tetano
Editor, Senior Moderator
Cell Rep Med
. 2024 May 15:101577.
doi: 10.1016/j.xcrm.2024.101577. Online ahead of print. Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies
Daniel J Sheward[SUP] 1 [/SUP], Pradeepa Pushparaj[SUP] 2 [/SUP], Hrishikesh Das[SUP] 3 [/SUP], Allison J Greaney[SUP] 4 [/SUP], Changil Kim[SUP] 2 [/SUP], Sungyong Kim[SUP] 2 [/SUP], Leo Hanke[SUP] 2 [/SUP], Erik Hyllner[SUP] 2 [/SUP], Robert Dyrdak[SUP] 2 [/SUP], Jimin Lee[SUP] 4 [/SUP], Xaquin Castro Dopico[SUP] 2 [/SUP], Pia Dosenovic[SUP] 2 [/SUP], Thomas P Peacock[SUP] 5 [/SUP], Gerald M McInerney[SUP] 2 [/SUP], Jan Albert[SUP] 2 [/SUP], Martin Corcoran[SUP] 2 [/SUP], Jesse D Bloom[SUP] 6 [/SUP], Ben Murrell[SUP] 7 [/SUP], Gunilla B Karlsson Hedestam[SUP] 8 [/SUP], B Martin Hällberg[SUP] 9 [/SUP]
Affiliations
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.
Keywords: IGHV3-53; SARS-CoV-2; affinity maturation; cross neutralization; cryo-EM; germinal center; public antibodies; somatic hypermutation.
. 2024 May 15:101577.
doi: 10.1016/j.xcrm.2024.101577. Online ahead of print. Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies
Daniel J Sheward[SUP] 1 [/SUP], Pradeepa Pushparaj[SUP] 2 [/SUP], Hrishikesh Das[SUP] 3 [/SUP], Allison J Greaney[SUP] 4 [/SUP], Changil Kim[SUP] 2 [/SUP], Sungyong Kim[SUP] 2 [/SUP], Leo Hanke[SUP] 2 [/SUP], Erik Hyllner[SUP] 2 [/SUP], Robert Dyrdak[SUP] 2 [/SUP], Jimin Lee[SUP] 4 [/SUP], Xaquin Castro Dopico[SUP] 2 [/SUP], Pia Dosenovic[SUP] 2 [/SUP], Thomas P Peacock[SUP] 5 [/SUP], Gerald M McInerney[SUP] 2 [/SUP], Jan Albert[SUP] 2 [/SUP], Martin Corcoran[SUP] 2 [/SUP], Jesse D Bloom[SUP] 6 [/SUP], Ben Murrell[SUP] 7 [/SUP], Gunilla B Karlsson Hedestam[SUP] 8 [/SUP], B Martin Hällberg[SUP] 9 [/SUP]
Affiliations
- PMID: 38761799
- DOI: 10.1016/j.xcrm.2024.101577
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.
Keywords: IGHV3-53; SARS-CoV-2; affinity maturation; cross neutralization; cryo-EM; germinal center; public antibodies; somatic hypermutation.