Document text
Principal Investigator: PAUL JOSEPH UTZ
Organization: STANFORD UNIVERSITY
Fiscal Year: 2022
Award: $329,868
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
The overarching goal of this R21 proposal is to test the hypothesis that DNA vaccines induce durable innate
memory in HIV-infected humans by characterizing the evolution of the epigenetic and transcriptional landscape
in subjects who have been immunized using a novel HIV DNA vaccine. We recently used a “systems
immunology” approach to successfully map the epigenomic and transcriptional landscape of immunity to
influenza vaccination in healthy humans. Vaccination against seasonal influenza, with or without AS03 adjuvant,
resulted in persistently reduced expression of H3K27ac in monocytes and myeloid dendritic cells (mDCs), which
was associated with impaired cytokine responses to toll like receptor (TLR) stimulation. Single cell analysis
revealed an epigenomically-distinct subcluster of myeloid cells with reduced chromatin accessibility at activator
protein-1 (AP-1) targeted loci after vaccination, persistently increased chromatin accessibility at loci targeted by
interferon (IFN) response factors (IRFs), which was associated with elevated expression of antiviral genes, type
1 IFN production, and heightened resistance to infection with the heterologous viruses Zika and dengue. In
another recent paper, we have shown that the Pfizer-BioNTech mRNA prime-boost vaccine (BNT162b2) resulted
in enhanced innate immune responses, evidenced by a greater frequency of CD14+CD16+ inflammatory
monocytes, higher plasma IFN-γ, and a transcriptional signature of innate antiviral immunity. We will replicate
this “systems immunology” framework to characterize innate memory using peripheral blood mononuclear cells
(PBMCs) from HIV+ subjects in the A5369 prime-boost DNA vaccine trial (NCT03560258). Induction and
durability of innate memory will be studied across 3 aims in this R21. Aim 1 will identify histone posttranslational
modifications (HPTMs) in PBMCs at single-cell resolution using Epigenetic Landscape Profiling using Cytometry
by Time Of Flight (EpiTOF). We will test the hypothesis that antigen-specific DNA vaccination induces innate
memory through epigenetic reprogramming, expands with each sequential prime and boost (week 0 < week 6
<< week 26), and is preserved at week 48. Aim 2 will identify gene transcript modules, and their evolution over
time, associated with innate memory. We will test the hypothesis that antigen-specific DNA vaccination induces
durable innate memory through transcriptomic changes and expands with each sequential prime and boost
(week 0 << week 26 > week 48). We will test the hypothesis that transcriptional modules that characterize innate
memory in influenza and SARS-CoV-2 vaccination are generalizable to HIV DNA vaccines. We also expect to
identify unique subsets of cells, transcripts, and pathways associated with innate memory that differ from
influenza and SARS-CoV-2. Aim 3 will perform systems immunology analysis by integrating EpiTOF and
transcriptomic data from Aims 1 &2, and comparing with similar data from influenza and SARS-CoV-2 vaccinated
subjects testing the hypothesis that there are generalizable mechanisms underlying innate memory across
vaccine platforms, and cells and pathways specific to DNA vaccines and/or HIV infection.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><7S Gamma Globulin><AACTG><ACTG><AIDS Virus><AIDS clinical trial group><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><ATAC-seq><ATACseq><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Activator Protein-1><Adjuvant><Antigens><Attenuated><Autoimmune Status><Autoimmunity><BCG Live><BNT 162b2><BNT162b2><Bacille Calmette-Guérin><Bacillus Calmette Guérin><Bacteria><Blood Cells><Blood Plasma><Blood Precursor Cell><Blood monocyte><CD14><CD14 gene><CD16><CD16B><CD34><CD34 gene><CITE sequencing><CITE-seq><CITEseq><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID19 vaccination><COVID19 vaccine><COVID19 virus><Cell Body><Cells><Cellular Indexing of Transcriptomes and Epitopes by Sequencing><ChIP Sequencing><ChIP-seq><Chromatin><Chronic><CoV-2><CoV2><Communicable Diseases><Cryofixation><Cryopreservation><Cytometry><Cytotoxic cell><DNA><DNA Vaccines><Data><Data Set><Dataset><Dendritic Cells><Dengue><Deoxyribonucleic Acid><Elements><Enhancer-Binding Protein AP1><Enrollment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evolution><Expression Signature><FCGR3B><FCGR3B gene><Fc Receptor III-1><Fc gamma IIIb receptor><Fc-Gamma RIII-Beta><Fc-Gamma RIIIB><FcRIIIB><Flu vaccination><Frequencies><Future><G(s), alpha Subunit><G(s), α Subunit><G(s)alpha><G(s)α><GTP-Binding Protein alpha Subunits, Gs><GTP-Binding Protein α Subunits, Gs><Gene Expression Profile><Gene Transcription><Genes><Genetic Transcription><Goals><Grippe><Gs alpha Family G-Protein><Gsα><Gαs><HIV><HIV Infections><HIV prevention trial><HPCA1><HTLV-III Infections><HTLV-III-LAV Infections><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Histone Deacetylation><Histones><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IFN><IgG><IgG Fc Receptor IIIB><Immune><Immune memory><Immunes><Immunity><Immunization><Immunize><Immunoglobulin G><Immunologic Memory><Immunologic Sensitization><Immunologic Stimulation><Immunological Memory><Immunological Sensitization><Immunological Stimulation><Immunology><Immunostimulation><Impairment><Individual><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Influenza><Influenza Vaccines><Influenza immunization><Influenza vaccination><Innate Immune Response><Innate Immunity><Interferons><Investigators><K lymphocyte><LAV-HTLV-III><Leukapheresis><Leukocytapheresis><Link><Low Affinity IgG Fc Receptor IIIB><Low Affinity Immunoglobulin Gamma Fc Region Receptor III-B><Lymphadenopathy-Associated Virus><Maps><Marrow monocyte><Measurement><Measures><Memory><Messenger RNA><Methods><Modern Man><Myelogenous><Myeloid><Myeloid Cells><NK Cells><Naked DNA Vaccines><Native Immunity><Natural History><Natural Immunity><Natural Killer Cells><Non-Specific Immunity><Nonspecific Immunity><Outcome><PBMC><Paper><Participant><Pathway interactions><Patients><Peripheral Blood Cell><Peripheral Blood Mononuclear Cell><Persons><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Placebos><Plasma><Plasma Serum><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Production><Prophylactic vaccination against influenza><Protein Modification><RNA Expression><Recombinant DNA Vaccines><Regulatory Ns Protein><Research Personnel><Researchers><Resistance to infection><Resolution><Reticuloendothelial System, Serum, Plasma><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SHIV><SIV><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Sham Treatment><Simian Immunodeficiency Viruses><Staining method><Stains><Stimulatory Gs G-Protein><System><T cell response><T-Cells><T-Lymphocyte><TLR protein><Testing><Therapeutic Leukopheresis><Time><Toll-Like Receptor Family Gene><Toll-like receptors><Training><Transcript><Transcription><Transcription Factor AP-1><Vaccinated><Vaccination><Vaccinee><Vaccines><Validation><Veiled Cells><Virus><Virus-HIV><Wuhan coronavirus><ZIKA><acquired immunodeficiency syndrome clinical trial group><active method><active technique><active treatment><alpha Subunit Stimulatory GTP-Binding Protein><alpha-Gs><anamnestic reaction><anti-viral immunity><antiviral immunity><arm><blood stem cell><cellular indexing of transcriptomes and epitopes by single cell sequencing><chromatin immunoprecipitation-sequencing><cold preservation><cold storage><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19 vaccine><coronavirus disease-19 virus><cytokine><enroll><epigenomics><flu immunisation><flu vaccine><flu virus vaccine><gene expression pattern><gene expression signature><hCoV19><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><immunogen><infection resistance><influenza virus vaccination><influenza virus vaccine><innovate><innovation><innovative><intervention arm><mRNA><monocyte><nCoV2><novel><pathway><preservation><response><seasonal flu><seasonal influenza><secondary immune response><sham therapy><simian HIV><simian human immunodeficiency virus><single cell analysis><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transcriptomics><treatment arm><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccination against influenza><vaccination study><vaccination trial><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine against flu><vaccine against influenza><vaccine for novel coronavirus><vaccine platform><vaccine study><vaccine trial><α-Gs>