In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

1st Medical Faculty at Biocev Charles University Vestec Prague Czechia

AMED CREST Japan Agency for Medical Research and Development Tokyo Japan

Center for Animal Disease Control University of Miyazaki Miyazaki Japan

Center for iPS Cell Research and Application Kyoto University Kyoto Japan

Collaboration Unit for Infection Joint Research Center for Human Retrovirus infection Kumamoto University Kumamoto Japan

CREST Japan Science and Technology Agency Kawaguchi Japan

Department of Biomolecular Sciences Weizmann Institute of Science Rehovot Israel

Department of Cancer Pathology Faculty of Medicine Hokkaido University Sapporo Japan

Department of Clinical Pathology Faculty of Medicine Suez Canal University Ismailia Egypt

Department of Medicinal Sciences Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan

Department of Microbiology and Immunology Faculty of Medicine Hokkaido University Sapporo Japan

Department of Veterinary Science Faculty of Agriculture University of Miyazaki Miyazaki Japan

Division of International Research Promotion International Institute for Zoonosis Control Hokkaido University Sapporo Japan

Division of Molecular Pathobiology International Institute for Zoonosis Control Hokkaido University Sapporo Japan

Division of Molecular Virology and Genetics Joint Research Center for Human Retrovirus infection Kumamoto University Kumamoto Japan

Division of Pathogen Structure International Institute for Zoonosis Control Hokkaido University Sapporo Japan

Division of Risk Analysis and Management International Institute for Zoonosis Control Hokkaido University Sapporo Japan

Division of Systems Virology Department of Microbiology and Immunology The Institute of Medical Science The University of Tokyo Tokyo Japan

Global Station for Biosurfaces and Drug Discovery Hokkaido University Sapporo Japan

Graduate School of Frontier Sciences The University of Tokyo Kashiwa Japan

Graduate School of Medicine and Veterinary Medicine University of Miyazaki Miyazaki Japan

Graduate School of Medicine The University of Tokyo Tokyo Japan

HiLung Inc Kyoto Japan

Institute for Chemical Reaction Design and Discovery Hokkaido University Sapporo Japan

Institute for Genetic Medicine Hokkaido University Sapporo Japan

Institute for Medical Virology and Epidemiology of Viral Diseases University Hospital Tübingen Tübingen Germany

Institute for Vaccine Research and Development HU IVReD Hokkaido University Sapporo Japan

International Collaboration Unit International Institute for Zoonosis Control Hokkaido University Sapporo Japan

International Research Center for Infectious Diseases The Institute of Medical Science The University of Tokyo Tokyo Japan

International Vaccine Design Center The Institute of Medical Science The University of Tokyo Tokyo Japan

Laboratory of Biomolecular Science and Center for Research and Education on Drug Discovery Faculty of Pharmaceutical Sciences Hokkaido University Sapporo Japan

Laboratory of Medical Virology Institute for Life and Medical Sciences Kyoto University Kyoto Japan

Laboratory of Virus Control Research Institute for Microbial Diseases Osaka University Suita Japan

Medical Research Council University of Glasgow Centre for Virus Research Glasgow UK

One Health Research Center Hokkaido University Sapporo Japan

Tokyo Metropolitan Institute of Public Health Tokyo Japan

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Multiple mutations of SARS-CoV-2 Omicron BA.2 variant orchestrate its virological characteristics

Virological characteristics of the SARS-CoV-2 omicron XBB.1.16 variant

Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant

Enhanced transmissibility, infectivity, and immune resistance of the SARS-CoV-2 omicron XBB.1.5 variant