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Principal Investigator: Swaminathan Smita Iyer
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $737,761
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
This proposal aims to enhance HIV prevention with a vaccine approach that promotes durable immunity. The
studies center on CD4 T helper cells within lymph nodes, crucial for humoral and cytolytic memory. Our objective
is to induce robust CD4 T follicular helper (Tfh) cells as they are essential for vigorous B cell activity within
germinal centers (GC). We aim to promote Tfh cells that facilitate differentiation of GC B cells to plasma cells,
essential for persistent antibodies, by fine-tuning the innate inflammatory response with adjuvanted
vector/protein immunization in rhesus macaques.
Our published studies in macaques have shown that stimulating specific Tfh1 cell subset promotes HIV Envelope
(Env) antibodies with enhanced persistence and avidity (JVI, 2020; eLife, 2023). In this proposal, we will examine
whether a vaccine platform tailored to promote Tfh1 cell differentiation during both the prime and boost, in
combination with trimeric Env antigens, enhances Env antibody durability leading to increased protective efficacy
20 weeks after final immunization. Our approach uses adjuvanted Clade A Env DNA (weeks 0, 4, and 8) to prime
Tfh1 cells. To intensify the Tfh1 response, a second group will receive an adjuvanted mRNA prime. Groups primed
with unadjuvanted DNA and mRNA will assess significance of Tfh1 priming in sustaining humoral immunity. All
four groups will receive Clade A Env protein boosts formulated in ALFQ (weeks 16 and 24) to reinforce Tfh1 cell
memory and drive sustained GC responses.
In Aim 1, we will perform detailed immune analyses across DNA and mRNA platforms to uncover mechanisms
of effective Tfh help in humoral immunity against HIV. In Aim 2, we will evaluate the long-term effectiveness by
measuring protection at week 44, 20 weeks post final boost. In addition to comprehensive cellular immunology
analysis of blood and lymph nodes and serological assessments in blood and mucosal sites, animals will be
monitored for potential vaccine-related adverse events. Our comprehensive and multifaceted approach, pairing
adjuvanted nucleic acid priming with a protein boost and directly comparing mRNA and DNA priming modalities
for immunogenicity and protection, aims to enhance longevity and affinity of HIV-Env antibodies. This innovative
strategy targets Tfh cells in a way not previously attempted, offering the potential for insights in HIV vaccine
development. These collaborative studies are supported by teams from the University of Pittsburgh, Emory
University, and Louisiana State University. These teams bring a wealth of expertise in adjuvanted vector design,
Tfh biology, humoral immunity, as well as bioinformatics and biostatistics. In summary, our studies, centered
around leveraging molecular adjuvants to enhance the Tfh1 cell response, have the potential to innovate HIV
vaccine design. Our long-term objectives are to integrate strategies to induce Tfh cells, optimized for B cell helper
function, into potent broadly neutralizing antibody-inducing platforms to improve HIV vaccine efficacy.
Terms: <7S Gamma Globulin><AIDS Virus><AIDS prevention><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Affinity><Animals><Antibodies><Antibody Affinity><Autologous><Avidity><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocytes><B-cell><BCDF><BSF-2><BSF2><Bio-Informatics><Bioinformatics><Biology><Biometrics><Biometry><Biostatistics><Blood><Blood Plasma Cell><Blood Reticuloendothelial System><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Cellular Immunology><Characteristics><Clinical><Collaborations><DNA><DNA Vaccines><Data><Deoxyribonucleic Acid><Envelope Protein><Generations><Germinal Center><Glycoproteins><Goals><HIV><HIV Prevention><HIV envelope><HIV envelope protein><HIV vaccine><HIV-1><HIV-I><HIV/AIDS Vaccines><HIV/AIDS prevention><HIV1><HPGF><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatocyte-Stimulating Factor><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Humoral Immunities><Hybridoma Growth Factor><IFN><IFN-beta 2><IFNB2><IL-6><IL6 Protein><IgA><IgG><Immune><Immune memory><Immunes><Immunity><Immunization><Immunochemical Immunologic><Immunoglobulin A><Immunoglobulin G><Immunologic><Immunologic Memory><Immunological><Immunological Memory><Immunologically><Immunologics><Inducer Cells><Inducer T-Lymphocytes><Inflammatory Response><Interferons><Interleukin-6><LAV-HTLV-III><Laboratories><Length of Life><Longevity><Louisiana><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><M mulatta><M. mulatta><MGI-2><Macaca><Macaca mulatta><Macaque><Memory><Messenger RNA><Modality><Modeling><Molecular><Molecular Fingerprinting><Molecular Profiling><Monitor><Mucosa><Mucosal Tissue><Mucous Membrane><Myeloid Differentiation-Inducing Protein><Naked DNA Vaccines><Nucleic Acids><Persons><Phenotype><Plasma Cells><Plasmacytes><Plasmacytoma Growth Factor><Proliferating><Proteins><Publishing><RNA vaccine><RNA-based vaccine><Recombinant DNA Vaccines><Rectum><Regimen><Reporting><Rhesus Macaque><Rhesus Monkey><SHIV><Serology><Structure of germinal center of lymph node><T cell response><T4 Cells><T4 Lymphocytes><Testing><Time><Tissues><Universities><Vaccine Design><Vaccines><Viral><Virus><Virus-HIV><anamnestic reaction><antibody-based immunity><antigen antibody affinity><cellular differentiation><design><designing><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><effectiveness measure><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><env Antigens><env Gene Products><env Polyproteins><env Protein><evaluate efficacy><examine efficacy><gp160><high dimensionality><human immunodeficiency virus vaccine><immunogenicity><improved><in vivo><innovate><innovation><innovative><insight><interferon beta 2><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA vaccine><mRNA-based vaccine><molecular profile><molecular signature><mucosal layer of the rectum><mucosal site><neutralizing antibody><peripheral blood><plasmocyte><prevent><preventing><protective efficacy><rectal epithelium><rectal lining><rectal mucosa><rectal mucosal tissue><response><secondary immune response><simian HIV><simian human immunodeficiency virus><tool><vaccination adverse event><vaccination associated adverse event><vaccination induced adverse event><vaccination related adverse event><vaccine adverse event><vaccine associated adverse event><vaccine development><vaccine efficacy><vaccine induced adverse event><vaccine platform><vaccine related adverse event><vector>