Category A filoviruses and arenaviruses cause severe and rapidly progressing hemorrhagic fever, for which no specific treatments or vaccines are available. Among the possible pre- and post-exposure treatments vetted, monoclonal antibodies are currently thought to be the most effective, provide the longest window for post-exposure treatment, and be most likely to achieve FDA approval for reasons of safety, availability and efficacy. In the last year, members of our team were first to identify specific antibodies and cocktails of antibodies that confer effective post-exposure protection against Ebola virus and Lassa virus in multiple animal models. We will translate these therapies and fill critical resource gaps in antibodies against other pathogenic filoviruses (Sudan, Marburg and Bundibugyo) and arenaviruses (Lujo, Machupo, Junin, etc.). this proposal describes a large, multidisciplinary consortium from academic and industrial investigators. We have gathered -315 monoclonal antibodies against the filoviruses and -100 monoclonal antibodies against the arenaviruses. These are the largest antibody pools ever assembled for these viruses and include the most potent antibodies known. The consortium includes directors of three BSL4 laboratories - experts in post exposure therapeutic development and evaluation; other leaders in high-throughput and human antibody discovery and analysis with access to unique, large cohorts of human survivors of outbreaks in 2012; structural biologists with intimate knowledge of the filovirus and arenavirus glycoproteins able to map the epitope of nearly every antibody in the pools during the course of the project; and industrial scientists who are experts in large-scale production and evaluation of therapeutics for human use. Our consortium is open to all investigators and to all antibodies they wish to contribute. We will provide a public, comprehensive and definitive analysis of which antibodies are most effective against these antibodies and why, which antibodies can be combined for greatest synergy and why, and which epitopes lead to broad-spectrum reactivity. The over-arching goal is to advance mAb-based immunotherapeutic products to fill the need for treatments against these families of viruses and to file one or more Investigational New Drug applications by year 5.
This project will perform an unprecedented, field-wide analysis of antibodies against viral hemorrhagic fevers and will translate the most effective antibody cocktails to clinical use. These products will provide a much needed pre- or post-exposure therapy against some of the word's most lethal viruses.
|Saphire, Erica Ollmann; Schendel, Sharon L; Fusco, Marnie L et al. (2018) Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection. Cell 174:938-952.e13|
|Siragam, Vinayakumar; Wong, Gary; Qiu, Xiang-Guo (2018) Animal models for filovirus infections. Zool Res 39:15-24|
|West, Brandyn R; Moyer, Crystal L; King, Liam B et al. (2018) Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope. MBio 9:|
|Gilchuk, Pavlo; Mire, Chad E; Geisbert, Joan B et al. (2018) Efficacy of Human Monoclonal Antibody Monotherapy Against Bundibugyo Virus Infection in Nonhuman Primates. J Infect Dis 218:S565-S573|
|Yang, Shu; Xu, Miao; Lee, Emily M et al. (2018) Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry. Cell Discov 4:31|
|Gilchuk, Pavlo; Kuzmina, Natalia; Ilinykh, Philipp A et al. (2018) Multifunctional Pan-ebolavirus Antibody Recognizes a Site of Broad Vulnerability on the Ebolavirus Glycoprotein. Immunity 49:363-374.e10|
|Nyakatura, Elisabeth K; Zak, Samantha E; Wec, Anna Z et al. (2018) Design and evaluation of bi- and trispecific antibodies targeting multiple filovirus glycoproteins. J Biol Chem 293:6201-6211|
|Zhu, Wenjun; Zhang, Zirui; He, Shihua et al. (2018) Successful treatment of Marburg virus with orally administrated T-705 (Favipiravir) in a mouse model. Antiviral Res 151:39-49|
|Wong, Gary; Mendoza, Emelissa J; Plummer, Francis A et al. (2018) From bench to almost bedside: the long road to a licensed Ebola virus vaccine. Expert Opin Biol Ther 18:159-173|
|Wong, Gary; Qiu, Xiangguo (2018) Funding vaccines for emerging infectious diseases. Hum Vaccin Immunother 14:1760-1762|
Showing the most recent 10 out of 62 publications