1A and S1D). In doing so, we note the caveat that predictive algorithms such as NetMHCIIpan have proven value in prediction of T cell epitopes, but a prediction of "strong binding" need not necessarily equate to a strongly stimulatory T cell epitope. Furthermore, because of the greater variation in peptide lengths, the predictive algorithms are somewhat less robust for HLAII than for HLAI. We focused on common HLA-DRB1 alleles in countries currently encountering the spread of B.1.1.7: HLA-DRB1∗0101, 0301, 0401, 0701, 1101, 1301, and 1501. Nucleocapsid is epitope rich and, in most analyses, accounts for as great a component of the overall T cell response as spike. The B.1.1.7 mutation D3L is not predicted to lie within an epitope, and the S235F mutation may impact a potential weak binder in individuals who are DRB1∗0101. The coding mutations within the spike sequence are predicted to impact six "strong-binder" epitopes for people carrying some HLA alleles. The 69–70 HV deletion is predicted to impair the binding of a strong binder in people who are DRB1∗1501 while enhancing binding in those who are DRB1∗0101; Tarke et al. found responses to this epitope restricted by DR15 or DR16.13Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. et al.Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.Cell Rep Med. 2021; 2: 100204https://doi.org/10.1016/j.xcrm.2021.100204Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar The N501Y mutation would be predicted to generate a less stimulatory epitope only in people who are DRB1∗0401. Similarly, the D1118 mutation would likely have differential effects depending on HLA type, with improved binding in people who are DRB1∗0701 or DRB1∗1501 but loss of the response in those who are DRB1∗0301 or DRB1∗0401. Responses to this epitope have been found in a small minority of convalescent donors.13Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. et al.Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.Cell Rep Med. 2021; 2: 100204https://doi.org/10.1016/j.xcrm.2021.100204Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar Looking at likely epitope changes resulting from mutations in the South African 501Y.V2 variant, note that most of the changes have little effect, and the key, E484K mutation does not overlap a predicted CD4 epitope. The 242-244 LAL deletion/R2461 mutation is predicted to impair the binding of a weak binder in people who are DRB1∗0401 while enhancing binding in those who are DRB1∗0101 and DRB1∗0701. The D215G mutation is predicted to be associated with a loss of response in those who are DRB1∗0301 or DRB1∗0401, and the mutation A701V is predicted to be associated with a loss of response in DRB1∗0401. To understand this in context, one needs to appreciate that, with fine-mapping of spike T cell epitopes very much still ongoing, around 280 CD4 epitopes have already been identified13Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. et al.Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.Cell Rep Med. 2021; 2: 100204https://doi.org/10.1016/j.xcrm.2021.100204Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar; in individuals with a history of prior SARS-CoV-2 infection, on average, 3.2 and 2.7 proteins are strongly recognized by CD4+ or CD8+ SARS-CoV-2-specific T cells, respectively. None of the epitopes changed by the coding mutations seen in the B.1.1.7 and B.1.351 variants impacts the key immunodominant or subdominant CD4 epitopes elucidated by Nelde et al.14Nelde A. Bilich T. Heitmann J.S. Maringer Y. Salih H.R. Roerden M. Lübke M. Bauer J. Rieth J. Wacker M. et al.SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition.Nat. Immunol. 2021; 22: 74-85Crossref PubMed Scopus (331) Google Scholar As will be seen from the above analysis, such ablation of CD4 epitope recognition that does occur would impact differentially in people expressing different HLA alleles. Note also that mutations within a given epitope may yield one likely to be stronger as much as a weaker one: note, for example, that the 69–70 HV deletion in spike is predicted to generate improved immunogenicity for HLA-DR1 individuals but reduced immunogenicity for HLA-DR1501. T cell epitopes may be gained, lost, or unchanged in a variant compared to original sequence virus, as summarized in Figure 1. While most attention on likely correlates of protection centers on neutralizing antibody titer and, to a lesser extent, on CD4 T cell response, it is likely that CD8 immunity is important, and this response is strongly correlated with the antiviral CD4 response. While some 450 CD8 epitopes have been described across HLAI alleles,13Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. et al.Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.Cell Rep Med. 2021; 2: 100204https://doi.org/10.1016/j.xcrm.2021.100204Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar recognition of only 5 of these would be impaired (for some alleles) in an individual primed by natural infection or vaccination to the wild-type virus and then encountering the B.1.1.7 variant (Tables S1B and S1C). Note that, as seen for HLAII predictions, CD8 responses might be either gained or lost when challenged by variant sequence, depending on HLA type: the NP D3L mutation in B.1.1.7 causes gain of a predicted HLA∗A301 epitope. The N501Y mutation leads to loss of a predicted strong binder in HLA∗A101 individuals but gain of a predicted strong epitope in people who are HLA∗A1101. For the South African 501Y.V2 variant, CD8 responses might be either gained or lost when challenged by variant sequence, depending on HLA type (Tables S1E and S1F). From this analysis, it may be concluded that the B.1.1.7 variant has gained an advantage for population spread through several factors including enhanced ACE2 binding and greater potential for transmission due to increased copy number in the nasopharynx, but it is unlikely that it gains a substantial advantage through immune evasion at the level of either B cell or T cell recognition. There is a considerably higher degree of concern over the ability of mutations in the South African and Brazilian variants to evade immune memory elicited by wild-type spike vaccines, at least with respect to neutralizing antibody repertoire. R.J.B. and D.M.A. receive support from NIHR-GECO MR/V036939/1, United Kingdom,MR/S019553/1 and MR/R02622X/1, Medical Research Council Newton Fund, United Kingdom, NIHR Imperial Biomedical Research Centre (BRC): ITMAT, United Kingdom, Cystic Fibrosis Trust UK SRC (2019SRC015), and Horizon 2020 Marie Skłodowska-Curie Innovative Training Network (ITN) European Training Network (no. 860325). Professors Altmann and Boyton have received remuneration for consultancies with Oxford ImmunoTec. Download .pdf (.43 MB) Help with pdf files Document S1. Data S1 and Table S1