Microglia, the resident mononuclear phagocytic cells, are critical for immune responses within the CNS. They recognize and are activated by various Pathogen Associated Molecular Patterns (PAMPs). β‐glucans are PAMPs present within fungal cell walls that are known to trigger protective responses in a number of immune cells. To better understand microglial responses to β‐glucans and the underlying signaling pathways, we sought to determine if Dectin‐1, a major β‐glucan receptor recently identified in leukocytes, mediates β‐glucan induced activation of microglia. Here, we report that Dectin‐1 is 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 Syk, a hallmark feature of the Dectin‐1 signaling pathway. Moreover, phagocytosis of β‐glucan particles and subsequent intracellular production of ROS were also mediated by Dectin‐1. Further, interaction of β‐glucan with Dectin‐1 resulted in activation of Vav and PI3K/Akt pathways, suggesting that β‐glucan induce multiple signaling pathways in microglia. However, unlike in leukocytes, β‐glucan mediated microglial activation did not result in production of cytokines. Thus, the interaction of microglial Dectin‐1 with glucan elicits a unique response, suggesting that the Dectin‐1 pathway may play an important role in antifungal immunity in the CNS.

We previously described the generation of a novel Ebola virus (EBOV) vaccine based on inactivated rabies virus (RABV) containing EBOV glycoprotein (GP) incorporated in the RABV virion. Our results demonstrated safety, immunogenicity, and protective efficacy in mice and nonhuman primates (NHPs). Protection against viral challenge depended largely on the quality of the humoral immune response against EBOV GP.Here we present the extension and improvement of this vaccine by increasing the amount of GP incorporation into virions via GP codon-optimization as well as the addition of Sudan virus (SUDV) and Marburg virus (MARV) GP containing virions. Immunogenicity studies in mice indicate similar immune responses for both SUDV GP and MARV GP compared to EBOV GP. Immunizing mice with multiple antigens resulted in immune responses similar to immunization with a single antigen. Moreover, immunization of NHP with the new inactivated RABV EBOV vaccine resulted in high titer neutralizing antibody levels and 100% protection against lethal EBOV challenge when applied with adjuvant.Our results indicate that an inactivated polyvalent vaccine against RABV filoviruses is achievable. Finally, the novel vaccines are produced on approved VERO cells and a clinical grade RABV/EBOV vaccine for human trials has been produced.

The 2013-2016 West African Ebola virus (EBOV) disease outbreak was the largest filovirus outbreak to date. Over 28 000 suspected, probable, or confirmed cases have been reported, with a 53% case-fatality rate. The magnitude and international impact of this EBOV outbreak has highlighted the urgent need for a safe and efficient EBOV vaccine. To this end, we demonstrate the immunogenicity and protective efficacy of FILORAB1, a recombinant, bivalent, inactivated rabies virus-based EBOV vaccine, in rhesus and cynomolgus monkeys. Our results demonstrate that the use of the synthetic Toll-like receptor 4 agonist glucopyranosyl lipid A in stable emulsion (GLA-SE) as an adjuvant increased the efficacy of FILORAB1 to 100% protection against lethal EBOV challenge, with no to mild clinical signs of disease. Furthermore, all vaccinated subjects developed protective anti-rabies virus antibody titers. Taken together, these results support further development of FILORAB1/GLA-SE as an effective preexposure EBOV vaccine.

Long-term control of viral outbreaks requires the use of vaccines to impart acquired resistance and ensuing protection. In the wake of an epidemic, established immunity against a particular disease can limit spread and significantly decrease mortality. Creation of a safe and efficacious vaccine against Ebola virus (EBOV) has proven elusive so far, but various inventive strategies are now being employed to counteract the threat of outbreaks caused by EBOV and related filoviruses. Here, we present a current overview of progress in the field of Ebola virus vaccine development.

Nipah Virus (NiV) is a re-emerging zoonotic pathogen in the genus Henipavirus of the Paramyxoviridae family of viruses. NiV is endemic to Bangladesh and Malaysia and is highly fatal to both livestock and humans (human case fatality rate = 74.5%). Currently, there is no approved vaccine against NiV on the market. The goal of this study was to use a recombinant RABV vector expressing NiV glycoprotein (NiV G) to develop a bivalent candidate vaccine against NiV disease and rabies virus (RABV) disease, which is also a significant health burden in the regions where NiV is endemic. The rabies vector is a well-established vaccine strain that lacks neurovirulence and can stably expresses foreign antigens that are immunogenic in various animal models. Mice inoculated intranasally with the live recombinant RABV/NiV vaccine (NIPARAB) showed no signs of disease. To test the immunogenicity of the vaccine candidate, groups of C57BL/6 mice were immunized intramuscularly with a single dose of live vaccine particles or two doses of chemically inactivated viral particles. Both vaccination groups showed NiV G-specific seroconversion, and the inactivated (INAC) vaccine group yielded higher titers of NiV G-specific antibodies. Furthermore, cross-reactivity of NiV G-specific immune sera against Hendra virus (HeV), was confirmed by immunofluorescence (IF) and indirect ELISA against soluble recombinant HeV glycoprotein (HeV G). Both live and killed vaccines induced neutralizing antibodies. These results indicate that NIPARAB may be used as a killed virus vaccine to protect humans against NiV and RABV, and possibly as a preventative measure against HeV as well.