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Principal Investigator: Alexander Bukreyev
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2020
Award: $769,175
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
The Marburg virus (MARV) and Ravn virus (RAVV), which both belong to the genus Marburgvirus of the family
Filoviridae, cause the severe disease in humans, with case fatality rates up to 90%. There are no licensed
vaccines against marburgviruses. Clinical trials of vaccine candidates against Ebola virus (EBOV), which
belongs to the genus Ebolavirus of the family Filoviridae, demonstrated that the high vaccine doses that are
required to induce an immune response at the protective level result in toxic effects associated with their
principal component EBOV glycoprotein (GP). We and others have recently isolated and characterized human
monoclonal antibodies (mAbs) to MARV and EBOV and defined the principal antigenic determinants for
neutralization and protection on filovirus GP. We have demonstrated the successful protection of non-human
primates against MARV by passively transferred mAbs. The central hypothesis of this study is that the epitopes
of naturally-occurring human protective antibodies from survivors of a MARV infection can be used as
templates for optimal rationally-designed structure-based vaccines. This hypothesis is supported by our recent
extensive progress in the isolation of protective mAbs from survivors in conjunction with the recent advances in
computational immunology techniques. We propose the rational design of structure-based vaccine MARV
candidates that present the immunogenic determinants on GP. As in the wild-type (wt) GP, antigenic elements
on the protein are obscured by glycosylation, the glycan cap and the mucin-like domain. The designed
antigens are expected to better present protective determinants than the wt GP. We also propose that a
vaccine based on conserved GP epitopes will be protective against both MARV and RAVV. The vaccine will
use a highly innovative vaccine delivery platform based on pseudouridin-modified RNA delivered in a lipid
nanoparticle formulation. The proposal is based on an interdisciplinary approach with a diverse team of experts
in computational modeling, antibody and antigen discovery, filovirus virology, immunology and vaccinology.
The Meiler computational group will use the ROSETTA software platform techniques to design novel structure-
based vaccine candidate antigens, using high-resolution structures of antigen-antibody complexes in the GP
receptor-binding domain. The Crowe laboratory will generate recombinant antigens and antibodies, validate
proper structure and function of the constructs, and determine the fine details of their biomolecular interaction.
Moderna Therapeutics will provide the innovative mRNA vaccine platform. The Bukreyev and Geisbert
laboratories will test the vaccine constructs expressing the designed antigens in rodent and non-human
primate models of marburgviruses, and the Bukreyev laboratory will perform in-depth characterization of the
immune response. The completion of this proposal will result in the development of a universal and safe next-
generation vaccine, which will be protective against both MARV and RAVV. The generated antigen will be
compatible with any existing advanced vaccine platform currently in clinical trials.
Terms: <Adverse effects><Algorithm Design><Algorithmic Design><Algorithmic Engineering><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Repertoire><Antigen-Antibody Complex><Antigenic Determinants><Antigens><BDBV><Binding><Binding Determinants><Bundibugyo ebola virus><Bundibugyo ebolavirus><Bundibugyo virus><Case Fatality Rates><Cell Body><Cells><Central Africa><Clinical Treatment Moab><Clinical Trials><Complex><Computational Biology><Computer Models><Computer software><Computerized Models><Crystallization><DNA Molecular Biology><Data><Dermal><Dermatitis><Development><Disease><Disease Outbreaks><Disorder><Dose><EBOV><Ebola><Ebola Vaccines><Ebola Virus Vaccines><Ebola virus><Elements><Epidemic><Epitope Mapping><Epitopes><Family><Filoviridae><Filovirus><Formulation><Frankfurt-Marburg Syndrome Virus><Future><Generations><Genetic Alteration><Genetic Change><Genetic defect><Geography><Glycans><Glycoproteins><Hu-mABs><Human><Immune><Immune Complex><Immune response><Immunes><Immunological response><Immunology><Laboratories><Marburg><Marburg virus><Mediating><Membrane><Messenger RNA><Metabolic Glycosylation><Mission><Modeling><Modern Man><Molecular Biology><Molecular Interaction><Monoclonal Antibodies><Mucins><Mucus Glycoprotein><Mutation><NIH><National Institutes of Health><Non-Polyadenylated RNA><Outbreaks><Pathogenicity><Polysaccharides><Probability><Protein Conformation><Protein Engineering><Proteins><Pseudouridine><RNA><RNA Gene Products><RNA vaccine><Recombinants><Research Design><Resolution><Reston><Ribonucleic Acid><Rodent><Rodentia><Rodents Mammals><SUDV><Scaffolding Protein><Software><Structure><Study Type><Sudan><Sudan Ebola virus><Sudan ebolavirus><Sudan virus><Survivors><Techniques><Testing><Therapeutic><Toxic effect><Toxicities><Transplantation><United States National Institutes of Health><Vaccine Antigen><Vaccine Clinical Trial><Vaccine Design><Vaccines><Validation><Viral><Viral Antibodies><Viral Diseases><Virus><Virus Diseases><Western Africa><Wing><algorithm engineering><algorithmic composition><anti-viral antibody><antiviral antibody><base><computational modeling><computational models><computer based models><computer biology><computerized modeling><design><designing><develop a vaccine><development of a vaccine><developmental><ebolavirus><forest><genetic protein engineering><genome mutation><glycosylation><host response><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><immunogen><immunogenic><immunogenicity><immunoresponse><improved><in silico><in vivo><innovate><innovation><innovative><interdisciplinary approach><lipid nanoparticle><mAbs><mRNA><mRNA vaccine><membrane structure><model of animal><model organism><multidisciplinary approach><neutralizing antibody><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><pathogen><pathogenic virus><protective efficacy><protein design><receptor binding><receptor bound><response><scaffold><scaffolding><screening><study design><transplant><vaccine candidate><vaccine delivery><vaccine development><vaccine evaluation><vaccine formulation><vaccine screening><vaccine testing><vaccinology><viral infection><viral pathogen><virology><virus infection><virus-induced disease>