Influence of HLA Class II Polymorphism on Predicted Cellular Immunity Against SARS-CoV-2 at the Population and Individual Level

Abstract

Development of adaptive immunity after COVID-19 and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented on HLA class II molecules, by CD4+ T-cells. We capitalised on extensive high-resolution HLA data on twenty five human race/ethnic populations to investigate the role of HLA polymorphism on SARS-CoV-2 immunogenicity at the population and individual level. Within populations, we identify wide inter-individual variability in predicted peptide presentation from structural, non-structural and accessory SARS-CoV-2 proteins, according to individual HLA genotype. However, we find similar potential for anti-SARS-CoV-2 cellular immunity at the population level suggesting that HLA polymorphism is unlikely to account for observed disparities in clinical outcomes after COVID-19 among different race/ethnic groups. Our findings provide important insight on the potential role of HLA polymorphism on development of protective immunity after SARS-CoV-2 infection and after vaccination and a firm basis for further experimental studies in this field.

Keywords: COVID-19; SARS-CoV-2; T-cells; cellular immunity; human leukocyte antigens.

Figure 1

SARS-CoV-2 viral proteome presentation at the molecular HLA class II level. The number of viral peptides presented by individual HLA is shown for (A) the entire SARS-CoV-2 proteome; (B). Spike protein (S protein); (C) Nucleocapsid protein (N protein); (D) Membrane protein (M protein); and (E) Envelope protein (E protein). The HLA frequency in four broad ethnic populations is shown (AFA, African Americans; API, Asian and Pacific Islanders; CAU, Caucasians; HIS, Hispanics). Bars are coloured according to HLA locus, as shown. HLA were included in the figure if they had a frequency of ≥ 1% in any haplotype distribution from the four broad population groups.

Figure 2

SARS-CoV-2 derived peptide presentation at the HLA haplotype level. Panels depict SARS-CoV-2 peptide presentation by HLA class II haplotypes representing 99% of total haplotypes within four broad population groups (African Americans, Asian Pacific Islanders, Caucasians and Hispanics). (A) Whole Proteome. (B) Spike protein (S protein). (C) Nucleocapsid protein (N protein). (D) Membrane protein (M protein). (E) Envelope protein (E protein). The width of each step in the curves is proportional to the relative frequency of a specific HLA haplotype.

Figure 3

SARS-CoV-2 derived peptide presentation at the HLA genotype level (broad population groups). Panels depict the number of SARS-CoV-2 peptides presented by individual HLA class II genotypes in simulated populations of 10,000 individuals for four broad population groups (African Americans, Asian Pacific Islanders, Caucasians and Hispanics). (A) Whole Proteome. (B) Spike protein (S protein). (C). Nucleocapsid protein (N protein). (D) Membrane protein (M protein). (E) Envelope protein (E protein). (F) Receptor Binding Domain of Spike protein. The width of each step in the curves is proportional to the relative frequency of a specific HLA genotype. The boxplot charts depict the median, interquartile range (box) and range (whiskers - excluding outliers) for the number of viral peptides presented at the population level for each of the above ethnic groups.

Figure 4

Immunogenicity maps of SARS-CoV-2 proteome at the population level. The panels depict the percentage of HLA class II genotypes, within populations of 10,000 individuals (AFA, African Americans; API, Asian Pacific Islanders; CAU, Caucasians and HIS, Hispanics), that are predicted to present individual SARS-CoV-2 peptides from (A). Spike protein (S protein), S1, S2 and Receptor Binding Domain (RBD) are also shown; (B). Nucleocapsid protein (N protein); (C). Membrane protein (M protein); (D). Envelope protein (E protein); and (E). Open Reading Frame (ORF) 1ab polyprotein.