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 world's most lethal viruses.
|Qiu, Xiangguo; Wong, Gary; Audet, Jonathan et al. (2014) Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 514:47-53|
|Chen, Gang; Koellhoffer, Jayne F; Zak, Samantha E et al. (2014) Synthetic antibodies with a human framework that protect mice from lethal Sudan ebolavirus challenge. ACS Chem Biol 9:2263-73|
|Murin, Charles D; Fusco, Marnie L; Bornholdt, Zachary A et al. (2014) Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proc Natl Acad Sci U S A 111:17182-7|
|Schieffelin, John S; Shaffer, Jeffrey G; Goba, Augustine et al. (2014) Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med 371:2092-100|