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An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.
Luo, Sai; Zhang, Jun; Kreutzberger, Alex J B; Eaton, Amanda; Edwards, Robert J; Jing, Changbin; Dai, Hai-Qiang; Sempowski, Gregory D; Cronin, Kenneth; Parks, Robert; Ye, Adam Yongxin; Mansouri, Katayoun; Barr, Maggie; Pishesha, Novalia; Williams, Aimee Chapdelaine; Vieira Francisco, Lucas; Saminathan, Anand; Peng, Hanqin; Batra, Himanshu; Bellusci, Lorenza; Khurana, Surender; Alam, S Munir; Montefiori, David C; Saunders, Kevin O; Tian, Ming; Ploegh, Hidde; Kirchhausen, Tom; Chen, Bing; Haynes, Barton F; Alt, Frederick W.
  • Luo S; Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Zhang J; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Kreutzberger AJB; Division of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Eaton A; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • Edwards RJ; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Jing C; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Dai HQ; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • Sempowski GD; Department of Surgery, Duke University, Durham, NC 27710, USA.
  • Cronin K; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • Parks R; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
  • Ye AY; Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Mansouri K; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Barr M; Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Pishesha N; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Williams AC; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • Vieira Francisco L; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
  • Saminathan A; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • Peng H; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
  • Batra H; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • Bellusci L; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
  • Khurana S; Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Alam SM; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Montefiori DC; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • Saunders KO; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • Tian M; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
  • Ploegh H; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Kirchhausen T; Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Chen B; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Haynes BF; Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • Alt FW; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Sci Immunol ; 7(76): eadd5446, 2022 10 28.
Article in English | MEDLINE | ID: covidwho-1992933
ABSTRACT
SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human VH1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several VH1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived VH1-2-based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy-based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Vaccines / Variants Limits: Animals / Humans Language: English Journal: Sci Immunol Year: 2022 Document Type: Article Affiliation country: Sciimmunol.add5446

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Vaccines / Variants Limits: Animals / Humans Language: English Journal: Sci Immunol Year: 2022 Document Type: Article Affiliation country: Sciimmunol.add5446