Document text
Principal Investigator: Jonathan R. Lai
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $4,622,541
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Alphaviruses are mosquito-transmitted viruses that cause severe disease in humans. The genus is divided into
two groups: Arthritogenic viruses cause arthralgia and musculoskeletal disease that can persist for years after
infection, and encephalitic viruses infect the brain and can cause long-term neurological injury or lethality. The
goal of FLARE Center Project 3 is a structure-based and epitope-focused design of next-generation vaccine
candidates for two prototype alphaviruses, one arthritogenic (chikungunya virus, CHIKV) and one encephalitic
(Venezuelan equine encephalitis virus, VEEV). CHIKV is globally distributed and has emerged in part due to
sequence adaptations that enabled an expanded range of mosquito vectors. VEEV is endemic to the Americas
and has caused large epidemics in South and Central America. We hypothesize that structural conservation
among alphaviruses, coupled with recent advancements in elucidating details of molecular interactions
between the alphavirus E1/E2 glycoprotein and protective monoclonal antibodies (mAbs) or host receptors, will
enable immunogen design strategies that yield safe and effective vaccines that can be rapidly adapted to other
alphaviruses. Our objective is to build a ‘plug-and-play’ workflow of immunogen and vaccine platform pairs that
can be deployed for emerging or new alphaviruses. Aim 1 focuses on optimization of the E2 B-domain (E2-B),
which is engaged by broadly protective mAbs. Aim 2 explores the E1 fusion loop (E1-FL) as a vaccine target,
based on the recent discovery that human E1-FL-specific mAbs have pan-alphavirus protective potential via
non-neutralizing, Fc-mediated mechanisms. In Aim 3, structures of the hexameric E1/E2 spike bound to host
receptors MXRA8 (CHIKV) or LDLRAD3 (VEEV) will be used as a template to engineer immunogens that
capture the prefusion complex (preE12), enabling exposure of key quaternary epitopes. Immunogens will be
integrated into protein nanoparticles or, in collaboration with our industry partner Moderna, encoded as lipid-
encapsulated mRNA vaccines. Successful designs will be compared head-to-head with virus-like particle
(VLPs)-based vaccines in murine models of arthritis (CHIKV) and lethal disease (CHIKV and VEEV) in Aim 4.
After down-selection and rigorous Go/No-Go decisions, the top vaccine candidates will be transitioned to
Animal Core D for further evaluation in mice and non-human primates. Project 3 will work closely with the
Scientific and Administrative Cores to accomplish these objectives and is conceptually and technically linked
to other FLARE Center Projects focused on flaviviruses and alphaviruses.
Terms: <Aedes><Alpha Virus><Americas><Animals><Antigenic Determinants><Antigens><Armed Forces Personnel><Arthralgia><Arthritis><Arthritogenic><Attenuated><Binding><Binding Determinants><Brain><Brain Inflammation><Brain Nervous System><Brazil><C1 q><C1q><CHIKV><CHIKV infection><Cell Attachment><Cell Body><Cell surface><Cell-Matrix Adhesions><Cell-Matrix Junction><Cells><Central America><Characteristics><Chikungunya virus><Clinical Treatment Moab><Clinical Trials><Collaborations><Complement 1q><Complement C1q><Complex><Country><Coupled><Culicidae><Development><Disease><Disease Outbreaks><Disorder><Encapsulated><Encephalitis><Encephalon><Engineering><Epidemic><Epitopes><Evaluation><Fever><Flavivirus><Glycoproteins><Goals><Group A Arboviruses><Group B Arbovirus><Head><Human><Immune response><Immunological response><Infection><Joint Pain><Laboratory Personnel><Link><Lipids><Mediating><Membrane><Messenger RNA><Mice><Mice Mammals><Military><Military Personnel><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monoclonal Antibodies><Mosquitoes><Murine><Mus><Musculoskeletal Diseases><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neurological Damage><Neurological Injury><Neurological trauma><Orthoflavivirus><Outbreaks><Paraguay><Play><Population><Protein Engineering><Proteins><Public Health><Pyrexia><RNA vaccine><RNA-based vaccine><Receptor Protein><Risk><Safety><South America><Structure><Surface><Syndrome><T-Cell Epitopes><T-Lymphocyte Epitopes><Testing><Transmission><VEE virus><VEEV><Vaccine Design><Vaccines><Venezuelan Equine Encephalitic Virus><Venezuelan Equine Encephalitis Virus><Venezuelan Equine Encephalomyelitis Virus><Viral><Viral Diseases><Virus><Virus Diseases><Virus-like particle><Work><arthritic><attenuate><attenuates><chikungunya infection><chikungunya virus infection><conformation><conformational><conformational state><conformationally><conformations><design><designing><developmental><dimer><endosome membrane><epidemic concern><epidemic potential><epidemic risk><epidemic threat><epizootic><febrile><febris><genetic protein engineering><head-to-head analysis><head-to-head comparison><host response><immune response to vaccination><immune response to vaccines><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><improved><in vivo><industrial partnership><industry partner><industry partnership><infected with CHIKV><infected with chikungunya><mAbs><mRNA><mRNA vaccine><mRNA-based vaccine><membrane structure><military population><monoclonal Abs><mouse model><murine model><musculoskeletal disorder><nano particle><nano-sized particle><nanoparticle><nanosized particle><neurotrauma><new approaches><new vaccines><next generation><next generation vaccines><non-human primate><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><novel vaccines><pandemic concern><pandemic potential><pandemic risk><pandemic threat><particle><pathogen><protein design><prototype><receptor><response><synergism><transmission process><vaccine associated immune response><vaccine candidate><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine platform><vector><vector mosquito><viral infection><viral transmission><virus infection><virus transmission><virus-induced disease><virus-like nanoparticles><viruslike particle>