Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that cycles directly between humans and mosquitoes and causes a debilitating febrile illness in humans on a global scale. Autochthonous transmission in the New World now has been described, with outbreaks in at least 19 countries in the Americas and over a quarter million cases in just 6 months. CHIKV disease cases have been reported to ArboNET in travelers returning to the US from the Caribbean in 29 states, as of July 1. The potential for epidemics in North and South America is high due to the ubiquitous distribution of one of its primary vectors, Aedes albopictus. Despite the possibility for infecting and causing disease in millions, specific treatments or vaccines for CHIKV are not available. A primary goal of this project is to define the molecular, genetic, immunologic, and structural characteristics of ultra-potent neutralizing human mAbs with broad activity against all genotypes of CHIKV. Additional goals include defining the mechanistic correlates of protection by these ultra-potent neutralizing mAbs. In these studies, we will elucidate how antiviral Abs with exceptional inhibitory activity exert their action in cell culture and in vivo. The approach will include high efficiency isolationof human mAbs, coupled with innovative antibody gene repertoire studies based on nextgen sequencing. Several hypotheses will be tested, including the concept that ultra-potent neutralizing activity results from features of both the antibodies (extensive mutations due to persistent CHIKV infection) and the antigen (binding to quaternary epitopes on multiple adjacent envelope proteins and blocking structural transitions critical for virus entry or release). Althoug our focus is to understand how and why ultra-potent human mAbs inhibit CHIKV, the studies likely will be relevant to general principles of antibody neutralization of many different viruses. Beyond defining the molecular and structural basis of Ab neutralization of CHIKV, these studies will generate a group of fully human mAbs that can prevent and treat CHIKV infection and persistence in mice, which could be developed in the future as a possible combination immunotherapeutic for humans. Studies in this project, while targeted against CHIKV, likely will inform future Ab-based and/or vaccine efforts against other alphaviruses that cause human disease. We have assembled a unique group of investigators, including a human Ab expert, a molecular virologist with experience in Ab-virus interactions, and two accomplished structural biologists with specific expertise in alphaviruses, including CHIKV, to pursue these studies.

Public Health Relevance

Chikungunya virus is a mosquito borne virus that causes acute febrile illness and chronic inflammatory joint disease that can be severely debilitating. The virus is spreading globally and currently is causing explosive epidemics in the Americas. This application proposes detailed basic studies of the human antibody response to Chikungunya virus that may provide the foundation for the design of new vaccines and antibody treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114816-05
Application #
9413977
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Repik, Patricia M
Project Start
2015-02-10
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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Crowe Jr, James E (2017) Principles of Broad and Potent Antiviral Human Antibodies: Insights for Vaccine Design. Cell Host Microbe 22:193-206
Nair, Sharmila; Poddar, Subhajit; Shimak, Raeann M et al. (2017) Interferon regulatory factor-1 (IRF-1) protects against chikungunya virus induced immunopathology by restricting infection in muscle cells. J Virol :
Miner, Jonathan J; Cook, Lindsey E; Hong, Jun P et al. (2017) Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis. Sci Transl Med 9:
Broeckel, Rebecca; Fox, Julie M; Haese, Nicole et al. (2017) Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques. PLoS Negl Trop Dis 11:e0005637
Hawman, David W; Fox, Julie M; Ashbrook, Alison W et al. (2016) Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence. Cell Rep 16:1326-1338
Fox, Julie M; Diamond, Michael S (2016) Immune-Mediated Protection and Pathogenesis of Chikungunya Virus. J Immunol 197:4210-4218
Long, Feng; Fong, Rachel H; Austin, Stephen K et al. (2015) Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity. Proc Natl Acad Sci U S A 112:13898-903
Fox, Julie M; Long, Feng; Edeling, Melissa A et al. (2015) Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress. Cell 163:1095-1107
Jin, Jing; Liss, Nathan M; Chen, Dong-Hua et al. (2015) Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis. Cell Rep 13:2553-2564

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