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Principal Investigator: Scott C Weaver
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $3,960,456
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY, Project 4
Alphaviruses regularly threaten global health, including long-established emerging viruses like Venezuelan
equine encephalitis virus (VEEV, the most important of the encephalitic alphaviruses) and chikungunya virus
(CHIKV, the most important arthritogenic alphaviruses) that unexpectedly emerged and spread globally.
Moreover, other alphaviruses also threaten to emerge into urban epidemic cycles and spread extensively. To
control these outbreaks and prepare for future alphavirus pandemics, we developed a new vaccine platform that
uses the insect-specific, vertebrate cell replication-incompetent alphavirus, Eilat virus (EILV), as a genetic
backbone for chimeras containing the structural polyprotein of target alphaviruses. CHIKV, VEEV, and eastern
equine encephalitis virus chimeras are thermostable and provide rapid, durable, single-dose protection,
advancing our goal of bridging the tradeoff between safety and rapid protection. A single dose of EILV-
CHIKV induced neutralizing antibodies and conferred protection against CHIKV challenge one year after
administration in non-human primates (NHPs). Here, in Project 4, we will extend these promising findings to
demonstrate that the EILV platform can be applied rapidly and predictably to diverse alphaviruses to quickly
generate safe and effective vaccines for future outbreak control. First, we will optimize the production protocols,
doses, and routes of vaccination for EILV-VEEV. We will perform detailed assessments of EILV-VEEV
immunogenicity in mice by measuring serum IgG binding and neutralization titers, and specific T cell responses.
We will also test the ability of EILV-based vaccines to prime germinal center (GC) B cell, T follicular helper cell
(Tfh), long-lived plasma cell (LLPCs), and memory B cell (MBC) responses. To identify early predictors of
immune durability, we will measure longitudinal serum neutralizing antibody titers as well as the induction,
magnitude, and specificity of antigen-specific MBC and GC B cells, recovered via fine needle aspirate of lymph
nodes at early and late time points post-vaccination. To demonstrate an efficient, rapid workflow leading to a
completely new, safe and immunogenic EILV-based vaccine for future outbreak control, we will develop a new
chimeric EILV-based vaccine for western equine encephalitis virus vaccine, which is in a different antigenic
alphavirus complex from CHIKV and VEEV. Finally, we will evaluate optimized EILV-based vaccines as a
platform for cross-protection against diverse alphaviruses by developing blended formulations and prime-
boost regimens. Lead multivalent (blended) candidates identified with mouse experiments with pan-alphavirus
potential will be advanced to NHP efficacy testing with Core D, and a lead nanoparticle or mRNA vaccine
candidate developed in Project 3 will be tested with the lead EILV-based vaccines in heterologous prime-boost
regimens. By the end of this project, a rapid, safe, refrigerator-stable, and highly efficacious, single-dose
vaccine platform will generate vaccines poised for final preclinical testing and a modular approach to address
future alphavirus threats.
Terms: <7S Gamma Globulin><Address><Adenoviridae><Adenoviruses><Alpha Virus><Antibody Response><Antibody titer measurement><Antigens><Arthritogenic><Assay><Attenuated Vaccines><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Bioassay><Biological Assay><Blood Plasma Cell><Blood Serum><CHIKV><Cell Body><Cells><Chikungunya virus><Chimera><Chimera organism><Clinical Trials><Combination Vaccines><Combined Vaccines><Complex><Crab-Eating Macaque><Crab-Eating Monkey><Cynomolgus Monkey><Cynomolgus macaque><DNA Vaccines><Development><Disease><Disease Outbreaks><Disorder><Dose><EEE Virus><ELISA><Early identification><Early-Stage Clinical Trials><Eastern Equine Encephalitis><Eastern Equine Encephalitis Virus><Eastern Equine Encephalomyelitis><Eastern Equine Encephalomyelitis Virus><Electroporation><Enzyme-Linked Immunosorbent Assay><Epidemic><FNA><Fine Needle Aspirate><Fine needle aspiration biopsy><Fine-Needle Aspiration><Flavivirus><Formulation><Future><Genetic><Germinal Center><Goals><Group A Arboviruses><Group B Arbovirus><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><IgG><Immune><Immunes><Immunity><Immunization><Immunoglobulin G><Inducer Cells><Inducer T-Lymphocytes><Infection><Insecta><Insecticide Resistance><Insects><Insects Invertebrates><Investigational Drugs><Investigational New Drugs><Lead><Live-attenuated Vaccine><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><M fascicularis><M. fascicularis><Macaca fascicularis><Measles><Measures><Memory B Cell><Memory B-Lymphocyte><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Naked DNA Vaccines><Orthoflavivirus><Outbreaks><Pathogenesis><Pb element><Persons><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma Cells><Plasmacytes><Polyproteins><Population><Preclinical Testing><Production><Protocol><Protocols documentation><RNA vaccine><RNA-based vaccine><Recombinant DNA Vaccines><Recommendation><Regimen><Research><Rodent><Rodentia><Rodents Mammals><Route><Rubeola><Safety><Serum><Specificity><Spinal Column><Spine><Structure of germinal center of lymph node><T cell response><Testing><Time><Transmission><VEE virus><VEEV><Vaccination><Vaccine Design><Vaccines><Venezuelan Equine Encephalitic Virus><Venezuelan Equine Encephalitis Virus><Venezuelan Equine Encephalomyelitis Virus><Vertebral column><Vertebrate Animals><Vertebrates><Virus><Virus-like particle><WEE Virus><WEEV><Western Equine Encephalitic Virus><Western Equine Encephalitis Virus><Western Equine Encephalomyelitis Virus><antibody titering><backbone><candidate identification><chimeras><clinical development><cross immunity><cross protection><deliver vaccines><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><electroporative delivery><emergent virus><emerging virus><enzyme linked immunoassay><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><future outbreak><gene electrotransfer><global health><heavy metal Pb><heavy metal lead><immunogen><immunogenic><immunogenicity><insecticide resistant><live vaccine><live vaccines><lymph gland><lymph nodes><lymphnodes><mRNA vaccine><mRNA-based vaccine><microbial><morbilli><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><new approaches><new vaccines><next generation vaccines><next outbreak><non-human primate><nonhuman primate><novel approaches><novel strategies><novel strategy><novel vaccines><outbreak containment><outbreak control><outbreak in the future><outbreak mitigation><pandemic><pandemic disease><pathogen><phase I protocol><plasmocyte><pre-clinical testing><protective efficacy><prototype><response><safety testing><seroconversion><thermolability><thermostability><transmission process><vaccine candidate><vaccine delivery><vaccine development><vaccine platform><vector><vector competence><vector mosquito><vectorial competence><vertebrata><viral emergence><virus-like nanoparticles><viruslike particle><volunteer>