HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) indicates the development and acquisition of medical countermeasures for filoviruses as a high priority. However, currently no vaccine candidates against Ebola virus (EBOV) or Marburg virus (MARV) are nearing licensure and the need to develop a safe and efficacious vaccine against filoviruses continues. Whereas several preclinical vaccine candidates against EBOV or MARV exist, their further development is a major challenge based on i) safety concerns, ii) pre-existing vector immunity, and iii) issues such as manufacturing, dosage, and marketability. Here we propose to further develop a new and promising vaccine platform based on chemically inactivated (killed) rabies virus (RABV) virions containing EBOV glycoprotein (GP) in their envelope. Our previous research showed that immunization with such recombinant RABV virions provided excellent protection in mice against lethal challenge with the mouse adapted MA-EBOV and RABV. Moreover, the novel antigen display vehicles are highly immunogenic in non-human primates (NHP). Based on our preliminary results, the goal of this application is to develop, characterize, and extend this nove and promising filovirus vaccine platform. We propose the development and characterization a trivalent filovirus vaccine based on the killed rabies virus virions technology for use in humans t confer protection from all medically relevant filoviruses and RABV. Specifically, two additional vectors containing EBOV Sudan GP or MARV GP will be constructed in addition to the previously developed EBOV Zaire GP containing vaccine. The efficiency of these vaccines against challenge with EBOV, MARV and RABV will be studied in mice, followed by the further testing of EBOV or MARV challenge experiments in NHP. Lastly, we propose to study the required immunogenicity induced by the vaccine vectors for protection from filovirus challenge. The work proposed above toward the further development of our vaccine is performed in parallel with the transfer of the vaccine technology from a laboratory setting to GMP conditions. For this approach, we will adapt the RABV recovery system to Vero cells in a GMP facility, establish a Vero cell bank suitable for production of the vaccine as well as viral seed stocks for the three viral vectors. A production plan for the vaccine has been established, and the final goal of this translational research application is characterization of a trivalent filovirus vaccin and the production of the vaccine in sufficient quantities for a phase I clinical trial. Of note, te further characterization of this vaccine platform will establish the necessary parameters not only for a filovirus vaccine but also the use of this platform for other emerging and reemerging infectious diseases.
Currently, no approved vaccine for humans exists to prevent infection by filoviruses. Therefore, the identification of vaccination strategies to combat Ebola and Marburg virus infections remains an important pursuit. The use of an established, safe vaccine platform may simplify the development and application of a vaccine that protects against three viruses (Marburg, Ebola, and Rabies virus) in humans.
|Perry, Donna L; Huzella, Louis M; Bernbaum, John G et al. (2018) Ebola Virus Localization in the Macaque Reproductive Tract during Acute Ebola Virus Disease. Am J Pathol 188:550-558|
|Abreu-Mota, Tiago; Hagen, Katie R; Cooper, Kurt et al. (2018) Non-neutralizing antibodies elicited by recombinant Lassa-Rabies vaccine are critical for protection against Lassa fever. Nat Commun 9:4223|
|da Fontoura Budaszewski, Renata; Hudacek, Andrew; Sawatsky, Bevan et al. (2017) Inactivated Recombinant Rabies Viruses Displaying Canine Distemper Virus Glycoproteins Induce Protective Immunity against Both Pathogens. J Virol 91:|
|Wirblich, Christoph; Coleman, Christopher M; Kurup, Drishya et al. (2017) One-Health: a Safe, Efficient, Dual-Use Vaccine for Humans and Animals against Middle East Respiratory Syndrome Coronavirus and Rabies Virus. J Virol 91:|
|Keshwara, Rohan; Johnson, Reed F; Schnell, Matthias J (2017) Toward an Effective Ebola Virus Vaccine. Annu Rev Med 68:371-386|
|Johnson, Reed F; Kurup, Drishya; Hagen, Katie R et al. (2016) An Inactivated Rabies Virus-Based Ebola Vaccine, FILORAB1, Adjuvanted With Glucopyranosyl Lipid A in Stable Emulsion Confers Complete Protection in Nonhuman Primate Challenge Models. J Infect Dis 214:S342-S354|
|Reardon, Thomas R; Murray, Andrew J; Turi, Gergely F et al. (2016) Rabies Virus CVS-N2c(?G) Strain Enhances Retrograde Synaptic Transfer and Neuronal Viability. Neuron 89:711-24|
|Papaneri, Amy B; Bernbaum, John G; Blaney, Joseph E et al. (2015) Controlled viral glycoprotein expression as a safety feature in a bivalent rabies-ebola vaccine. Virus Res 197:54-8|
|Davis, Benjamin M; Rall, Glenn F; Schnell, Matthias J (2015) Everything You Always Wanted to Know About Rabies Virus (But Were Afraid to Ask). Annu Rev Virol 2:451-71|
|Kurup, Drishya; Wirblich, Christoph; Feldmann, Heinz et al. (2015) Rhabdovirus-based vaccine platforms against henipaviruses. J Virol 89:144-54|
Showing the most recent 10 out of 13 publications