Development of soluble and membrane bound immunogens to shepherd HIV-1 MPER specific BCR maturation

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Olivia  Swanson
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $35,974
Funding agency: National Institute of Allergy and Infectious Diseases

Project Summary/Abstract.
A small fraction of individuals infected with HIV-1 generate antibodies that can potently neutralize
diverse circulating strains of HIV-1. Such broadly neutralizing antibodies (bnAbs) have provided
sterilizing immunity in passive immunization studies in animal models. Therefore, the induction of
such antibodies by vaccination is a global health priority as a means to prevent HIV infection. The
membrane proximal external region (MPER) of the HIV-1 envelope protein (Env) is a site of
particular interest. A promising strategy to initiate bnAb induction is germline targeting (GT) in
which immunogens are engineered to specifically activate B cell precursors of bnAbs. Previous
work generated germline-targeting priming MPER epitope scaffolds capable of activating and
expanding 10E8-like precursor B cell receptors (BCRs) in mouse and non-human primate (NHP)
models. This project seeks to develop soluble and membrane-bound boost immunogens that
present the MPER epitope in a more native-like context with the aim of maturing primed BCRs to
acquire bnAb features.
Known bnAbs have high degrees of somatic hypermutation (SHM); therefore, I hypothesize that
vaccine induction of bnAbs will require sequential immunization with multiple immunogens
designed to shepherd affinity maturation of the BCR to acquire neutralization breadth and
potency. I will test this hypothesis through three primary aims to: 1) determine effect of mRNA vs.
protein immunogen delivery on immunogenicity and BCR maturation of 10E8-GT priming
candidates; 2) develop and test epitope-scaffold boost candidates for the ability to engage and
mature B cells activated by GT primes; 3) generate stabilized transmembrane envelope
constructs that preferentially bind MPER targeting antibodies. I expect the results of these aims
will generate candidate immunogens that bind with high affinity to 10E8-like antibodies with
various levels of mutation and maturity in order to shepherd antibodies towards breadth.
During this process, I will receive training in immunology, structural biology, and immunology from
my interdisciplinary mentors. The resources available at Scripps Research and from other
collaborators will ensure I develop the skills needed for my long-term goal of leading a vaccine
development research group.

Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affinity><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Response><Antigenic Determinants><Antigens><B blood cells><B cell><B cell receptor><B cells><B-Cell Activation><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Biophysics><Cell Body><Cell Membrane Lipids><Cells><Complex><Computer Models><Computerized Models><Conserved Sequence><Development><Development and Research><Directed Molecular Evolution><Engineering><Ensure><Envelope Protein><Epitopes><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Genetic Alteration><Genetic Change><Genetic defect><Germ Lines><Germ-Line Mutation><Germinal Center><Germline Mutation><Goals><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV Infections><HIV env Protein gp120><HIV envelope><HIV envelope protein><HIV-1><HIV-I><HIV1><HTLV-III Infections><HTLV-III gp120><HTLV-III-LAV Infections><Health Priorities><Hereditary Mutation><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Ig Somatic Hypermutation><Immunity><Immunization><Immunoglobulin Somatic Hypermutation><Immunology><Individual><KI mice><Knock-in Mouse><LAV-HTLV-III><Lead><Length><Lymphadenopathy-Associated Virus><Mature B-Cell><Mature B-Lymphocyte><Membrane><Membrane Lipids><Mentors><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Mutate><Mutation><Passive Immunization><Pb element><Polishes><Process><Proteins><R & D><R&D><Research><Research Resources><Resources><Route><Site><Structure><Structure of germinal center of lymph node><Testing><Training><Vaccination><Vaccines><Virus-HIV><Work><activated B cells><biophysical foundation><biophysical principles><biophysical sciences><computational modeling><computational models><computer based models><computerized modeling><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><directed evolution><env Antigens><env Gene Products><env Polyproteins><env Protein><flow cytophotometry><genome mutation><germ-line defect><germline variant><global health><gp120><gp120 ENV Glycoprotein><gp120(HIV)><heavy metal Pb><heavy metal lead><immunogen><immunogenic><immunogenicity><interest><knockin mice><mRNA><mRNA delivery><membrane structure><messenger RNA delivery><model of animal><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neutralizing antibody><non-human primate><nonhuman primate><passive vaccination><prevent><preventing><recruit><research and development><response><scaffold><scaffolding><skills><somatic hypermutation><structural biology><vaccine development><viral resistance><virus resistance>