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TitleIn vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies.
Journal, issue, pagesCell, Vol. 184, Issue 16, Page 4203-4219.e32, Year 2021
Publish dateAug 5, 2021
AuthorsDapeng Li / Robert J Edwards / Kartik Manne / David R Martinez / Alexandra Schäfer / S Munir Alam / Kevin Wiehe / Xiaozhi Lu / Robert Parks / Laura L Sutherland / Thomas H Oguin / Charlene McDanal / Lautaro G Perez / Katayoun Mansouri / Sophie M C Gobeil / Katarzyna Janowska / Victoria Stalls / Megan Kopp / Fangping Cai / Esther Lee / Andrew Foulger / Giovanna E Hernandez / Aja Sanzone / Kedamawit Tilahun / Chuancang Jiang / Longping V Tse / Kevin W Bock / Mahnaz Minai / Bianca M Nagata / Kenneth Cronin / Victoria Gee-Lai / Margaret Deyton / Maggie Barr / Tarra Von Holle / Andrew N Macintyre / Erica Stover / Jared Feldman / Blake M Hauser / Timothy M Caradonna / Trevor D Scobey / Wes Rountree / Yunfei Wang / M Anthony Moody / Derek W Cain / C Todd DeMarco / Thomas N Denny / Christopher W Woods / Elizabeth W Petzold / Aaron G Schmidt / I-Ting Teng / Tongqing Zhou / Peter D Kwong / John R Mascola / Barney S Graham / Ian N Moore / Robert Seder / Hanne Andersen / Mark G Lewis / David C Montefiori / Gregory D Sempowski / Ralph S Baric / Priyamvada Acharya / Barton F Haynes / Kevin O Saunders /
PubMed AbstractSARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor- ...SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.
External linksCell / PubMed:34242577 / PubMed Central
MethodsEM (single particle)
Resolution2.97 - 19.3 Å
Structure data

EMDB-22920:
Negative stain electron microscopy structure of RBD-directed Fab DH1041 in complex with hexapro SARS-CoV-2 spike
Method: EM (single particle) / Resolution: 16.8 Å

EMDB-22921:
Negative stain electron microscopy reconstruction of RBD-directed Fab DH1042 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22923:
Negative stain electron microscopy reconstruction of Fab DH1043 in complex with hexapro SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22929:
Negative stain electron microscopy structure of RBD-directed Fab DH1044 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 13.8 Å

EMDB-22930:
Negative stain electron microscopy reconstruction of cross-reactive RBD-directed Fab DH1045 complexed with hexapro SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 10.2 Å

EMDB-22933:
Negative stain electro microscopy reconstruction of cross-reactive RBD-directed Fab DH1047 in complex with hexapro SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 8.4 Å

EMDB-22936:
Negative stain electron microscopy reconstruction of NTD-directed neutralizing antibody Fab DH1048 in complex with hexapro SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 16.8 Å

EMDB-22942:
Negative stain electron microscopy reconstruction of NTD-directed neutralizing antibody Fab DH1049 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 19.3 Å

EMDB-22944:
Negative stain electron microscopy reconstruction of NTD-directed Fab DH1050.1 in complex with hexapro SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 16.8 Å

EMDB-22945:
Negative stain electron microscopy reconstruction of neutralizing NTD-directed Fab DH1050.2 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 19.3 Å

EMDB-22946:
Negative stain electron microscopy reconstruction of neutralizing NTD-directed Fab DH1051 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 16.1 Å

EMDB-22947:
Negative stain electron microscopy reconstruction of non-neutralizing NTD-directed antibody Fab in complex with SARS-CoV-2 spike ectodomain in the 1-RBD-up state
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22948:
Negative stain electron microscopy reconstruction of non-neutralizing NTD-directed antibody Fab DH1053 in complex with SARS-CoV-2 spike ectodomain in the 3-RBD-down state
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22951:
Negative stain electron microscopy reconstruction of non-neutralizing NTD-directed Fab DH1054 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22952:
Negative stain electron microscopy reconstruction of non-neutralizing NTD-directed Fab DH1055 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 12.4 Å

EMDB-22953:
Negative stain electron microscopy of non-neutralizing NTD-directed Fab DH1056 in complex with 2P SARS-CoV-2 spike ectodomain
Method: EM (single particle) / Resolution: 13.3 Å

EMDB-22955:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1043 and DH1051
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22956:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1041 and DH1051
Method: EM (single particle) / Resolution: 19.3 Å

EMDB-22957:
Negative stain electron microscopy of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1043 and DH1047
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22958:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1047 and DH1051
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22969:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1045 and DH1050.1
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22970:
Negative stain electron microscopy of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1043 and DH1050.1
Method: EM (single particle) / Resolution: 17.5 Å

EMDB-22971:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1041 and DH1047
Method: EM (single particle) / Resolution: 18.4 Å

EMDB-22984:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1050.1 and DH1053
Method: EM (single particle) / Resolution: 14.3 Å

EMDB-22985:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1043, DH1047, and DH1050.1
Method: EM (single particle) / Resolution: 18.4 Å

EMDB-22986:
Negative stain electron microscopy reconstruction of 2P SARS-CoV-2 spike ectodomain in complex with Fabs DH1043, DH1047, and DH1051
Method: EM (single particle) / Resolution: 10.0 Å

23246

7laa

EMDB-23246: CryoEM map of SARS-CoV-2 S protein in complex with Receptor Binding Domain antibody DH1041
PDB-7laa: Structure of SARS-CoV-2 S protein in complex with Receptor Binding Domain antibody DH1041
Method: EM (single particle) / Resolution: 3.42 Å

23248

7lab

EMDB-23248: CryoEM map of SARS-CoV-2 S protein in complex with N-terminal domain antibody DH1052
PDB-7lab: Structure of SARS-CoV-2 S protein in complex with N-terminal domain antibody DH1052
Method: EM (single particle) / Resolution: 2.97 Å

23277

7lcn

EMDB-23277: CryoEM map of SARS-CoV-2 S protein in complex with N-terminal domain antibody DH1050.1
PDB-7lcn: Structure of SARS-CoV-2 S protein in complex with N-terminal domain antibody DH1050.1
Method: EM (single particle) / Resolution: 3.35 Å

23279

7ld1

EMDB-23279: CryoEM map of SARS-CoV-2 S protein in complex with Receptor Binding Domain antibody DH1047
PDB-7ld1: Structure of SARS-CoV-2 S protein in complex with Receptor Binding Domain antibody DH1047
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL PROTEIN / IMMUNE SYSTEM / RBD antibody / DH1041 / SARS / COVID-19 / SARS-CoV-2 2P S ectodomain / DH1052 / DH1050.1 / DH1047

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