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An antibody from single human V H -rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion.
- Source :
-
Science immunology [Sci Immunol] 2022 Oct 28; Vol. 7 (76), pp. eadd5446. Date of Electronic Publication: 2022 Aug 11. - Publication Year :
- 2022
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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 V <subscript>H</subscript> 1-2 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 V <subscript>H</subscript> 1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived V <subscript>H</subscript> 1-2-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.
Details
- Language :
- English
- ISSN :
- 2470-9468
- Volume :
- 7
- Issue :
- 76
- Database :
- MEDLINE
- Journal :
- Science immunology
- Publication Type :
- Academic Journal
- Accession number :
- 35951767
- Full Text :
- https://doi.org/10.1126/sciimmunol.add5446