The filoviruses are NIAID/CDC Category A biodefense pathogens that cause severe and rapidly progressing hemorrhagic fever with 50-90% human lethality. There are currently no FDA-approved vaccines or therapies for filovirus infection. Among the filoviruses, the Zaire Ebola virus species (EBOV) has been most extensively characterized. However, outbreaks ofthe Sudan Ebola virus species (SUDV) and Marburg virus (MARV) have been occurring with increased frequency and can be just as lethal as EBOV. Further, the pathogenic Bundibugyo Ebola virus species (BDBV) re-emerged in 2012 with increased lethality. Immunotherapy was recently demonstrated to provide post-exposure protection to EBOV challenge in nonhuman primates (NHPs). For MARV, convalescent sera from immunized NHPs can provide similar protection, suggesting that immunotherapy for all filoviruses will be tractable in humans. A robust pipeline of monoclonal antibodies (mAbs) targeting EBOV exists and will be developed in Project 1, but the pipeline for SUDV and MARV mAbs is less complete. Not a single SUDV or MARV mAb or mAb cocktail therapy has been evaluated in NHPs. Currently, there are no neutralizing BDBV mAbs. The goal of Project 2 is to fill these gaps in the filovirus therapeutic mAb portfolio. Among consortium investigators, a total of 216 murine mAbs against SUDV or MARV are available but have not been completely characterized;we will develop these mAbs and evaluate them for protection in rodent models and NHPs. In addition, we will identify new SUDV and MARV mAbs from human survivors of infection from outbreaks in Uganda, especially those in 2012. The consortium investigators have unprecedented access to four separate survivor cohorts of SUDV and MARV infection, and have demonstrated recently that neutralizing mAbs exist in peripheral blood of survivors. In addition, we will identify and characterize new anti-BDBV and broadly reactive anti-filovirus mAbs. Preliminary ELISA studies indicate that antibodies with cross-reactivity for the envelope glycoprotein (GP) from SUDV, BDBV and (in some cases) EBOV exist in peripheral blood of survivors who have been exposed to only a single filovirus species. We will use human hybridoma and antibody phage display technologies to screen the lymphocytes of survivors of filovirus infection for new BDBV and cross neutralizing filovirus mAbs. The most promising candidates will be further evaluated in rodent and nonhuman primate challenge models. The end-point of this work will be a robust pipeline of mAbs for these understudied and re-emerging filoviruses.
The filoviruses are highly pathogenic viruses that cause rapidly progressing hemorrhagic fever. There are currently no FDA approved therapies or vaccines to treat filovirus infection. The goal of this work is to develop therapeutic monoclonal antibodies that are effective against several ofthe most pathogenic filoviruses, as well as antibodies that are effective against more than one strain of filovirus.
|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|