Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus

Scott A. Smith; Laurie A. Silva; Julie M. Fox; Andrew I. Flyak; Nurgun Kose; Gopal Sapparapu; Solomiia Khomandiak; Alison W. Ashbrook; Kristen M. Kahle; Rachel H. Fong; Sherri Swayne; Benjamin J. Doranz; Charles E. McGee; Mark T. Heise; Pankaj Pal; James D. Brien; S. Kyle Austin; Michael S. Diamond; Terence S. Dermody; James E. Crowe

doi:10.1016/j.chom.2015.06.009

Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus

Scott A. Smith, Laurie A. Silva, Julie M. Fox, Andrew I. Flyak, Nurgun Kose, Gopal Sapparapu, Solomiia Khomandiak, Alison W. Ashbrook, Kristen M. Kahle, Rachel H. Fong, Sherri Swayne, Benjamin J. Doranz, Charles E. McGee, Mark T. Heise, Pankaj Pal, James D. Brien, S. Kyle Austin, Michael S. Diamond, Terence S. Dermody, James E. Crowe

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

110 Scopus citations

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure- based vaccine development.

Original language	English
Pages (from-to)	86-95
Number of pages	10
Journal	Cell Host and Microbe
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2015.06.009
State	Published - 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

Funding

We thank Aravinda de Silva (UNC Chapel Hill) for assistance with acquisition of the donor sample, Frances Smith-House at Vanderbilt University for excellent laboratory management support, Melissa Edeling and Katie O’Brien at WUSTL for generating E2 proteins and performing some of the initial mAb binding experiments, Edgar Davidson, Andrew Ettenger, Johnathan Guest, Trevor Barnes, Surabhi Srinivasan, and Bernard Lieberman at Integral Molecular for help with epitope mapping, and Chris Slaughter for assistance with biostatistical analysis of VRP neutralization data. This work was supported by U.S. National Institutes of Health grants R01 AI114816 (J.E.C and M.S.D.), K08 AI103038 (S.A.S.), F32 AI096833 (L.A.S.), T32 HL007751 (A.W.A.), T32 5T32AI007151-33 (C.E.M.) U54 AI057157 (T.S.D.), R01 AI104545 (M.S.D.), and NIH contract HHSN272200900055C (B.J.D.). The work also received support from the Elizabeth B. Lamb Center for Pediatric Research (T.S.D.), Infectious Diseases Society of America Education and Research Foundation (S.A.S.), and National Foundation for Infectious Diseases Young Investigator Award in Vaccine Development sponsored by Pfizer (S.A.S). The project described was supported by the National Center for Research Resources, Grant UL1 RR024975-01 and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06. The content is solely the responsibility of the authors and does not represent the official views of the NIH. Four of the authors (S.A.S., L.A.S., T.S.D. and J.E.C.) are designated co-inventors on a submitted patent application that includes the human monoclonal antibodies described in this paper.

Funders	Funder number
Elizabeth B. Lamb Center for Pediatric Research
Infectious Diseases Society of America Education and Research Foundation
National Institutes of Health (NIH)	HHSN272200900055C, T32 5T32AI007151-33, R01 AI104545, T32 HL007751, U54 AI057157, K08 AI103038, R01AI114816
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases	F32AI096833
National Institute of Allergy and Infectious Diseases
National Center for Research Resources	UL1RR024975
National Center for Research Resources
National Foundation for Infectious Diseases
Pfizer
National Center for Advancing Translational Sciences (NCATS)	2 UL1 TR000445-06
National Center for Advancing Translational Sciences (NCATS)

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chom.2015.06.009

Cite this

Smith, S. A., Silva, L. A., Fox, J. M., Flyak, A. I., Kose, N., Sapparapu, G., Khomandiak, S., Ashbrook, A. W., Kahle, K. M., Fong, R. H., Swayne, S., Doranz, B. J., McGee, C. E., Heise, M. T., Pal, P., Brien, J. D., Austin, S. K., Diamond, M. S., Dermody, T. S., & Crowe, J. E. (2015). Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus. Cell Host and Microbe, 18(1), 86-95. https://doi.org/10.1016/j.chom.2015.06.009

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abstract = "Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure- based vaccine development.",

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note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

doi = "10.1016/j.chom.2015.06.009",

language = "English",

volume = "18",

pages = "86--95",

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Smith, SA, Silva, LA, Fox, JM, Flyak, AI, Kose, N, Sapparapu, G, Khomandiak, S, Ashbrook, AW, Kahle, KM, Fong, RH, Swayne, S, Doranz, BJ, McGee, CE, Heise, MT, Pal, P, Brien, JD, Austin, SK, Diamond, MS, Dermody, TS & Crowe, JE 2015, 'Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus', Cell Host and Microbe, vol. 18, no. 1, pp. 86-95. https://doi.org/10.1016/j.chom.2015.06.009

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T1 - Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus

AU - Smith, Scott A.

AU - Silva, Laurie A.

AU - Fox, Julie M.

AU - Flyak, Andrew I.

AU - Kose, Nurgun

AU - Sapparapu, Gopal

AU - Khomandiak, Solomiia

AU - Ashbrook, Alison W.

AU - Kahle, Kristen M.

AU - Fong, Rachel H.

AU - Swayne, Sherri

AU - Doranz, Benjamin J.

AU - McGee, Charles E.

AU - Heise, Mark T.

AU - Pal, Pankaj

AU - Brien, James D.

AU - Austin, S. Kyle

AU - Diamond, Michael S.

AU - Dermody, Terence S.

AU - Crowe, James E.

PY - 2015

Y1 - 2015

N2 - Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure- based vaccine development.

AB - Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure- based vaccine development.

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Isolation and characterization of broad and ultrapotent human monoclonal antibodies with therapeutic activity against chikungunya virus

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

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