Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions

Andrea R. Shiakolas; Kevin J. Kramer; Daniel Wrapp; Simone I. Richardson; Alexandra Schäfer; Steven Wall; Nianshuang Wang; Katarzyna Janowska; Kelsey A. Pilewski; Rohit Venkat; Robert Parks; Nelia P. Manamela; Nagarajan Raju; Emilee Friedman Fechter; Clinton M. Holt; Naveenchandra Suryadevara; Rita E. Chen; David R. Martinez; Rachel S. Nargi; Rachel E. Sutton; Julie E. Ledgerwood; Barney S. Graham; Michael S. Diamond; Barton F. Haynes; Priyamvada Acharya; Robert H. Carnahan; James E. Crowe; Ralph S. Baric; Lynn Morris; Jason S. McLellan; Ivelin S. Georgiev

doi:10.1016/j.xcrm.2021.100313

Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions

Andrea R. Shiakolas, Kevin J. Kramer, Daniel Wrapp, Simone I. Richardson, Alexandra Schäfer, Steven Wall, Nianshuang Wang, Katarzyna Janowska, Kelsey A. Pilewski, Rohit Venkat, Robert Parks, Nelia P. Manamela, Nagarajan Raju, Emilee Friedman Fechter, Clinton M. Holt, Naveenchandra Suryadevara, Rita E. Chen, David R. Martinez, Rachel S. Nargi, Rachel E. SuttonJulie E. Ledgerwood, Barney S. Graham, Michael S. Diamond, Barton F. Haynes, Priyamvada Acharya, Robert H. Carnahan, James E. Crowe, Ralph S. Baric, Lynn Morris, Jason S. McLellan, Ivelin S. Georgiev

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

The continual emergence of novel coronaviruses (CoV), such as severe acute respiratory syndrome-(SARS)-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. From a recovered SARS-CoV donor sample, we identify and characterize a panel of six monoclonal antibodies that cross-react with CoV spike (S) proteins from the highly pathogenic SARS-CoV and SARS-CoV-2, and demonstrate a spectrum of reactivity against other CoVs. Epitope mapping reveals that these antibodies recognize multiple epitopes on SARS-CoV-2 S, including the receptor-binding domain, the N-terminal domain, and the S2 subunit. Functional characterization demonstrates that the antibodies mediate phagocytosis—and in some cases trogocytosis—but not neutralization in vitro. When tested in vivo in murine models, two of the antibodies demonstrate a reduction in hemorrhagic pathology in the lungs. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies.

Original language	English
Article number	100313
Journal	Cell Reports Medicine
Volume	2
Issue number	6
DOIs	https://doi.org/10.1016/j.xcrm.2021.100313
State	Published - Jun 15 2021

Keywords

COVID-19
Fc effector function
LIBRA-seq
SARS-CoV-2
antibody discovery
cross-reactivity
single-cell sequencing

Access to Document

10.1016/j.xcrm.2021.100313

Cite this

Shiakolas, A. R., Kramer, K. J., Wrapp, D., Richardson, S. I., Schäfer, A., Wall, S., Wang, N., Janowska, K., Pilewski, K. A., Venkat, R., Parks, R., Manamela, N. P., Raju, N., Fechter, E. F., Holt, C. M., Suryadevara, N., Chen, R. E., Martinez, D. R., Nargi, R. S., ... Georgiev, I. S. (2021). Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions. Cell Reports Medicine, 2(6), [100313]. https://doi.org/10.1016/j.xcrm.2021.100313

Shiakolas, Andrea R. ; Kramer, Kevin J. ; Wrapp, Daniel ; Richardson, Simone I. ; Schäfer, Alexandra ; Wall, Steven ; Wang, Nianshuang ; Janowska, Katarzyna ; Pilewski, Kelsey A. ; Venkat, Rohit ; Parks, Robert ; Manamela, Nelia P. ; Raju, Nagarajan ; Fechter, Emilee Friedman ; Holt, Clinton M. ; Suryadevara, Naveenchandra ; Chen, Rita E. ; Martinez, David R. ; Nargi, Rachel S. ; Sutton, Rachel E. ; Ledgerwood, Julie E. ; Graham, Barney S. ; Diamond, Michael S. ; Haynes, Barton F. ; Acharya, Priyamvada ; Carnahan, Robert H. ; Crowe, James E. ; Baric, Ralph S. ; Morris, Lynn ; McLellan, Jason S. ; Georgiev, Ivelin S. / Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions. In: Cell Reports Medicine. 2021 ; Vol. 2, No. 6.

@article{7cd0a78efac044389d2b18cc620c871e,

title = "Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions",

abstract = "The continual emergence of novel coronaviruses (CoV), such as severe acute respiratory syndrome-(SARS)-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. From a recovered SARS-CoV donor sample, we identify and characterize a panel of six monoclonal antibodies that cross-react with CoV spike (S) proteins from the highly pathogenic SARS-CoV and SARS-CoV-2, and demonstrate a spectrum of reactivity against other CoVs. Epitope mapping reveals that these antibodies recognize multiple epitopes on SARS-CoV-2 S, including the receptor-binding domain, the N-terminal domain, and the S2 subunit. Functional characterization demonstrates that the antibodies mediate phagocytosis—and in some cases trogocytosis—but not neutralization in vitro. When tested in vivo in murine models, two of the antibodies demonstrate a reduction in hemorrhagic pathology in the lungs. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies.",

keywords = "COVID-19, Fc effector function, LIBRA-seq, SARS-CoV-2, antibody discovery, cross-reactivity, single-cell sequencing",

author = "Shiakolas, {Andrea R.} and Kramer, {Kevin J.} and Daniel Wrapp and Richardson, {Simone I.} and Alexandra Sch{\"a}fer and Steven Wall and Nianshuang Wang and Katarzyna Janowska and Pilewski, {Kelsey A.} and Rohit Venkat and Robert Parks and Manamela, {Nelia P.} and Nagarajan Raju and Fechter, {Emilee Friedman} and Holt, {Clinton M.} and Naveenchandra Suryadevara and Chen, {Rita E.} and Martinez, {David R.} and Nargi, {Rachel S.} and Sutton, {Rachel E.} and Ledgerwood, {Julie E.} and Graham, {Barney S.} and Diamond, {Michael S.} and Haynes, {Barton F.} and Priyamvada Acharya and Carnahan, {Robert H.} and Crowe, {James E.} and Baric, {Ralph S.} and Lynn Morris and McLellan, {Jason S.} and Georgiev, {Ivelin S.}",

note = "Funding Information: We thank Angela Jones, Latha Raju, and Jamie Roberson of Vanderbilt Technologies for Advanced Genomics for their expertise regarding next-generation sequencing (NGS) and library preparation; David Flaherty and Brittany Matlock of the Vanderbilt Flow Cytometry Shared Resource for help with flow panel optimization; and members of the Georgiev laboratory for comments on the manuscript. The Vanderbilt VANTAGE Core provided technical assistance for this work. VANTAGE is supported in part by CTSA grant 5UL1 RR024975-03 , the Vanderbilt-Ingram Cancer Center ( P30 CA68485 ), the Vanderbilt Vision Center ( P30 EY08126 ), and NIH/NCRR ( G20 RR030956 ). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University (Nashville, TN). Flow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource. The VUMC Flow Cytometry Shared Resource is supported by the Vanderbilt-Ingram Cancer Center ( P30 CA68485 ) and the Vanderbilt Digestive Disease Research Center ( DK058404 ). For work described in this manuscript, I.S.G., A.R.S., K.J.K., S.W., K.A.P., R.V., N.R., E.F.F., and C.M.H. were supported in part by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease (NIAID) award R01AI131722-S1, the Hays Foundation COVID-19 Research Fund , Fast Grants , and CTSA award no. UL1 TR002243 from the National Center for Advancing Translational Sciences . J.S.M and D.W. were supported in part by a NIH/NIAID grant awarded to J.S.M. ( R01-AI127521 ). L.M. and S.I.R. acknowledge research funding from the South African Medical Research Council (MRC) Extramural Unit and SHIP-COVID19 programs and an H3 Africa grant ( U01A136677 ). S.I.R. is supported by the South African Research Chairs Initiative of the Department of Science and Technology and the NRF (grant no. 98341 ) and is a L{\textquoteright}Oreal/UNESCO South Africa Young Talents Award recipient. R.S.B., A.S., and D.R.M. were supported by NIH grants ( U54CA260543 and R01AI157155 ). P.A. and K.J. were supported by NIH grant R01 AI14567 . J.E.C., R.H.C., N.S., R.S.N., and R.E.S. were supported by the Defense Advanced Research Projects Agency (DARPA) grants HR0011-18-2-0001 and HR00 11-18-3-0001 ; NIH contracts 75N93019C00074 and 75N93019C00062 ; NIH grants U01 AI150739 , R01 AI130591 , and R35 HL145242 ; the Dolly Parton COVID-19 Research Fund at Vanderbilt ; and NIH grant S10 RR028106 for the Next Generation Nucleic Acid Sequencer, housed in VANTAGE. M.S.D. and R.E.C. were supported by grants from NIH ( R01 AI157155 ) and the Defense Advanced Research Projects Agency ( HR001117S0019 ). B.F.H. and R.P. were supported by NC State funding for COVID research . B.S.G. was supported by intramural funding from the NIAID . C.M.H. was supported in part by NIH grant T32 GM008320-30 . D.R.M. was supported by NIH F32 AI152296 , a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award , and was previously supported by NIH/NIAID T32 AI007151 . Funding Information: We thank Angela Jones, Latha Raju, and Jamie Roberson of Vanderbilt Technologies for Advanced Genomics for their expertise regarding next-generation sequencing (NGS) and library preparation; David Flaherty and Brittany Matlock of the Vanderbilt Flow Cytometry Shared Resource for help with flow panel optimization; and members of the Georgiev laboratory for comments on the manuscript. The Vanderbilt VANTAGE Core provided technical assistance for this work. VANTAGE is supported in part by CTSA grant 5UL1 RR024975-03, the Vanderbilt-Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University (Nashville, TN). Flow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource. The VUMC Flow Cytometry Shared Resource is supported by the Vanderbilt-Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). For work described in this manuscript, I.S.G. A.R.S. K.J.K. S.W. K.A.P. R.V. N.R. E.F.F. and C.M.H. were supported in part by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease (NIAID) award R01AI131722-S1, the Hays Foundation COVID-19 Research Fund, Fast Grants, and CTSA award no. UL1 TR002243 from the National Center for Advancing Translational Sciences. J.S.M and D.W. were supported in part by a NIH/NIAID grant awarded to J.S.M. (R01-AI127521). L.M. and S.I.R. acknowledge research funding from the South African Medical Research Council (MRC) Extramural Unit and SHIP-COVID19 programs and an H3 Africa grant (U01A136677). S.I.R. is supported by the South African Research Chairs Initiative of the Department of Science and Technology and the NRF (grant no. 98341) and is a L'Oreal/UNESCO South Africa Young Talents Award recipient. R.S.B. A.S. and D.R.M. were supported by NIH grants (U54CA260543 and R01AI157155). P.A. and K.J. were supported by NIH grant R01 AI14567. J.E.C. R.H.C. N.S. R.S.N. and R.E.S. were supported by the Defense Advanced Research Projects Agency (DARPA) grants HR0011-18-2-0001 and HR00 11-18-3-0001; NIH contracts 75N93019C00074 and 75N93019C00062; NIH grants U01 AI150739, R01 AI130591, and R35 HL145242; the Dolly Parton COVID-19 Research Fund at Vanderbilt; and NIH grant S10 RR028106 for the Next Generation Nucleic Acid Sequencer, housed in VANTAGE. M.S.D. and R.E.C. were supported by grants from NIH (R01 AI157155) and the Defense Advanced Research Projects Agency (HR001117S0019). B.F.H. and R.P. were supported by NC State funding for COVID research. B.S.G. was supported by intramural funding from the NIAID. C.M.H. was supported in part by NIH grant T32 GM008320-30. D.R.M. was supported by NIH F32 AI152296, a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award, and was previously supported by NIH/NIAID T32 AI007151. Methodology, A.R.S. K.J.K. and I.S.G.; investigation, A.R.S. K.J.K. D.W. S.I.R. A.S. S.W. N.W. K.J. K.A.P. R.V. R.P. N.P.M. N.R. E.F.F. C.M.H. N.S. R.E.C. D.R.M. R.S.N. R.E.S. J.E.L. B.S.G. M.S.D. B.F.H. P.A. R.H.C. J.E.C. R.S.B. L.M. J.S.M. and I.S.G.; software, A.R.S. R.V. and N.R.; validation, A.R.S. and K.J.K.; writing ? original draft, A.R.S. and K.J.K.; writing ? review & editing, all authors; funding acquisition, I.S.G. B.S.G. M.S.D. B.F.H. P.A. R.H.C. J.E.C. R.S.B. L.M. J.S.M. A.R.S. and K.J.K.; resources, B.S.G. M.S.D. B.F.H. P.A. R.H.C. J.E.C. R.S.B. L.M. J.S.M. and I.S.G.; supervision, I.S.G. A.R.S. and I.S.G. are co-founders of AbSeek Bio. A.R.S. K.J.K. I.S.G. D.W. N.W. and J.S.M. are listed as inventors on patents filed describing the antibodies mentioned here. D.W. J.S.M. B.S.G. and N.W. are also listed as inventors on US patent application no. 62/972,886 (2019-nCoV vaccine). M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has unrelated sponsored research agreements from Emergent BioSolutions, Moderna, and Vir Biotechnology. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline, and Luna Biologics; is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines; and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. R.S.B. has competing interests associated with Eli Lily, Takeda Pharmaceuticals, and Pfizer. The Georgiev laboratory at Vanderbilt University Medical Center has received unrelated funding from Takeda Pharmaceuticals. Funding Information: A.R.S. and I.S.G. are co-founders of AbSeek Bio. A.R.S., K.J.K., I.S.G., D.W., N.W., and J.S.M. are listed as inventors on patents filed describing the antibodies mentioned here. D.W., J.S.M., B.S.G., and N.W. are also listed as inventors on US patent application no. 62/972,886 (2019-nCoV vaccine). M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has unrelated sponsored research agreements from Emergent BioSolutions, Moderna, and Vir Biotechnology. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline, and Luna Biologics; is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines; and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. R.S.B. has competing interests associated with Eli Lily, Takeda Pharmaceuticals, and Pfizer. The Georgiev laboratory at Vanderbilt University Medical Center has received unrelated funding from Takeda Pharmaceuticals. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = jun,

day = "15",

doi = "10.1016/j.xcrm.2021.100313",

language = "English",

volume = "2",

journal = "Cell Reports Medicine",

issn = "2666-3791",

number = "6",

}

Shiakolas, AR, Kramer, KJ, Wrapp, D, Richardson, SI, Schäfer, A, Wall, S, Wang, N, Janowska, K, Pilewski, KA, Venkat, R, Parks, R, Manamela, NP, Raju, N, Fechter, EF, Holt, CM, Suryadevara, N, Chen, RE, Martinez, DR, Nargi, RS, Sutton, RE, Ledgerwood, JE, Graham, BS, Diamond, MS, Haynes, BF, Acharya, P, Carnahan, RH, Crowe, JE, Baric, RS, Morris, L, McLellan, JS & Georgiev, IS 2021, 'Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions', Cell Reports Medicine, vol. 2, no. 6, 100313. https://doi.org/10.1016/j.xcrm.2021.100313

Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions. / Shiakolas, Andrea R.; Kramer, Kevin J.; Wrapp, Daniel; Richardson, Simone I.; Schäfer, Alexandra; Wall, Steven; Wang, Nianshuang; Janowska, Katarzyna; Pilewski, Kelsey A.; Venkat, Rohit; Parks, Robert; Manamela, Nelia P.; Raju, Nagarajan; Fechter, Emilee Friedman; Holt, Clinton M.; Suryadevara, Naveenchandra; Chen, Rita E.; Martinez, David R.; Nargi, Rachel S.; Sutton, Rachel E.; Ledgerwood, Julie E.; Graham, Barney S.; Diamond, Michael S.; Haynes, Barton F.; Acharya, Priyamvada; Carnahan, Robert H.; Crowe, James E.; Baric, Ralph S.; Morris, Lynn; McLellan, Jason S.; Georgiev, Ivelin S.

In: Cell Reports Medicine, Vol. 2, No. 6, 100313, 15.06.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions

AU - Shiakolas, Andrea R.

AU - Kramer, Kevin J.

AU - Wrapp, Daniel

AU - Richardson, Simone I.

AU - Schäfer, Alexandra

AU - Wall, Steven

AU - Wang, Nianshuang

AU - Janowska, Katarzyna

AU - Pilewski, Kelsey A.

AU - Venkat, Rohit

AU - Parks, Robert

AU - Manamela, Nelia P.

AU - Raju, Nagarajan

AU - Fechter, Emilee Friedman

AU - Holt, Clinton M.

AU - Suryadevara, Naveenchandra

AU - Chen, Rita E.

AU - Martinez, David R.

AU - Nargi, Rachel S.

AU - Sutton, Rachel E.

AU - Ledgerwood, Julie E.

AU - Graham, Barney S.

AU - Diamond, Michael S.

AU - Haynes, Barton F.

AU - Acharya, Priyamvada

AU - Carnahan, Robert H.

AU - Crowe, James E.

AU - Baric, Ralph S.

AU - Morris, Lynn

AU - McLellan, Jason S.

AU - Georgiev, Ivelin S.

N1 - Funding Information: We thank Angela Jones, Latha Raju, and Jamie Roberson of Vanderbilt Technologies for Advanced Genomics for their expertise regarding next-generation sequencing (NGS) and library preparation; David Flaherty and Brittany Matlock of the Vanderbilt Flow Cytometry Shared Resource for help with flow panel optimization; and members of the Georgiev laboratory for comments on the manuscript. The Vanderbilt VANTAGE Core provided technical assistance for this work. VANTAGE is supported in part by CTSA grant 5UL1 RR024975-03 , the Vanderbilt-Ingram Cancer Center ( P30 CA68485 ), the Vanderbilt Vision Center ( P30 EY08126 ), and NIH/NCRR ( G20 RR030956 ). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University (Nashville, TN). Flow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource. The VUMC Flow Cytometry Shared Resource is supported by the Vanderbilt-Ingram Cancer Center ( P30 CA68485 ) and the Vanderbilt Digestive Disease Research Center ( DK058404 ). For work described in this manuscript, I.S.G., A.R.S., K.J.K., S.W., K.A.P., R.V., N.R., E.F.F., and C.M.H. were supported in part by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease (NIAID) award R01AI131722-S1, the Hays Foundation COVID-19 Research Fund , Fast Grants , and CTSA award no. UL1 TR002243 from the National Center for Advancing Translational Sciences . J.S.M and D.W. were supported in part by a NIH/NIAID grant awarded to J.S.M. ( R01-AI127521 ). L.M. and S.I.R. acknowledge research funding from the South African Medical Research Council (MRC) Extramural Unit and SHIP-COVID19 programs and an H3 Africa grant ( U01A136677 ). S.I.R. is supported by the South African Research Chairs Initiative of the Department of Science and Technology and the NRF (grant no. 98341 ) and is a L’Oreal/UNESCO South Africa Young Talents Award recipient. R.S.B., A.S., and D.R.M. were supported by NIH grants ( U54CA260543 and R01AI157155 ). P.A. and K.J. were supported by NIH grant R01 AI14567 . J.E.C., R.H.C., N.S., R.S.N., and R.E.S. were supported by the Defense Advanced Research Projects Agency (DARPA) grants HR0011-18-2-0001 and HR00 11-18-3-0001 ; NIH contracts 75N93019C00074 and 75N93019C00062 ; NIH grants U01 AI150739 , R01 AI130591 , and R35 HL145242 ; the Dolly Parton COVID-19 Research Fund at Vanderbilt ; and NIH grant S10 RR028106 for the Next Generation Nucleic Acid Sequencer, housed in VANTAGE. M.S.D. and R.E.C. were supported by grants from NIH ( R01 AI157155 ) and the Defense Advanced Research Projects Agency ( HR001117S0019 ). B.F.H. and R.P. were supported by NC State funding for COVID research . B.S.G. was supported by intramural funding from the NIAID . C.M.H. was supported in part by NIH grant T32 GM008320-30 . D.R.M. was supported by NIH F32 AI152296 , a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award , and was previously supported by NIH/NIAID T32 AI007151 . Funding Information: We thank Angela Jones, Latha Raju, and Jamie Roberson of Vanderbilt Technologies for Advanced Genomics for their expertise regarding next-generation sequencing (NGS) and library preparation; David Flaherty and Brittany Matlock of the Vanderbilt Flow Cytometry Shared Resource for help with flow panel optimization; and members of the Georgiev laboratory for comments on the manuscript. The Vanderbilt VANTAGE Core provided technical assistance for this work. VANTAGE is supported in part by CTSA grant 5UL1 RR024975-03, the Vanderbilt-Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University (Nashville, TN). Flow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource. The VUMC Flow Cytometry Shared Resource is supported by the Vanderbilt-Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). For work described in this manuscript, I.S.G. A.R.S. K.J.K. S.W. K.A.P. R.V. N.R. E.F.F. and C.M.H. were supported in part by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Disease (NIAID) award R01AI131722-S1, the Hays Foundation COVID-19 Research Fund, Fast Grants, and CTSA award no. UL1 TR002243 from the National Center for Advancing Translational Sciences. J.S.M and D.W. were supported in part by a NIH/NIAID grant awarded to J.S.M. (R01-AI127521). L.M. and S.I.R. acknowledge research funding from the South African Medical Research Council (MRC) Extramural Unit and SHIP-COVID19 programs and an H3 Africa grant (U01A136677). S.I.R. is supported by the South African Research Chairs Initiative of the Department of Science and Technology and the NRF (grant no. 98341) and is a L'Oreal/UNESCO South Africa Young Talents Award recipient. R.S.B. A.S. and D.R.M. were supported by NIH grants (U54CA260543 and R01AI157155). P.A. and K.J. were supported by NIH grant R01 AI14567. J.E.C. R.H.C. N.S. R.S.N. and R.E.S. were supported by the Defense Advanced Research Projects Agency (DARPA) grants HR0011-18-2-0001 and HR00 11-18-3-0001; NIH contracts 75N93019C00074 and 75N93019C00062; NIH grants U01 AI150739, R01 AI130591, and R35 HL145242; the Dolly Parton COVID-19 Research Fund at Vanderbilt; and NIH grant S10 RR028106 for the Next Generation Nucleic Acid Sequencer, housed in VANTAGE. M.S.D. and R.E.C. were supported by grants from NIH (R01 AI157155) and the Defense Advanced Research Projects Agency (HR001117S0019). B.F.H. and R.P. were supported by NC State funding for COVID research. B.S.G. was supported by intramural funding from the NIAID. C.M.H. was supported in part by NIH grant T32 GM008320-30. D.R.M. was supported by NIH F32 AI152296, a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award, and was previously supported by NIH/NIAID T32 AI007151. Methodology, A.R.S. K.J.K. and I.S.G.; investigation, A.R.S. K.J.K. D.W. S.I.R. A.S. S.W. N.W. K.J. K.A.P. R.V. R.P. N.P.M. N.R. E.F.F. C.M.H. N.S. R.E.C. D.R.M. R.S.N. R.E.S. J.E.L. B.S.G. M.S.D. B.F.H. P.A. R.H.C. J.E.C. R.S.B. L.M. J.S.M. and I.S.G.; software, A.R.S. R.V. and N.R.; validation, A.R.S. and K.J.K.; writing ? original draft, A.R.S. and K.J.K.; writing ? review & editing, all authors; funding acquisition, I.S.G. B.S.G. M.S.D. B.F.H. P.A. R.H.C. J.E.C. R.S.B. L.M. J.S.M. A.R.S. and K.J.K.; resources, B.S.G. M.S.D. B.F.H. P.A. R.H.C. J.E.C. R.S.B. L.M. J.S.M. and I.S.G.; supervision, I.S.G. A.R.S. and I.S.G. are co-founders of AbSeek Bio. A.R.S. K.J.K. I.S.G. D.W. N.W. and J.S.M. are listed as inventors on patents filed describing the antibodies mentioned here. D.W. J.S.M. B.S.G. and N.W. are also listed as inventors on US patent application no. 62/972,886 (2019-nCoV vaccine). M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has unrelated sponsored research agreements from Emergent BioSolutions, Moderna, and Vir Biotechnology. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline, and Luna Biologics; is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines; and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. R.S.B. has competing interests associated with Eli Lily, Takeda Pharmaceuticals, and Pfizer. The Georgiev laboratory at Vanderbilt University Medical Center has received unrelated funding from Takeda Pharmaceuticals. Funding Information: A.R.S. and I.S.G. are co-founders of AbSeek Bio. A.R.S., K.J.K., I.S.G., D.W., N.W., and J.S.M. are listed as inventors on patents filed describing the antibodies mentioned here. D.W., J.S.M., B.S.G., and N.W. are also listed as inventors on US patent application no. 62/972,886 (2019-nCoV vaccine). M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has unrelated sponsored research agreements from Emergent BioSolutions, Moderna, and Vir Biotechnology. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline, and Luna Biologics; is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines; and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. R.S.B. has competing interests associated with Eli Lily, Takeda Pharmaceuticals, and Pfizer. The Georgiev laboratory at Vanderbilt University Medical Center has received unrelated funding from Takeda Pharmaceuticals. Publisher Copyright: © 2021 The Author(s)

PY - 2021/6/15

Y1 - 2021/6/15

N2 - The continual emergence of novel coronaviruses (CoV), such as severe acute respiratory syndrome-(SARS)-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. From a recovered SARS-CoV donor sample, we identify and characterize a panel of six monoclonal antibodies that cross-react with CoV spike (S) proteins from the highly pathogenic SARS-CoV and SARS-CoV-2, and demonstrate a spectrum of reactivity against other CoVs. Epitope mapping reveals that these antibodies recognize multiple epitopes on SARS-CoV-2 S, including the receptor-binding domain, the N-terminal domain, and the S2 subunit. Functional characterization demonstrates that the antibodies mediate phagocytosis—and in some cases trogocytosis—but not neutralization in vitro. When tested in vivo in murine models, two of the antibodies demonstrate a reduction in hemorrhagic pathology in the lungs. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies.

AB - The continual emergence of novel coronaviruses (CoV), such as severe acute respiratory syndrome-(SARS)-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. From a recovered SARS-CoV donor sample, we identify and characterize a panel of six monoclonal antibodies that cross-react with CoV spike (S) proteins from the highly pathogenic SARS-CoV and SARS-CoV-2, and demonstrate a spectrum of reactivity against other CoVs. Epitope mapping reveals that these antibodies recognize multiple epitopes on SARS-CoV-2 S, including the receptor-binding domain, the N-terminal domain, and the S2 subunit. Functional characterization demonstrates that the antibodies mediate phagocytosis—and in some cases trogocytosis—but not neutralization in vitro. When tested in vivo in murine models, two of the antibodies demonstrate a reduction in hemorrhagic pathology in the lungs. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies.

KW - COVID-19

KW - Fc effector function

KW - LIBRA-seq

KW - SARS-CoV-2

KW - antibody discovery

KW - cross-reactivity

KW - single-cell sequencing

UR - http://www.scopus.com/inward/record.url?scp=85107567133&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2021.100313

DO - 10.1016/j.xcrm.2021.100313

M3 - Article

C2 - 34056628

AN - SCOPUS:85107567133

VL - 2

JO - Cell Reports Medicine

JF - Cell Reports Medicine

SN - 2666-3791

IS - 6

M1 - 100313

ER -

Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions

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