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Principal Investigator: JOANN M TUFARIELLO
Organization: GEORGIA STATE UNIVERSITY
Fiscal Year: 2021
Award: $31,000
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
This developmental project seeks to develop methods to dramatically boost immunogenicity of virus-like particle
(VLP) vaccines. Ebola virus (EBOV) and Marburg virus (MARV) are members of the filovirus family of enveloped,
negative-sense RNA viruses that causes outbreaks of severe human disease. Due to their lethality, filoviruses
are among the handful of emerging viruses for which biosafety level 4 (BSL4) containment is required for their
study. Although progress has been made toward EBOV vaccines, there remains a need for development of
vaccines for other filoviruses, particularly MARV. VLPs are an often-explored vaccine platform for a variety of
viruses, including for EBOV and MARV. Advantages of VLPs include their relative safety, as they cannot replicate
and cause viral disease; their close resemblance to authentic virus, such that they present antigens in their native
state; their capacity to elicit both B and T cell responses and their proven efficacy for a variety of systems.
Potential challenges of VLPs as vaccines include relatively lower immunogenicity, as compared to live virus.
Filovirus VLPs can be produced by co-expression of the viral matrix protein VP40, the viral glycoprotein (GP),
with or without expression of the viral nucleoprotein (NP). Such VLPs have been demonstrated to stimulate
dendritic cell (DC) responses, to elicit B and T cell mediated immunity and to protect mice, guinea pigs and non-
human primates (NHPs) from lethal challenge. Therefore, filovirus VLPs are viable vaccine candidates. However,
filovirus VLP immunogenicity is weak with protection requiring coadministration with an adjuvant and multiple
doses. This is not ideal for vaccines that are mainly deployed in response to outbreaks. This application seeks
to dramatically improve immunogenicity of EBOV and MARV VLPs by the rational incorporation of type I
interferon (IFN) signaling domains from the cellular pattern recognition receptors RIG-I or TRIF into the particles.
This enables delivery into cells of the IFN inducing domain by the VLPs, triggering robust innate immune
responses reminiscent of live virus infection, to boost adaptive immune responses. To further pursue this
direction, we will explore approaches to optimize the incorporation of IFN-inducing signaling domains into EBOV
and MARV VLPs. We will then evaluate the capacity of the different enhanced VLP strategies to elicit B and T
cell immune responses in vivo, and finally, test the most promising enhanced VLPs for the capacity to elicit rapid
protection against EBOV and MARV challenge in mice. Successful completion of these studies will provide a
novel platform for the development of filovirus vaccines and an approach that can likely be applied to other
emerging viral pathogens.
Terms: <Address><Adjuvant><Africa><Angola><Antibodies><Antibody Response><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Belgian Congo><Case Fatality Rates><Cavia><Cell Body><Cell Communication and Signaling><Cell Mediated Immunology><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Immunity><Cessation of life><Containment><Data><Death><Democratic Republic of the Congo><Dendritic Cells><Development><Development and Research><Disease><Disease Outbreaks><Disorder><Dose><EBOV><Ebola><Ebola Vaccines><Ebola Virus Vaccines><Ebola virus><Ebola-like Viruses><Engineering><Family><Filoviridae><Filovirus><Frankfurt-Marburg Syndrome Virus><Glycoproteins><Goals><Guinea Pigs><Guinea Pigs Mammals><Human><IFN><Immune><Immune memory><Immune response><Immunes><Immunity><Immunization><Immunologic Memory><Immunologic Sensitization><Immunologic Stimulation><Immunological Memory><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><In Vitro><Innate Immune Response><Interferon Type I><Interferons><Intracellular Communication and Signaling><Knowledge><Marburg><Marburg virus><Marburg-like Viruses><Marburgvirus><Methods><Mice><Mice Mammals><Modern Man><Murine><Mus><Nucleoproteins><Outbreaks><Pattern recognition receptor><Public Health><R & D><R&D><RNA Viruses><Regimen><Research><SUDV><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Subunit Vaccines><Sudan Ebola virus><Sudan ebolavirus><Sudan virus><System><T cell response><T-Cells><T-Lymphocyte><Testing><Vaccines><Veiled Cells><Viral><Viral Diseases><Viral M Proteins><Viral Matrix Proteins><Viral Membrane Proteins><Virus><Virus Diseases><Virus-like particle><World Health Organization><ZEBOV><Zaire><Zaire Ebola virus><Zaire ebolavirus><Zoonoses><Zoonotic><Zoonotic Infection><adaptive immune response><anamnestic reaction><biological signal transduction><comparative efficacy><compare efficacy><design><designing><develop a vaccine><development of a vaccine><developmental><ebolavirus><global health><host response><human disease><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><improved><in vivo><medical countermeasure><member><new approaches><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><novel vaccines><particle><pathogen><pathogenic virus><research and development><response><secondary immune response><systemic inflammation><systemic inflammatory response><thymus derived lymphocyte><vaccination study><vaccination trial><vaccine candidate><vaccine development><vaccine formulation><vaccine study><vaccine trial><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><virus-like nanoparticles><viruslike particle>