An antibody from single human V-H-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion

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(H)1-2 heavy chain (HC) and, substantially, a human V.1-33 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(H)1-2/V.1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived V(H)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.

Automated summary

The Omicron subvariants of SARS-CoV-2 have caused a global crisis as they are resistant to most approved neutralizing antibodies and evade vaccination-induced antibodies. In this study, researchers describe a mouse model that produces a diverse repertoire of humanized SARS-CoV-2 neutralizing antibodies. Through immunization with SARS-CoV-2 spike protein, they identified a potent and broadly neutralizing antibody, SP1-77, which bound to the receptor-binding domain in a unique way. This antibody showed potential therapeutic value and could inform vaccine strategies. Furthermore, this humanized mouse model may contribute to the development of therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.