The SARS-CoV-2 Omicron BA.1 spike G446S mutation potentiates antiviral T cell recognition

Points

• We identified two immunodominant epitopes (NF9/A24 and QI9/A24) presented by HLA-A*24:02 in BNT162b2 or mRNA-1273 vaccinated donors.
• We found that NF9/A24 specific CD8⁺ T cells strongly suppress Omicron BA.1 replication.
• We demonstrated that the G446S mutation in the Omicron BA.1 variant affects antigen processing/presentation and potentiates antiviral activity by vaccine-induced T cells.

Backgrounds

The SARS-CoV-2 Omicron variant (BA.1; B.1.1.529.1), first identified in November 2021, is a novel variant that has rapidly spread around the globe.
BA.1 has >30 mutations in the spike protein that contribute to reduced sensitivity to vaccine-induced antibody neutralization. In contrast, vaccine induced SARS-CoV-2-specific T cells retain their reactivity to a number of different variants. However, the characteristics of vaccine-induced T cells cross-reactive for the Omicron virus are only poorly understood.

Results

We showed that CD8⁺ T cells specific for NF9/A24 (S_448-456: NYNYLYRLF) and QI9/A24 (S_1208-1216: QYIKWPWYI) are predominantly induced in vaccinated donors with HLA-A*24:02 that is one of the most widely distributed HLA-I alleles globally (predominantly in Est Asia). We newly established the system to evaluate antiviral activity of T cells against SARS-CoV-2 infected cells by monitoring suppression of viral replication by T cells in vitro (Figure 1) and demonstrated that NF9/A24-specific T cells strongly suppressed replication of Omicron BA.1 variant to a greater extent than the prototype or Omicron BA.2 (Figure 2). No suppression was observed against the Delta variant, presumably due to the T-cell escape mutation L452R in the Delta spike protein^1-2. Mutagenesis analyses revealed that a G446S mutation, located just outside the N-terminus of the cognate epitope, augmented T cell recognition of Omicron BA.1 variant (Figure 3).

Future direction

Although the Omicron variant of the SARS-CoV-2 virus shows resistance to neutralizing antibody, we here demonstrated that SARS-CoV-2 spike mutation enhances antiviral activity of T cells against SARS-CoV-2-infected cells. These findings provide better insights for the rational design of vaccine antigens to induce efficient cellular immunity via antigen processing/presentation.

Reference

1. Kimura I et al. The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance. Cell Reports, 38(2):110218, 2022.

2. Motozono C et al. SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity. Cell Host & Microbe 29(7):1124-1136.e11., 2021.

Title

The SARS-CoV-2 Omicron BA.1 spike G446S mutation potentiates antiviral T cell recognition

Authors

Chihiro Motozono^{1, 2*}, Mako Toyoda¹, Toong Seng Tan¹, Hiroshi Hamana³, Yoshihiko Goto^{1, 4}, Yoshiki Aritsu⁵, Yusuke Miyashita^{6, 7}, Hiroyuki Oshiumi⁶, Kimitoshi Nakamura⁷, Seiji Okada⁸, Keiko Udaka⁹, Mizuki Kitamatsu⁵, Hiroyuki Kishi³, Takamasa Ueno^1*

¹ Division of Infection and immunity, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
² Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita 5650871, Japan
³ Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama 9300194, Japan
⁴ Department of Respiratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 8608556, Japan
⁵ Department of Applied Chemistry, Faculty of Science and Engineering, Kindai University, Osaka 577-8502, Japan
⁶ Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 8608556, Japan
⁷ Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 8608556, Japan
⁸ Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 8600811, Japan
⁹ Department of Immunology, Kochi University, Kochi 783-8505, Japan

Nature Communications

doi£º10.1038/s41467-022-33068-4
URL£ºhttps://www.nature.com/articles/s41467-022-33068-4