A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model

Abstract

Marburg virus (MARV) is a filovirus related to Ebola virus (EBOV) associated with human hemorrhagic disease. Outbreaks are sporadic and severe, with a reported case mortality rate of upward of 88%. There is currently no antiviral or vaccine available. Given the sporadic nature of outbreaks, vaccines provide the best approach for long-term control of MARV in regions of endemicity. We have developed an inactivated rabies virus-vectored MARV vaccine (FILORAB3) to protect against Marburg virus disease. Immunogenicity studies in our labs have shown that a Th1-biased seroconversion to both rabies virus and MARV glycoproteins (GPs) is beneficial for protection in a preclinical murine model. As such, we adjuvanted FILORAB3 with glucopyranosyl lipid adjuvant (GLA), a Toll-like receptor 4 agonist, in a squalene-in-water emulsion. Across two different BALB/c mouse challenge models, we achieved 92% protection against murine-adapted Marburg virus (ma-MARV). Although our vaccine elicited strong MARV GP antibodies, it did not strongly induce neutralizing antibodies. Through bothin vitroandin vivoapproaches, we elucidated a critical role for NK cell-dependent antibody-mediated cellular cytotoxicity (ADCC) in vaccine-induced protection. Overall, these findings demonstrate that FILORAB3 is a promising vaccine candidate for Marburg virus disease.IMPORTANCEMarburg virus (MARV) is a virus similar to Ebola virus and also causes a hemorrhagic disease which is highly lethal. In contrast to EBOV, only a few vaccines have been developed against MARV, and researchers do not understand what kind of immune responses are required to protect from MARV. Here we show that antibodies directed against MARV after application of our vaccine protect in an animal system but fail to neutralize the virus in a widely used virus neutralization assay against MARV. This newly discovered activity needs to be considered more when analyzing MARV vaccines or infections.

The protective potential of Fc‐mediated antibody functions against influenza virus and other viral pathogens

“…A promising rabies‐vectored Marburg virus vaccine (FILORAB3) achieved >90% protection against a murine‐adapted Marburg virus challenge, despite the absence of NAbs. Sera from FILORAB3‐vaccinated mice had high levels of ADCC activity in vitro and FcγR −/− mice were not protected by FILORAB3 vaccination …”

Lyssavirus Vaccine with a Chimeric Glycoprotein Protects across Phylogroups

“…Another approach is to add multiple Gs to a single vaccine construct ( Kgaladi et al., 2017 ). Foreign viral Gs have been successfully added to the RABV genome, and their Gs expressed to comparable amounts as the native RABV G ( Abreu-Mota et al., 2018 ; Keshwara et al., 2019 ; Willet et al., 2015 ). However, the stability of multiple lyssavirus Gs has not been rigorously tested.…”

Development of an antibody-dependent cellular cytotoxicity reporter assay for measuring anti-Middle East Respiratory Syndrome antibody bioactivity

“…In recent years, the therapeutic antibodies have been rapidly developed, raising the high requirement for bioactivity determination assay. ADCC activity serves as a critical mechanism of action of many therapeutic antibodies, including antiviral antibodies [31][32][33][34][35][36] . The effector Table 2.…”