Development of a Rabies-Vectored Marburg Virus Vaccine and Elucidation of a Potential Mechanism of Protection

Filoviruses are categorically one of the most alarming viral pathogens because they cause severe and highly-lethal hemorrhagic fever in humans. Development of vaccines against filoviruses are essential for long-term control in endemic regions in Africa and as post-exposure prophylaxis. A live attenuated filovirus vaccine is ideal but not feasible due extremely high pathogenicity. Instead, inactivated vectored vaccines are safer but still retain antigenicity. Non-segmented negative stranded virus (NNSV) have a long history of successfully being utilized as viral vaccine vectors. We have chosen to use recombinant rabies virus (rRABV) expressing glycoproteins (GPs) from medically-relevant filoviruses (Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV)) as a well-characterized and established platform to develop bivalent vaccines to protect against these deadly diseases. Based on prior research demonstrating both safety and efficacy (i.e., full protection) of adjuvanted rRABV/EBOV in non-human primates, we sought to develop and characterize rRABV/MARV as a potential vaccine against MARV. We performed experimental studies to determine both proper production and pre clinical safety and immunogenicity in animal models. Furthermore, we aimed to define antibody-mediated mechanisms of rRABV/MARV vaccine-induced protection using both in vitro and in vivo studies in order to better understand potential correlates of MARV (and possibly filovirus) protection and to inform strategies to improve vaccine efficacy. We found that multiple doses of adjuvanted rRABV/MARV vaccination led to survival in mice and robust elicitation of both RABV G and MARV GP immunoglobulin G (IgG). MARV GP-specific antibodies did not neutralize in vitro but were unequivocally involved in Fcγ receptor-dependent effector functions, including NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). However, in vivo evidence suggested that Fcγ receptor-independent mechanisms may also play an important role in rRABV/MARV vaccine-induced protection. These findings bring us closer to the advancement of a successful vaccine against Marburg virus disease (MVD) and have important implications for understanding parameters of viral infection control