Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies
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, r...
| Autors principals: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Idioma: | English |
| Publicat: |
Cell Press
2024
|
| _version_ | 1826314559003033600 |
|---|---|
| author | Sheward, DJ Pushparaj, P Das, H Greaney, AJ Kim, C Kim, S Hanke, L Hyllner, E Dyrdak, R Lee, J Dopico, XC Dosenovic, P Peacock, TP McInerney, GM Albert, J Corcoran, M Bloom, JD Murrell, B Karlsson Hedestam, GB Hällberg, BM |
| author_facet | Sheward, DJ Pushparaj, P Das, H Greaney, AJ Kim, C Kim, S Hanke, L Hyllner, E Dyrdak, R Lee, J Dopico, XC Dosenovic, P Peacock, TP McInerney, GM Albert, J Corcoran, M Bloom, JD Murrell, B Karlsson Hedestam, GB Hällberg, BM |
| author_sort | Sheward, DJ |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-09-25T04:35:54Z |
| format | Journal article |
| id | oxford-uuid:f52a87f8-1e28-4784-a9fb-3063232450b7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:35:54Z |
| publishDate | 2024 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:f52a87f8-1e28-4784-a9fb-3063232450b72024-09-17T14:28:38ZStructural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodiesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f52a87f8-1e28-4784-a9fb-3063232450b7EnglishSymplectic ElementsCell Press2024Sheward, DJPushparaj, PDas, HGreaney, AJKim, CKim, SHanke, LHyllner, EDyrdak, RLee, JDopico, XCDosenovic, PPeacock, TPMcInerney, GMAlbert, JCorcoran, MBloom, JDMurrell, BKarlsson Hedestam, GBHällberg, BMDescendants 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. |
| spellingShingle | Sheward, DJ Pushparaj, P Das, H Greaney, AJ Kim, C Kim, S Hanke, L Hyllner, E Dyrdak, R Lee, J Dopico, XC Dosenovic, P Peacock, TP McInerney, GM Albert, J Corcoran, M Bloom, JD Murrell, B Karlsson Hedestam, GB Hällberg, BM Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies |
| title | Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies |
| title_full | Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies |
| title_fullStr | Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies |
| title_full_unstemmed | Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies |
| title_short | Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies |
| title_sort | structural basis of broad sars cov 2 cross neutralization by affinity matured public antibodies |
| work_keys_str_mv | AT shewarddj structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT pushparajp structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT dash structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT greaneyaj structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT kimc structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT kims structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT hankel structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT hyllnere structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT dyrdakr structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT leej structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT dopicoxc structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT dosenovicp structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT peacocktp structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT mcinerneygm structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT albertj structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT corcoranm structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT bloomjd structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT murrellb structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT karlssonhedestamgb structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies AT hallbergbm structuralbasisofbroadsarscov2crossneutralizationbyaffinitymaturedpublicantibodies |