A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection

Zhou, Panpan; Yuan, Meng; Song, Ge; Beutler, Nathan; Shaabani, Namir; Huang, Deli; He, Wanting; Zhu, Xueyong; Callaghan, Sean; Yong, Peter; Anzanello, Fabio; Peng, Linghang; Ricketts, James; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A.; Smith, Davey M; Nemazee, David; Teijaro, John R.; Rogers, Thomas F.; Wilson, Ian A.; Burton, Dennis R.; Andrabi, Raiees

doi:10.1101/2021.03.30.437769

Cited by 67 publications

(87 citation statements)

References 116 publications

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“…The development of universal vaccination strategies against Sarbecoviruses will be improved by the identification and characterization of broadly protective and conserved epitopes across SARS-like virus strains. Recent studies described broadly reactive antibodies that target the subunit 2 (S2) portion of the spike protein [28][29][30][31] . While the broad recognition of these S2specific antibodies is encouraging, these antibodies weakly neutralized diverse CoVs.…”

Section: Discussionmentioning

confidence: 99%

A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice

Martinez

Schaefer

Gobeil

et al. 2021

Preprint

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SARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.

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Section: Discussionmentioning

confidence: 99%

A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice

Martinez

Schaefer

Gobeil

et al. 2021

Preprint

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“…Though S2H97-like antibodies are rare in polyclonal sera, the protective capacity and exceptional breadth of S2H97 indicates that pan-sarbecovirus vaccines could seek to improve responses to this epitope by unmasking this and other cryptic broadly neutralizing epitopes 5,37,41 . Broader cross-reactivity among betacoronavirus lineages including MERS and OC43 has been reported for antibodies that bind the spike S2 domain 32,38,42 . Though S2H97 breadth does not extend beyond sarbecoviruses, its discovery expands our view of what can be achieved via a potent RBD-directed antibody response.…”

Section: Principles For Optimizing Antibody and Vaccine Developmentmentioning

confidence: 99%

SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape

Starr

Czudnochowski

Liu

et al. 2021

Nature

440

532

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An ideal anti-SARS-CoV-2 antibody would resist viral escape [1][2][3] , have activity against diverse SARS-related coronaviruses (sarbecoviruses) [4][5][6][7] , and be highly protective through viral neutralization [8][9][10][11] and effector functions 12,13 . Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a tradeoff between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we characterize one potent RBM antibody (S2E12 8 ) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth, and potency among antibodies targeting the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.The most potently neutralizing antibodies to SARS-CoV-2-including those in clinical use 14 and dominant in polyclonal sera 15,16 -target the spike receptor-binding domain (RBD). Mutations in the RBD that reduce binding by antibodies have emerged among SARS-CoV-2 variants [17][18][19][20][21] , highlighting the need for antibodies and vaccines that are robust to viral escape. We have previously described an antibody, S309 4 , that exhibits potent effector functions and neutralizes all current SARS-CoV-2 variants 22,23 and the divergent sarbecovirus SARS-CoV-1. S309 forms the basis for an antibody therapy (VIR-7831, recently renamed sotrovimab) that has received Emergency Use Authorization from the FDA for treatment of COVID-19 24 . Longer term, antibodies with broad activity across SARS-related coronaviruses (sarbecoviruses) would be useful to combat potential future spillovers 6 . These efforts would be aided by a systematic understanding of the relationships among antibody epitope,

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“…The S2 subunit contains the fusion machinery and undergoes large-scale conformational changes to drive fusion of the virus and host membranes (14), enabling genome delivery and initiation of infection. Abs that bind to specific sites on the RBD (15)(16)(17)(18)(19)(20)(21)(22), the NTD (23)(24)(25)(26), or the fusion machinery stem helix (27)(28)(29)(30)(31) interfere with receptor attachment or membrane fusion. Serum neutralizing Ab titers are a correlate of protection against SARS-CoV-2 in non-human primates (32)(33)(34)(35).…”

mentioning

confidence: 99%

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

McCallum

Walls

Sprouse

et al. 2021

Preprint

110

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Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.

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A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection

Cited by 67 publications

References 116 publications

A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice

A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice

SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

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