Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses

Dacon, Cherrelle; Peng, Linghang; Lin, Ting-Hui; Tucker, Courtney; Lee, Chang-Chun David; Yu, Cong; Wang, Lingshu; Purser, Lauren; Cooper, Andrew J.; Williams, Jazmean K.; Pyo, Chul‐Woo; Yuan, Meng; Košík, Ivan; Hu, Zhe; Zhao, Ming; Mohan, Divya; Peterson, Mary; Skinner, Jeff; Dixit, Saurabh; Kollins, Erin; Huzella, Louis; Perry, Donna L.; Byrum, Russell; Lembirik, Sanae; Murphy, Michael; Zhang, Yi; Yang, Eun Sung; Chen, Man; Leung, Kwanyee; Weinberg, Rona Singer; Pegu, Amarendra; Geraghty, Daniel E.; Davidson, Edgar; Doranz, Benjamin J.; Douagi, Iyadh; Moir, Susan; Yewdell, Jonathan W.; Schmaljohn, Connie S.; Crompton, Peter D.; Mascola, John R.; Holbrook, Michael R.; Nemazee, David; Wilson, Ian A.; Tan, Joshua

doi:10.1016/j.chom.2022.10.010

Cited by 36 publications

(39 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15 ). S2hlx-Ex15 and -Ex19 binding was also tested against broadly reactive stem helix antibodies Cov89-22 and Cov30-14, which were recently discovered and were not explicitly targeted by the design 23 . Both ESs bound tightly by ELISA ( Supp.…”

Section: Resultsmentioning

confidence: 99%

Engineered Immunogens to Elicit Antibodies Against Conserved Coronavirus Epitopes

Kapingidza

Marston

Harris

et al. 2023

Preprint

View full text Add to dashboard Cite

Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which can readily mutate to escape acquired immunity. Other regions in the spike S2 subunit, such as the fusion peptide and the stem helix, are highly conserved across sarbecoviruses and recognized by broadly reactive antibodies, providing hope that targeting these epitopes by vaccination could offer protection against both current and emergent viruses. Here we employed computational modeling to design epitope scaffolds that display the fusion peptide and the stem helix epitopes. The engineered proteins bound both mature and germline versions of multiple broad and protective human antibodies with high affinity. Binding specificity was confirmed both biochemically and via high resolution crystal structures. Finally, the epitope scaffolds showed potent engagement of antibodies and memory B-cells from subjects previously exposed to SARS-CoV2, illustrating their potential to elicit antibodies against the fusion peptide and the stem helix by vaccination.

show abstract

Section: Resultsmentioning

confidence: 99%

Engineered Immunogens to Elicit Antibodies Against Conserved Coronavirus Epitopes

Kapingidza

Marston

Harris

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…This site has the potential to be a pan-α-HCoV epitope for vaccine development if neutralisation activity is conserved across α-HCoVs. In addition to the NTD, several pan-β-HCoV and pan-CoV mAbs directed against conserved sites within the S2 domain have been reported (16)(17)(18)(19). One such mAb, 76E1, recognises a highly conserved epitope between the S2' site and fusion peptide and could neutralise 6 human coronaviruses, with IC50 values ranging from 0.4-4.8µg/ml (16).…”

Section: Discussionmentioning

confidence: 99%

Monoclonal antibodies against human coronavirus NL63 spike

Conlan

Tan

Esterbauer

et al. 2023

Preprint

View full text Add to dashboard Cite

The COVID-19 pandemic has illustrated the potential for monoclonal antibody therapeutics as prophylactic and therapeutic agents against pandemic viruses. No such therapeutics currently exist for other human coronaviruses. NL63 is a human alphacoronavirus that typically causes the common cold and uses the same receptor, ACE2, as the highly pathogenic SARS-CoV and SARS-CoV-2 pandemic viruses. In a cohort of healthy adults, we characterised humoral responses against the NL63 spike protein. While NL63 spike and receptor binding domain-specific binding antibodies and neutralisation activity could be detected in plasma of all subjects, memory B cells against NL63 spike were variable and relatively low in frequency compared to that against SARS-CoV-2 spike. From these donors, we isolated a panel of antibodies against NL63 spike and characterised their neutralising potential. We identified potent neutralising antibodies that recognised the receptor binding domain (RBD) and other non-RBD epitopes within spike.

show abstract

“…The S2 subunit is more conserved than S1 and, therefore, considered an attractive target for the development of neutralizing antibodies with broad anti-sarbecovirus potential. Several monoclonal antibodies that recognize conserved sites in the S2 subunit such as the stem helix or the fusion peptide of SARS coronaviruses have been described (6)(7)(8)(9)(10). In general, however, S2-specific monoclonal antibodies exhibit poor virus neutralizing activity.…”

Section: Introductionmentioning

confidence: 99%

Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that bind a conserved membrane proximal epitope of the spike

Molle

Schie

et al. 2023

Preprint

View full text Add to dashboard Cite

Currently circulating SARS-CoV-2 variants have gained complete or significant resistance to all SARS-CoV-2-neutralizing antibodies that have been used in the clinic. Such antibodies can prevent severe disease in SARS-CoV-2 exposed patients for whom vaccines may not provide optimal protection. Here, we describe single-domain antibodies (VHHs), also known as nanobodies, that can broadly neutralize SARS-CoV-2 with unusually high potency. Structural analysis revealed their binding to a unique, highly conserved, membrane proximal, quaternary epitope in the S2 subunit of the spike. Furthermore, a VHH-human IgG1 Fc fusion, efficiently expressed in Chinese hamster ovary cells as a stable antibody construct, protected hamsters against SARS-CoV-2 replication in a therapeutic setting when administered systemically at low dose. This VHH-based antibody represents a new candidate anti-COVID-19 biologic that targets the Achilles heel of the viral spike.

show abstract

Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses

Cited by 36 publications

References 74 publications

Engineered Immunogens to Elicit Antibodies Against Conserved Coronavirus Epitopes

Engineered Immunogens to Elicit Antibodies Against Conserved Coronavirus Epitopes

Monoclonal antibodies against human coronavirus NL63 spike

Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that bind a conserved membrane proximal epitope of the spike

Contact Info

Product

Resources

About