Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant
Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant
Abstract The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains an unusually high number of mutations (>30) in the spike protein, raising concerns of escape from vaccines, convalescent sera and therapeutic drugs. Here we analyze the alteration of neutralizing titer with Omicron pseudovirus. Sera obtained 3 months after double BNT162b2 vaccination exhibit approximately 18-fold lower neutralization titers against Omicron than parental virus. Convalescent sera from Alpha and Delta patients allow similar levels of breakthrough by Omicron. Domain-wise analysis using chimeric spike revealed that this efficient evasion was primarily achieved by mutations clustered in the receptor-binding domain, but that multiple mutations in the N-terminal domain contributed as well. Omicron escapes a therapeutic cocktail of imdevimab and casirivimab, whereas sotrovimab, which targets a conserved region to avoid viral mutation, remains effective. The ACE2 decoy is another virus-neutralizing drug modality that is free, at least in theory, from complete escape. Deep mutational analysis demonstrated that, indeed, engineered ACE2 prevented escape for each single-residue mutation in the receptor-binding domain, similar to immunized sera. Engineered ACE2 neutralized Omicron comparable to Wuhan and also showed a therapeutic effect against Omicron infection in hamsters and human ACE2 transgenic mice. Like previous SARS-CoV-2 variants, some sarbecoviruses showed high sensitivity against engineered ACE2, confirming the therapeutic value against diverse variants, including those that are yet to emerge. One Sentence SummaryOmicron, carrying ～30 mutations in the spike, exhibits effective immune evasion but remains highly susceptible to blockade by engineered ACE2.
Hoshino Atsushi、Taminishi Shunta、Arimori Takao、Suzuki Tatsuya、Itoh Yumi、Ozaki Yuki、Nakamura Shota、Okamoto Toru、Takagi Junichi、Katoh Kazutaka、Standley Daron M、Inaba Tohru、Ikemura Nariko、Motooka Daisuke、Kirita Yuhei、Higuchi Yusuke、Li Songling、Matoba Satoaki
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka UniversityInstitute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka UniversityInstitute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka UniversityInstitute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka UniversityLaboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka UniversityDepartment of Genome Informatics, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Genome Informatics, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Infection Control and Molecular Laboratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Genome Informatics, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
医药卫生理论医学研究方法生物科学现状、生物科学发展
Hoshino Atsushi,Taminishi Shunta,Arimori Takao,Suzuki Tatsuya,Itoh Yumi,Ozaki Yuki,Nakamura Shota,Okamoto Toru,Takagi Junichi,Katoh Kazutaka,Standley Daron M,Inaba Tohru,Ikemura Nariko,Motooka Daisuke,Kirita Yuhei,Higuchi Yusuke,Li Songling,Matoba Satoaki.Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2021.12.22.473804.点此复制
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