The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), are important human pathogens with case fatality rates ranging from 40% to 90% for EBOV and up to 90% for MARV. Filoviruses are classified as Category A Priority Pathogens by the NIAID/NIH and CDC, and there are presently no approved active or passive interventions for exposure resulting from natural outbreak, laboratory accident, or deliberate misuse. Public health concern is based on both the emerging infectious disease status of these viruses and their potential use as biologic weapons. An effective post-exposure vaccine would find application with medical personnel and close contacts during outbreaks in endemic areas of Africa, with laboratory workers engaged in filovirus research, and with military and civilian personnel threatened by weaponized filoviruses. The ideal vaccine to meet both the outbreak and bio-weapon scenarios would confer post-exposure protection against all species of EBOV and MARV with a single administration. Among the vaccine technologies investigated to date, a tri-valent filovirus vaccine vectored by recombinant vesicular stomatitis virus (rVSV) has shown the greatest potential as a single administration vaccine with the capacity to rapidly provide broad post-exposure protection against EBOV and MARV. Profectus BioSciences has developed a replication competent attenuated rVSV vaccine delivery platform (rVSVN4CT1) that: 1) retains the immunogenicity of vaccines based on the non-attenuated vector, 2) has been manufactured under cGMPs at commercial scale, and 3) has been shown to be safe and immunogenic in multiple clinical trials. Thus, this application proposes: 1) examine 4 rVSV vector designs to determine which provides the best combination of protective efficacy, stability, and manufacturing yield, 2) to confirm that an attenuated trivalent rVSVN4CT1 vectored filovirus vaccine will provide post-exposure protection of monkeys against challenge with filoviruses, 3) compliantly prepare seed stocks of the three viruses in the vaccine under conditions that will support future manufacture under cGMPs, 4) use the compliant seed stocks to prepare a tri-valent vaccine that will be tested in a GLP neuro-toxicology study in nonhuman primates (NHPs) to confirm safety, 5) use the compliant tri-valent vaccine in development studies to identify a lyophilized formulation with the stability characteristics required for practical field use, 6) test the lyophilized tri-valent vaccine to confirm that it protects NHPs from filoviruses when administered and postexposure, and 7) determine if tri-valent vaccine will synergize with small interfering RNA (siRNA) and/or monoclonal antibodies in postexposure protection from RPI and RP2.
The available data indicate that vaccines vectored by rVSV can provide postexposure protection when administered within hours of Ebola and Marburg infection. However, effective postexposure treatment administered days after exposure will likely require the combination of multiple treatments. This project will develop a practical pan-filovirus vaccine and determine the level of protection provided alone and in combination with monoclonal antibody and siRNA treatments.
|Thi, Emily P; Lee, Amy C H; Geisbert, Joan B et al. (2016) Rescue of non-human primates from advanced Sudan ebolavirus infection with lipid encapsulated siRNA. Nat Microbiol 1:16142|
|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|
|Bornholdt, Zachary A; Ndungo, Esther; Fusco, Marnie L et al. (2016) Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies. MBio 7:e02154-15|
|Mire, Chad E; Geisbert, Joan B; Agans, Krystle N et al. (2016) Passive Immunotherapy: Assessment of Convalescent Serum Against Ebola Virus Makona Infection in Nonhuman Primates. J Infect Dis 214:S367-S374|
|Flyak, Andrew I; Shen, Xiaoli; Murin, Charles D et al. (2016) Cross-Reactive and Potent Neutralizing Antibody Responses in Human Survivors of Natural Ebolavirus Infection. Cell 164:392-405|
|Ilinykh, Philipp A; Shen, Xiaoli; Flyak, Andrew I et al. (2016) Chimeric Filoviruses for Identification and Characterization of Monoclonal Antibodies. J Virol 90:3890-901|
|Mire, Chad E; Matassov, Demetrius; Geisbert, Joan B et al. (2015) Single-dose attenuated Vesiculovax vaccines protect primates against Ebola Makona virus. Nature 520:688-91|
|Matassov, Demetrius; Marzi, Andrea; Latham, Terri et al. (2015) Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus. J Infect Dis 212 Suppl 2:S443-51|
|Flyak, Andrew I; Ilinykh, Philipp A; Murin, Charles D et al. (2015) Mechanism of human antibody-mediated neutralization of Marburg virus. Cell 160:893-903|
|Hashiguchi, Takao; Fusco, Marnie L; Bornholdt, Zachary A et al. (2015) Structural basis for Marburg virus neutralization by a cross-reactive human antibody. Cell 160:904-12|
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