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 Jr

doi:10.1016/j.chom.2015.06.009

Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus

Cell Host Microbe. 2015 Jul 8;18(1):86-95. doi: 10.1016/j.chom.2015.06.009.

Authors

Scott A Smith¹, Laurie A Silva², Julie M Fox³, Andrew I Flyak⁴, Nurgun Kose⁵, Gopal Sapparapu⁵, Solomiia Khomandiak, Alison W Ashbrook⁶, Kristen M Kahle⁷, Rachel H Fong⁷, Sherri Swayne⁷, Benjamin J Doranz⁷, Charles E McGee⁸, Mark T Heise⁸, Pankaj Pal³, James D Brien³, S Kyle Austin³, Michael S Diamond³, Terence S Dermody⁶, James E Crowe Jr⁹

Affiliations

¹ Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
² Department of Pediatrics, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
³ Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁴ Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
⁵ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
⁶ Department of Pediatrics, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
⁷ Integral Molecular, Philadelphia, PA 19104, USA.
⁸ Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁹ Department of Pediatrics, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: james.crowe@vanderbilt.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / isolation & purification
Antibodies, Monoclonal / therapeutic use*
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / isolation & purification
Antibodies, Neutralizing / therapeutic use
Antibodies, Viral / immunology*
Antibodies, Viral / isolation & purification
Antibodies, Viral / therapeutic use*
Chemoprevention / methods
Chikungunya Fever / therapy*
Chikungunya virus / immunology*
Chikungunya virus / physiology
Disease Models, Animal
Humans
Immunization, Passive / methods*
Inhibitory Concentration 50
Mice
Protein Binding
Survival Analysis
Treatment Outcome
Viral Envelope Proteins / immunology
Virus Internalization / drug effects

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Viral Envelope Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding