title: Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus.
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.
authors.affiliation: 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.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Silva
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Flyak
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Nurgun
authors.initials: N
authors.lastname: Kose
authors.affiliation: Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Sapparapu
authors.forename: Solomiia
authors.initials: S
authors.lastname: Khomandiak
authors.affiliation: 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.
authors.forename: Solomiia
authors.initials: S
authors.lastname: Khomadiak
authors.affiliation: 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.
authors.forename: Alison W
authors.initials: AW
authors.lastname: Ashbrook
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Kahle
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Fong
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Swayne
authors.affiliation: Integral Molecular, Philadelphia, PA 19104, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Doranz
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: McGee
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Pal
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Brien
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: S Kyle
authors.initials: SK
authors.lastname: Austin
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: 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.
authors.forename: Terence S
authors.initials: TS
authors.lastname: Dermody
authors.affiliation: 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.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000302:isolation & purification / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000276:immunology* / Q000302:isolation & purification / Q000627:therapeutic use*; D018890:Chemoprevention / Q000379:methods; D065632:Chikungunya Fever / Q000628:therapy*; D002646:Chikungunya virus / Q000276:immunology* / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D020128:Inhibitory Concentration 50; D051379:Mice; D011485:Protein Binding; D016019:Survival Analysis; D016896:Treatment Outcome; D014759:Viral Envelope Proteins / Q000276:immunology; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014759:Viral Envelope Proteins