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Principal Investigator: KEVIN O SAUNDERS
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $4,794,780
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT – OVERALL
HIV-1 broadly neutralizing antibodies (bnAbs) are protective in animal models of HIV-1 infection, but are not
elicited in humans by current vaccine regimens. To elicit bnAbs, the B cell lineage vaccine design approach aims
to administer multiple immunogens in a specific sequence to shepherd bnAb maturation through immunologic
roadblocks that typically halt bnAb development. One roadblock we recently identified are somatic mutations
that encode key amino acids for antibody function but that are rarely made by the somatic mutation enzyme
activation-induced cytidine deaminase. Our central vaccine design hypothesis is that antibodies (Abs)
encoding these improbable mutations, will be rare; thus, vaccine immunogens will need to have higher affinity
for Abs with these desired amino acid changes than Abs without the amino acid changes in order to select for
them. The problem facing this strategy is that the only antigen for HIV-1 bnAbs is HIV-1 envelope (Env), which
is poorly immunogenic and for which bnAb precursors generally have low affinity. We and others have found
these two obstacles can be overcome by designing Envs with high affinity for bnAb precursors and by
multimerizing these Envs on nanoparticles (NPs) to provide avidity and improved antigen trafficking to germinal
centers. However, Env trimer NPs can have low expression and present misfolded Env trimers that elicit
undesired non-neutralizing Abs. This application is significant because it will establish a cGMP-compliant
vaccine platform that rapidly generates higher quality HIV-1 Env trimer NP vaccines without time-consuming
iterative immunogen design. This platform uses the sortase A enzyme to site-specifically, covalently-link well-
folded HIV-1 Env trimers to intact Helicobacter pylori ferritin NPs. The resultant HIV-1 Env trimer sortase A-
conjugated NPs (scNPs) display only well-folded Env trimers, and in preliminary studies, have successfully
initiated CD4 binding site bnAb lineages in human bnAb precursor knock-in mice and CD4bs nAbs in rhesus
macaques. The scNP platform is universal in nature since it can incorporate diverse viral type I fusion proteins
by simply adding a 6-amino acid sortase A tag to their C-terminus. In Specific Aim 1, we will compare the ability
of monovalent and bivalent HIV-1 Env scNPs to guide affinity maturation of CD4 binding site bnAbs in humanized
mice and rhesus macaques. In Specific Aim 2, we will produce and assemble two CD4 binding site-bnAb-
targeting HIV-1 Env trimer scNPs (CH505 TF scNP and a second sequential Env trimer scNP) under cGMP
conditions. This program will deliver an optimized cGMP process for making scNPs, two cGMP-produced Env
trimer scNPs, and additional ferritin and sortase A components for the manufacture of future immunogens. The
CH505 TF Env trimer scNPs will be used in a Phase I trial through the HIV Vaccine Trial Network. Ultimately,
the impact of this platform is that it will enable multiple Env trimer scNPs to be made rapidly under cGMP, making
it feasible to do iterative testing in clinical trials of complete sequential nanoparticle vaccines that target bnAbs.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><AICDA><AICDA protein><AID gene><AID protein><Affinity><Amino Acids><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Affinity><Antigens><Avidity><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Sites><Biomanufacturing><Blood Serum><C pylori><C. pylori><CDA2 protein><COVID-19 S protein><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><Campylobacter pylori><Cell Line><Cell Lineage><CellLine><Chimera Protein><Chimeric Proteins><Clinical Trials><Combining Site><Complex><Consumption><Data><Development><Doctor of Philosophy><Documentation><Drugs><Early-Stage Clinical Trials><Electron Microscopy><Ensure><Enzyme Activation><Enzyme Gene><Enzymes><Ferritin><Food and Drug Administration><Frequencies><Fusion Protein><Future><Gene Fusion><Generations><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Goals><Good Manufacturing Process><Good manufacturing practice><H pylori><H pylory><H. pylori><H. pylory><HIV Antigens><HIV Vaccine Trials Network><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-Associated Antigens><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><HTLV-III Antigens><HTLV-III-LAV Antigens><HVTN><Helicobacter pylori><Human><Human Immunodeficiency Virus Type 1><Human T-Lymphotropic Virus Type III Antigens><Human immunodeficiency virus 1><Immune system><Immunization><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Immunology><Industry><Infection><Influenza HA><Influenza Hemagglutinin><Investigational New Drug Application><KI mice><Knock-in Mouse><LAV Antigens><Lead><Link><Lymphadenopathy-Associated Antigens><M mulatta><M. mulatta><Macaca mulatta><Medication><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutation><Nature><Negative Staining><Outcome><Pb element><Ph.D.><PhD><Pharmaceutical Preparations><Phase 1 Clinical Trials><Phase I Clinical Trials><Process><Production><Qualifying><Reaction><Reactive Site><Regimen><Rhesus Macaque><Rhesus Monkey><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><Series><Serum><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Site><Somatic Mutation><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Strains Cell Lines><Structure><Structure of germinal center of lymph node><Testing><Time><Toxic effect><Toxicities><USFDA><United States Food and Drug Administration><Vaccine Design><Vaccines><Viral><Virion><Virus Particle><activation-induced cytidine deaminase><activation-induced deaminase><aminoacid><antigen antibody affinity><booster dose><booster shot><booster vaccine><conformation><conformational><conformational state><conformationally><conformations><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><cross reactivity><cultured cell line><design><designing><developmental><drug/agent><evaluate vaccines><experience><flu HA><flu hemagglutinin><genome mutation><heavy metal Pb><heavy metal lead><human immunodeficiency virus vaccine><humanized mice><humanized mouse><immunization strategy><immunogen><immunogenic><immunogenicity><improved><influenza viral HA><influenza viral hemagglutinin><influenza virus HA><influenza virus hemagglutinin><innovate><innovation><innovative><knockin mice><manufacture><model of animal><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><non-human primate><nonhuman primate><pandemic><pandemic disease><phase 1 trial><phase I protocol><phase I trial><process optimization><programs><quality assurance><somatic variant><sortase><spike proteins on SARS-CoV-2><srtA gene product><statistical analysis><trafficking><transpeptidation><trial planning><vaccination strategy><vaccination study><vaccination trial><vaccine antibodies><vaccine boost><vaccine evaluation><vaccine induced antibodies><vaccine platform><vaccine screening><vaccine study><vaccine testing><vaccine trial><vaccine-induced antibodies>