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Principal Investigator: Christopher Parks
Organization: INTERNATIONAL AIDS VACCINE INITIATIVE
Fiscal Year: 2020
Award: $14,125
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
The overall goal of this project is to develop and compare three new HIV envelope (Env) trimer delivery
vaccines that are designed to mimic the natural presentation of the transmembrane glycoprotein complex (the
spike) that occurs during HIV infection. Our vaccine design approach emphasizes delivery of authentic Env
trimer primarily because antibodies (Abs) with broad HIV-neutralizing activity (bNAbs) have been elicited only
in patients infected with HIV. Recently, several new Env glycoprotein designs have been developed that should
enable improved presentation of the native trimeric Env. These new immunogens assemble into correctly
folded trimeric complexes that are significantly more stable, which should make it possible to stimulate B cells
with a more uniform well-ordered mimic of the functional Env trimer. An additional challenge to realizing the
potential benefits of the improved immunogen will be identification and development of vaccine delivery
platforms that can present the correctly-configured glycoprotein complex in vivo and also stimulate immune
system functions required to drive the B cell response beyond development of antibodies with limited
neutralization breadth. Accordingly, the goal of this research project is to apply this promising Env trimer
stabilization technology to the development of three novel vaccines that will present nearly identical stable,
well-ordered viral spikes, but use substantially different delivery mechanisms that will stimulate distinctive
profiles of immune system functions. This will make it possible to conduct comparative studies to specifically
analyze how vaccine platforms and their unique immunostimulatory properties affect the qualities of the Env
antibody response. Each vaccine will deliver a stabilized HIV clade C strain 1086 (C.1086) Env immunogen
that will be developed using the new native flexibly-linked (NFL) Env trimer technology (EnvNFL), which will be
adapted for expression of transmembrane glycoproteins. The three Specific Aims for the project are focused
on development and evaluation of the new vaccines and production of vaccine material needed to support
preclinical testing in animal models, which will be conducted in collaboration with the Research Project Teams
and Technical Cores that are members of this HIVRAD Program. This Project Team will develop novel
stabilized spike delivery vaccines based on three immunogenic vaccine platforms, including: 1) an innovative
mRNA vector and adjuvant delivery system called RNActive®; 2) EnvNFL trimers arrayed on inactivated
vesicular stomatitis virus (VSV) particles formulated with adjuvant; and 3) EnvNFL delivered with a live
replication-competent VSV vector that incorporates Env in its viral envelope. The Project Team will generate
and optimize the three novel vaccine candidates, ensure that they effectively deliver stabilized transmembrane
spikes with the expected antigenicity profiles, and provide well-characterized, high-quality vaccine material for
evaluation in preclinical immunogenicity and efficacy studies.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Affect><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cells><Chemicals><Chimera><Chimera organism><Collaborations><Comparative Study><Complex><Cytoplasmic Membrane><Development><Domestic Rabbit><Ensure><Epitopes><Evaluation><Glycoproteins><Goals><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Inbred Mouse><Intracellular Communication and Signaling><LAV-HTLV-III><Link><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Messenger RNA><Mice><Mice Mammals><Modern Man><Modification><Murine><Mus><Oryctolagus cuniculus><Patients><Performance><Plasma Membrane><Preclinical Testing><Property><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RNA vaccine><Rabbits><Rabbits Mammals><Recombinants><Regimen><Research Grants><Research Project Grants><Research Projects><Rhesus Macaque><Rhesus Monkey><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Stimulus><Surface><System><Technology><Testing><VSV><Vaccination><Vaccine Design><Vaccine Production><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Diseases><Virion><Virus><Virus Diseases><Virus Particle><Virus-HIV><Work><base><biological signal transduction><cell envelope><comparative><design><designing><develop a vaccine><development of a vaccine><developmental><efficacy study><flexibility><flexible><functional mimics><immune system function><immunogen><immunogenic><immunogenicity><improved><in vivo><innovate><innovation><innovative><mRNA><mRNA vaccine><member><model of animal><model organism><neutralizing antibody><new vaccines><next generation vaccines><novel><novel vaccines><particle><plasmalemma><pre-clinical><pre-clinical evaluation><pre-clinical testing><preclinical><preclinical evaluation><programs><response><vaccine candidate><vaccine delivery><vaccine development><vaccine formulation><vector><viral infection><virus infection><virus-induced disease>