The spike receptor-binding motif G496S substitution determines the replication fitness of SARS-CoV-2 Omicron sublineage

Emerg Microbes Infect. 2022 Dec;11(1):2093-2101. doi: 10.1080/22221751.2022.2111977.

Abstract

The replication and pathogenicity of SARS-CoV-2 Omicron BA.2 are comparable to that of BA.1 in experimental animal models. However, BA.2 has rapidly emerged to overtake BA.1 to become the predominant circulating SARS-CoV-2 variant worldwide. Here, we compared the replication fitness of BA.1 and BA.2 in cell culture and in the Syrian hamster model of COVID-19. Using a reverse genetics approach, we found that the BA.1-specific spike mutation G496S compromises its replication fitness, which may contribute to BA.1 being outcompeted by BA.2 in the real world. Additionally, the BA.1-unique G496S substitution confers differentiated sensitivity to therapeutic monoclonal antibodies, which partially recapitulates the immunoevasive phenotype of BA.1 and BA.2. In summary, our study identified G496S as an important determinant during the evolutionary trajectory of SARS-CoV-2.

Keywords: COVID-19; G496S; Omicron BA.1; Omicron BA.2; fitness.

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • COVID-19*
  • Cricetinae
  • Humans
  • Mesocricetus
  • Mutation, Missense
  • SARS-CoV-2* / genetics
  • Spike Glycoprotein, Coronavirus / genetics

Substances

  • Antibodies, Monoclonal
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

This study was partly supported by funding from the Health and Medical Research Fund (COVID1903010 – Project 7 and Project 15, COVID190114, 21200562), the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region; Health@InnoHK, Innovation and Technology Commission, the Government of the Hong Kong Special Administrative Region; and the Collaborative Research Fund (C7060-21G and C7142-20GF) and the Theme-Based Research Scheme of the Research Grants Council (T11-709/21-N) of the Hong Kong Special Administrative Region; the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for Department of Health of the Hong Kong Special Administrative Region Government; the National Program on Key Research Project of China (2020YFA0707500 and 2020YFA0707504); Emergency COVID-19 Project, Major Projects on Public Security, National Key Research and Development Program (2021YFC0866100); Sanming Project of Medicine in Shenzhen, China (SZSM201911014); the High Level-Hospital Program, Health Commission of Guangdong Province, China; the research project of Hainan Academician Innovation Platform (YSPTZX202004); Emergency Collaborative Project of Guangzhou Laboratory (EKPG22-01); the University of Hong Kong Outstanding Young Researcher Award; and the University of Hong Kong Research Output Prize (Li Ka Shing Faculty of Medicine); and donations from the Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Lee Wan Keung Charity Foundation Limited, Providence Foundation Limited (in memory of the late Lui Hac Minh), Hong Kong Sanatorium & Hospital, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, The Chen Wai Wai Vivien Foundation Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie & George Ho Charitable Foundation, Perfect Shape Medical Limited, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation Limited, Betty Hing-Chu Lee, Ping Cham So, and Lo Ying Shek Chi Wai Foundation. The funding sources had no role in the study design, data collection, analysis, interpretation, or writing of the report.