Antigenic variation of SARS-CoV-2 in response to immune pressure

Abstract

Analysis of the bat viruses most closely related to SARS-CoV-2 indicated that the virus probably required limited adaptation to spread in humans. Nonetheless, since its introduction in human populations, SARS-CoV-2 must have been subject to the selective pressure imposed by the human immune system. We exploited the availability of a large number of high-quality SARS-CoV-2 genomes, as well as of validated epitope predictions, to show that B cell epitopes in the spike glycoprotein (S) and in the nucleocapsid protein (N) have higher diversity than nonepitope positions. Similar results were obtained for other human coronaviruses and for sarbecoviruses sampled in bats. Conversely, in the SARS-CoV-2 population, epitopes for CD4⁺ and CD8⁺ T cells were not more variable than nonepitope positions. A significant reduction in epitope variability was instead observed for some of the most immunogenic proteins (S, N, ORF8 and ORF3a). Analysis over longer evolutionary time frames indicated that this effect is not due to differential constraints. These data indicate that SARS-CoV-2 evolves to elude the host humoral immune response, whereas recognition by T cells is not actively avoided by the virus. However, we also found a trend of lower diversity of T cell epitopes for common cold coronaviruses, indicating that epitope conservation per se is not directly linked to disease severity. We suggest that conservation serves to maintain epitopes that elicit tolerizing T cell responses or induce T cells with regulatory activity.

Keywords: B cell epitope; COVID‐19; SARS‐CoV‐2; T cell epitope; human coronavirus; sarbecovirus.

FIGURE 1

Amino acid variability of the SARS‐CoV‐2 spike protein. Shannon's entropy (H) values for each amino acid position calculated using 10,000 SARS‐CoV‐2 spike proteins are shown. B cell predicted epitopes and T cell predicted epitopes are also reported in blue and green, respectively. B cell epitopes identified in the sera of COVID‐19 patients (Farrera‐Soler et al., ; Poh et al., 2020) are also reported in red

FIGURE 2

Variability of epitope and nonepitope positions among SARS‐CoV‐2 proteins. Shannon's entropy (H) mean values along with standard errors are shown for all SARS‐CoV‐2 proteins longer than 60 residues. Epitope positions are shown in dark grey and nonepitopes in light grey. Significant comparisons, calculated by a permutation approach, are indicated with asterisks (*p < .05; **p < .01; ***p < .001). Immunogenic proteins are shown in blue and the length of each protein is reported in the bottom panel

FIGURE 3

Variability of epitope and nonepitope positions among sarbecoviruses. Shannon's entropy (H) mean values along with standard errors are shown for a set of sarbecovirus ORFs. SARS‐CoV‐2 epitope positions are shown in dark grey and nonepitopes in light grey. Significant comparisons, calculated by a permutation approach, are indicated with asterisks (*p < .05; ** p < .01; *** p < .001)

FIGURE 4

Variability of epitope and nonepitope positions among human coronaviruses. Shannon's entropy (H) mean values along with standard errors are shown for human coronavirus spike and nucleocapsid proteins. Epitope positions are shown in dark grey and nonepitopes in light grey. Significant comparisons, calculated by a permutation approach, are indicated with asterisks (*p < .05; ** p < .01; *** p < .001)