Chikungunya virus (CHIKV) is a mosquito-transmitted, single-stranded RNA alphavirus of the Togaviridae family that causes explosive epidemics of a severe febrile illness characterized by debilitating polyarthalgias in humans. CHIKV (NIAID Category C pathogen) caused an estimated 1.4 million new cases in India alone in 2006, and has the potential to spread globally because of the distribution and abundance of its primary mosquito vector, Aedes aegypti. During recent outbreaks, more severe forms of CHIKV infection were observed including encephalopathy and hemorrhagic fever, suggesting the emergence of more virulent strains. Currently, no specific treatment or vaccine is available. Given its global burden, the increased travel into CHIKV-endemic areas, and the worldwide spread of its vector, there is a pressing need for the development of prophylactic and therapeutic agents against CHIKV. In preliminary experiments, we have generated strongly neutralizing monoclonal antibodies (MAbs) against CHIKV that prevent infection in mice. Here, an established academic-industry collaborative partnership between the Diamond laboratory and MacroGenics will develop humanized antibody therapeutics that protect against virtually all strains of CHIKV.
In Aim 1, panels of mouse MAbs against the E1 and E2 envelope proteins of CHIKV will be generated and screened functionally. The most potent neutralizing MAbs that recognize an array of genetically diverse CHIKV strains will be evaluated for protection in mice.
In Aim 2, mechanistic correlates of antibody protection will be defined by characterizing the cellular stages of antibody blockade. Additionally, we will identify CHIKV recognition determinants using high-throughput yeast surface display epitope-mapping technology.
In Aim 3, we will engineer humanized MAbs that block infection of CHIKV. These will be tested for neutralizing activity in cell culture and in mice. Humanized MAbs will be tested for protective efficacy, durability, and therapeutic effect in vivo. High-expressing cell lines producing the best candidates will be established. Overall, the generation of strongly protective humanized MAbs against CHIKV will foster the clinical development of immunotherapeutic agents against CHIKV infection.

Public Health Relevance

Chikungunya virus (CHIKV) is a mosquito-transmitted, single-stranded RNA alphavirus of the Togaviridae family that causes explosive epidemics of a severe febrile illness characterized by debilitating polyarthalgias in humans. Here, an established academic-industry collaborative partnership between the Diamond laboratory and MacroGenics will develop humanized antibodies that protect against virtually all strains of CHIKV. Overall, the generation of strongly protective monoclonal antibodies will foster the clinical development of immunotherapeutic agents against CHIKV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089591-03
Application #
8279166
Study Section
Special Emphasis Panel (ZAI1-FDS-M (M2))
Program Officer
Repik, Patricia M
Project Start
2010-06-05
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$944,844
Indirect Cost
$179,914
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Fox, Julie M; Diamond, Michael S (2016) Immune-Mediated Protection and Pathogenesis of Chikungunya Virus. J Immunol 197:4210-4218
Hawman, David W; Fox, Julie M; Ashbrook, Alison W et al. (2016) Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence. Cell Rep 16:1326-38
Poddar, Subhajit; Hyde, Jennifer L; Gorman, Matthew J et al. (2016) The Interferon-Stimulated Gene IFITM3 Restricts Infection and Pathogenesis of Arthritogenic and Encephalitic Alphaviruses. J Virol 90:8780-94
Smith, Scott A; Silva, Laurie A; Fox, Julie M et al. (2015) Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell Host Microbe 18:86-95
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 163:1095-107
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
Pierson, Theodore C; Diamond, Michael S (2015) A game of numbers: the stoichiometry of antibody-mediated neutralization of flavivirus infection. Prog Mol Biol Transl Sci 129:141-66
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 13:2553-64
Pal, Pankaj; Dowd, Kimberly A; Brien, James D et al. (2013) Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus. PLoS Pathog 9:e1003312
Sun, Siyang; Xiang, Ye; Akahata, Wataru et al. (2013) Structural analyses at pseudo atomic resolution of Chikungunya virus and antibodies show mechanisms of neutralization. Elife 2:e00435

Showing the most recent 10 out of 12 publications