Filoviruses and arenaviruses are two major families of lethal hemorrhagic fever viruses for which no vaccines or treatments are currently available. Previous work by several investigators involved in this proposal has unequivocally demonstrated the feasibility of protecting non-human primates against viral challenge with immunotherapy. This highly translational proposal will identify the most effective monoclonal antibodies and from them, create broad-spectrum antibody cocktails for pre- or post-exposure use. To achieve this goal, we will leverage the consortium's large collection of anti-filovirus and anti-arenavirus antibodies, as well as new antibodies to be derived from ongoing and proposed discovery efforts. However, it will not be feasible to test each of our hundreds of candidate antibodies and thousands of potential antibody combinations in animals without some initial in vitro downselection. To generate a manageable set of candidate antibodies and cocktails, Core C (working together the three project teams and the Gore D team) will categorize antibodies into structural and functional groups, perform rules-based triage of antibody candidates, and design antibody cocktails based on antiviral activity and functional diversity. Finally and importantly. Core C will prioritize candidate cocktails based on their susceptibility to escape mutations, and will, together with Core D, identify antibodies most resistant to escape, as well as replacement antibodies that will "mop up" escaping virions. In addition to selection of the most effective single antibodies and cocktails of antibodies to forward for patient use, this Gore will provide essential information that addresses major, basic knowledge gaps in the field. Our comprehensive analysis will illustrate which epitopes lead to the most effective protection, which in vitro assays are the best predictors of in vivo efficacy, and which epitopes lead to broad-spectrum reactivity and protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109762-01
Application #
8654214
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
2014-03-15
Project End
2019-02-28
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$761,167
Indirect Cost
$105,104
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Holtsberg, Frederick W; Shulenin, Sergey; Vu, Hong et al. (2016) Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses. J Virol 90:266-78
Wec, Anna Z; Nyakatura, Elisabeth K; Herbert, Andrew S et al. (2016) A "Trojan horse" bispecific antibody strategy for broad protection against ebolaviruses. Science :
Pallesen, Jesper; Murin, Charles D; de Val, Natalia et al. (2016) Structures of Ebola virus GP and sGP in complex with therapeutic antibodies. Nat Microbiol 1:16128
Frei, Julia C; Nyakatura, Elisabeth K; Zak, Samantha E et al. (2016) Bispecific Antibody Affords Complete Post-Exposure Protection of Mice from Both Ebola (Zaire) and Sudan Viruses. Sci Rep 6:19193
Natesan, Mohan; Jensen, Stig M; Keasey, Sarah L et al. (2016) Human Survivors of Disease Outbreaks Caused by Ebola or Marburg Virus Exhibit Cross-Reactive and Long-Lived Antibody Responses. Clin Vaccine Immunol 23:717-24
Qiu, Xiangguo; Audet, Jonathan; Lv, Ming et al. (2016) Two-mAb cocktail protects macaques against the Makona variant of Ebola virus. Sci Transl Med 8:329ra33
Bornholdt, Zachary A; Turner, Hannah L; Murin, Charles D et al. (2016) Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak. Science 351:1078-83
Goba, Augustine; Khan, S Humarr; Fonnie, Mbalu et al. (2016) An Outbreak of Ebola Virus Disease in the Lassa Fever Zone. J Infect Dis 214:S110-S121
Robinson, James E; Hastie, Kathryn M; Cross, Robert W et al. (2016) Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits. Nat Commun 7:11544
Zeitlin, Larry; Whaley, Kevin J; Olinger, Gene G et al. (2016) Antibody therapeutics for Ebola virus disease. Curr Opin Virol 17:45-9

Showing the most recent 10 out of 27 publications