Mortality rates associated with Marburg virus (MARV) outbreaks range from 20% to over 90%. MARV is included by the Centers for Disease Control and Prevention as among the Category A agents, or "high- priority agents ... that pose a risk to national security." MARV not only causes acute and terrifying disease, but it is relatively stable in wet or dry aerosols;it is highly infectious whether infection occurs parenterally or by aerosol-- 1 LD50 is approximately 1 plaque-forming unit;it is subject to nosocomial and iatrogenic spread to and by health care personnel;and as an endemic African virus it could be acquired from recurrent natural outbreaks by a resourceful individual or group. There are currently no drugs available for preventing or treating infections with MARV. There is a clear unmet need for a MARV immunoprotectant to address biowarfare threats as well as public health concerns raised by naturally occurring outbreaks. Passive immunization with antibodies has been shown to be effective against a wide variety of viruses. Because of their excellent safety profile and efficacy mAbs are a rapidly growing class of therapeutic drug. We have shown that a cocktail of mAbs can provide post-exposure and therapeutic protection against lethal challenge with another filovirus (Ebola) in the non-human primate (NHP) model (i.e. the model most representative of humans). As a result of successful completion of our Phase 1 SBIR efforts, we have identified six potent anti-MARV mAbs that protect mice from lethal challenge. Further, in this proposal we are combining forces with Integrated Biotherapeutics (Dr. Kelly Warfield;Gaithersburg, MD) and the Public Health Agency of Canada (PHAC;Dr. Gary Kobinger), whose teams have identified additional protective mAbs via separate funding. Together with Dr. Tom Geisbert (UTMB;Galveston, TX) we will determine which of these combinations of mAbs is the most appropriate for continued development. The Long Range Objective of this project is to develop a safe and effective immunoprotectant for Marburg virus.
In Specific Aim 1, the existing protective mAbs will be produced using a well-characterized transient Nicotiana production system. Experiments in rodents will be used to select a lead mAb cocktail for advancement to non-human primate (NHP) testing.
In Specific Aim 2, the cocktail will be evaluated in NHPs against lethal MARV challenge.
In Specific Aim 3 IND-enabling testing will be completed and an IND submitted.
The efforts in this proposal will help in the development of a drug product for preventing and treating infection with Marburg virus, a highly lethal virus that causes sporadic outbreaks and is a biowarfare threat.