9 research outputs found

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

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    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

    Î’-Glucan Activates Microglia Without Inducing Cytokine Production in Dectin-1-Dependent Manner

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    Microglia are the resident mononuclear phagocytic cells that are critical for innate and adaptive responses within the CNS. Like other immune cells, microglia recognize and are activated by various pathogen-associated molecular patterns. β-glucans are pathogen-associated molecular patterns present within fungal cell walls that are known to trigger protective responses in a number of immune cells. In an effort to better understand microglial responses to β-glucans and the underlying response pathways, we sought to determine whether Dectin-1, a major β-glucan receptor recently identified in leukocytes, plays a similar role in β-glucan-induced activation in microglia. In this study, we report that Dectin-1 is indeed expressed on the surface of murine primary microglia, and engagement of the receptor with particulate β-glucan resulted in an increase in tyrosine phosphorylation of spleen tyrosine kinase, a hallmark feature of the Dectin-1 signaling pathway. Moreover, phagocytosis of β-glucan particles and subsequent intracellular production of reactive oxygen species were also mediated by Dectin-1. However, unlike in macrophages and dendritic cells, β-glucan-mediated microglial activation did not result in significant production of cytokines or chemokines; thus, the interaction of microglial Dectin-1 with glucan elicits a unique response. Our results suggest that the Dectin-1 pathway may play an important role in antifungal immunity in the CNS

    Rabies-based vaccine induces potent immune responses against Nipah virus

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    Viral vaccines: bivalent vaccine immunizes mice against Nipah virus The Nipah virus (NiV) infects livestock and humans with high mortality, but to date no vaccine has been approved that protects against NiV. Here, Matthias Schnell and colleagues developed a bivalent vaccine based on a highly immunogenic rabies virus vector and on expression of NiV glycoprotein. The vaccine led to the formation of neutralizing antibodies against the NiV glycoprotein in inoculated mice, which developed no disease as a consequence of immunization. Notably, the researchers also show that NiV neutralizing antibodies generated in the inoculated mice were cross-reactive to the Hendra virus, broadening the spectrum of the vaccine. The work provides a candidate for a NiV vaccine that uses a highly immunogenic vector and that has the potential to induce protection against not only NiV, but to rabies virus and Hendra virus as well

    A recombinant rabies virus expressing the Marburg Virus Glycoprotein Is dependent upon ADCC for protection against Marburg Virus Disease in a Murine Model

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    Accepted ManuscriptMarburg 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 both in vitro and in vivo approaches, 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.IMPORTANCE Marburg 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.This work was funded in part through the U.S. National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research and the NIAID Division of Clinical Research. Battelle Memorial Institute's prime contract with the NIAID is under contract no. HHSN272200700016I
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