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Principal Investigator: Sean PJ Whelan
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $6,793,772
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY.
The long term goals of Project 3 of the Respiro, Rubula, Peribunya, Phenui (R2P2) ReVAMPP are to use a
prototype pathogen approach to identify and validate generalizable vaccine strategies against peribunyaviruses,
and advance therapeutically useful monoclonal antibodies (mAb). To achieve those goals, we selected
Oropouche virus (OROV) as the prototype and will test our findings by extension into La Crosse virus (LACV).
A central goal of this project is to understand how to stabilize the pre-fusion form of the class II fusogen Gc to
determine whether principles successfully employed for class I fusogens and their advancement as vaccines
can be leveraged to stabilize class II fusion machines. In doing so, we will generate foundational mechanistic
knowledge regarding the structure and functions of the the attachment protein (Gn) and the fusion protein (Gc)
in viral entry and as immunogens, that will also inform the optimal targets for therapeutic antibodies. In
preliminary studies we identify viral entry factors including proteinaceous receptors in the LDL receptor
superfamily, extending mechanistic parallels with studies of the Phenuiviridae in Project 4 of R2P2-ReVAMPP.
In Aim 1, in conjunction with Core C Structure, we conduct a systematic structural and functional analysis of Gn
and Gc to help inform those regions of Gn and Gc recognized by the human immune system capitalizing on the
2,500 monoclonal antibodies obtained from PBMC of convalescent humans generated in Aim 2 in conjunction
with Core D Antibody. This knowledge will be leveraged to optimize the regions of Gn and Gc as immunogens.
In aim 2, we interrogate the mechanism of action of those antibodies in vitro will be examined using a suite of
assays to identify subsets that are neutralizing and define the precise steps at which they interfere with infection.
Understanding the mechanism of neutralization will permit us to determine whether there are correlates between
mechanism, genetic barriers to viral resistance, and optimal efficacy of antibodies in vivo. In Aim 3, we will
iteratively test optimized immunogens as both protein subunit and mRNA-LNP vaccines and extend our work on
VSV-vectored OROV vaccines, testing their efficacy in small animal challenge studies. This work will leverage
the full power and expertise of Core E-Correlates to identify the correlates of protection against infection, and
against disease. The close relationship between P3 and P4, ensures direct comparison of the extent to which a
prototype peribunyavirus informs the related studies of phenuiviruses and vice-versa, bringing exceptionally
strong synergy between the two projects that will accelerate go/no-go decision making.
Terms: <Acceleration><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigens><Appearance><Assay><Bioassay><Biochemical><Biological Assay><Blocking Antibodies><Brain Inflammation><Bunyavirus><Chimera Protein><Chimeric Proteins><Clinical Treatment Moab><Complex><Core Protein><Decision Making><Development><Disease><Disorder><ELISA><Encephalitis><Engineering><Ensure><Envelope Protein><Enzyme-Linked Immunosorbent Assay><Family member><Fusion Protein><Genetic><Goals><History><Human><Immune response><Immune system><Immunological response><In Vitro><Infection><Knowledge><LDL Receptors><La Crosse encephalitis virus><La Crosse virus><LaCrosse encephalitis virus><LaCrosse virus><Lipoprotein LDL Receptors><Low Density Lipoprotein Receptor><MAb Therapeutics><Measures><Mediating><Membrane Fusion><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Modern Man><Monitor><Monoclonal Antibodies><ORFs><Open Reading Frames><Oropouche><Oropouche virus><Orthobunyavirus><PBMC><Peripheral Blood Mononuclear Cell><Persons><Polymerase><Polyproteins><Protein Biosynthesis><Protein Coding Region><Protein Subunits><Proteins><Proteolytic Clipping><Proteolytic Processing><Receptor Protein><Recording of previous events><Reporting><Resistance><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Site><Structure><Surface Proteins><Testing><Therapeutic><Therapeutic Monoclonal Antibodies><Therapeutic antibodies><VSV><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Diseases><Viral Genome><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Work><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease model><disorder model><env Antigens><env Gene Products><env Polyproteins><env Protein><enzyme linked immunoassay><genome scale><genome-wide><genomewide><group competition><histories><host response><immune system response><immunogen><immunogenicity><immunoresponse><in vivo><in vivo Model><lipid based nanoparticle><lipid nanoparticle><loss of function><mAbs><mRNA><mRNA lipid nano particle vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><member><model of animal><monoclonal Abs><monoclonal antibody drugs><mouse model><murine model><neutralizing antibody><novel><particle><pathogen><plasmid vaccine><prophylactic><protective efficacy><protein synthesis><prototype><receptor><receptor binding><receptor bound><resistant><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic mAbs><tool><vaccine antibodies><vaccine development><vaccine induced antibodies><vaccine platform><vaccine strategy><vaccine-induced antibodies><vector><vector vaccine><viral infection><viral multiplication><viral replication><viral resistance><virus genome><virus infection><virus multiplication><virus resistance><virus-induced disease>