The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.

Center for iPS Cell Research and Application Kyoto University Kyoto Japan

Center for iPS Cell Research and Application Tokyo Japan

Department of Biomolecular Sciences Weizmann Institute of Science Rehovot Israel

Department of Biomolecular Sciences Weizmann Institute of Science Rehovot Israel; 1st Medical Faculty at Biocev Charles University Vestec Prague Czechia

Department of Cancer Pathology Faculty of Medicine Hokkaido University Sapporo Japan

Department of Cancer Pathology Faculty of Medicine Hokkaido University Sapporo Japan; Institute for Chemical Reaction Design and Discovery Hokkaido University Sapporo Japan

Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan

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 Microbiology and Immunology Faculty of Medicine Hokkaido University Sapporo Japan; Laboratory of Virus Control Research Institute for Microbial Diseases Osaka University Suita Japan

Department of Veterinary Science Faculty of Agriculture University of Miyazaki Miyazaki Japan; Graduate School of Medicine and Veterinary Medicine University of Miyazaki Miyazaki Japan

Department of Veterinary Science Faculty of Agriculture University of Miyazaki Miyazaki Japan; Graduate School of Medicine and Veterinary Medicine University of Miyazaki Miyazaki Japan; Center for Animal Disease Control University of Miyazaki Miyazaki Japan

Division of Infection and immunity Joint Research Center for Human Retrovirus infection Kumamoto University Kumamoto 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 Pathobiology International Institute for Zoonosis Control Hokkaido University Sapporo Japan; Division of International Research Promotion International Institute for Zoonosis Control Hokkaido University Sapporo Japan; One Health Research Center Hokkaido University Sapporo Japan

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

Division of Molecular Virology and Genetics Joint Research Center for Human Retrovirus infection Kumamoto University Kumamoto Japan; Department of Clinical Pathology Faculty of Medicine Suez Canal University Ismailia Egypt

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

Division of Systems Virology Department of Microbiology and Immunology The Institute of Medical Science The University of Tokyo Tokyo Japan; Faculty of Medicine Kobe University Kobe Japan

Division of Systems Virology Department of Microbiology and Immunology The Institute of Medical Science The University of Tokyo Tokyo Japan; Graduate School of Medicine The University of Tokyo Tokyo Japan

Division of Systems Virology Department of Microbiology and Immunology The Institute of Medical Science The University of Tokyo Tokyo Japan; Graduate School of Medicine The University of Tokyo Tokyo 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; Graduate School of Frontier Sciences The University of Tokyo Kashiwa Japan; Collaboration Unit for Infection Joint Research Center for Human Retrovirus infection Kumamoto University Kumamoto Japan; CREST Japan Science and Technology Agency Kawaguchi Japan

Global Station for Biosurfaces and Drug Discovery Hokkaido University Sapporo Japan; Division of Pathogen Structure International Institute for Zoonosis Control Hokkaido University Sapporo Japan

Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan

HiLung Inc Kyoto Japan

Institute for Genetic Medicine Hokkaido University Sapporo Japan

Interpark Kuramochi Clinic Utsunomiya Japan; Department of Global Health Promotion Tokyo Medical and Dental University 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 Biomolecular Science and Center for Research and Education on Drug Discovery Faculty of Pharmaceutical Sciences Hokkaido University Sapporo Japan; Global Station for Biosurfaces and Drug Discovery Hokkaido University Sapporo Japan; Division of Pathogen Structure International Institute for Zoonosis Control Hokkaido University Sapporo Japan

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

One Health Research Center Hokkaido University Sapporo Japan; International Collaboration Unit International Institute for Zoonosis Control Hokkaido University Sapporo Japan; Division of Risk Analysis and Management International Institute for Zoonosis Control Hokkaido University Sapporo Japan

Tokyo Metropolitan Institute of Public Health Tokyo Japan

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