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Principal Investigator: Sara Lustigman
Organization: NEW YORK BLOOD CENTER
Fiscal Year: 2024
Award: $719,415
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT ABSTRACT
Infectious diseases are a major cause of morbidity and mortality in the expanding older population. While
vaccines are efficient measures to prevent infections, a critical problem is that aging-associated changes in the
immune system lead to decreased immunogenicity and clinical efficacy of most currently used vaccines. Novel
strategies that increase vaccination efficacy and specifically target the aged immune system are imperative. An
essential facet of these efforts is the use of combinatory adjuvants that synergistically potentiate more effective
vaccine-induced immune responses against various pathogens. In this project we will define the mechanism of
action (MOA) of a combination of a unique parasite protein adjuvant, rASP-1 with each of three well-
characterized innate adjuvants: STING, TLR7/8 and RIG-I agonists, known to activate cytoplasmic pattern
recognition receptors and Type I IFN signaling, which are specifically dampened in the aged population. We
have shown that rASP-1 is a powerful adjuvant as it activates human and mouse dendritic cells to potentiate
the differentiation of naïve CD4+ T cells into Th1, Th17 and Tfh-like cells. Transcriptomic analyses of rASP-1-
activated hMoDCs revealed upregulation of the MyD88-independent activation pathway and interferon related
genes. In mice, rASP-1 elicits a balanced Th1/Th2 antibody response, Th1-biased cellular immunity, and
enhanced responses when co-administered with vaccines leading to increased survival following microbial
challenge. Importantly, our preliminary data indicate that rASP-1 in combination with 2’3’-cGAMP (STING),
R848 (TLR7/8) or 5’3p-hpRNA (RIG-I) in activated adult and aged mouse BMDCs can dramatically synergize
beyond merely additive effects; it enhanced secretion of IL-12p40, IP-10 and/or IL-10. The synergy is
exceptionally evident when it activates aged mouse BMDCs with the STING ligand. Therefore, we hypothesize
that combining rASP-1 with STING, TLR7/8 or RIG-I agonists will synergistically activate early innate immune
signaling that critically contributes to the establishment and nature of immune responses, and the duration and
intensity of immune activation. We posit that this will help restore the aging-associated deficits in the critical
regulatory pathways of the antiviral responses. Through comprehensive immunologic and transcriptomic
analyses, the MOA through which rASP-1 in combination with these three PRR agonists leads to optimal
activation of helper T cells driving humoral and cellular antiviral responses will be established in both mouse
(Aim 1) and human (Aim 2) DCs (adult and aged), to establish that they are conserved, and then test their
efficacy in vivo in adult and aged mice using the trivalent inactivated influenza vaccine (IIV3) as a model
antigen (Aim 3). This project brings together a dynamic team with a history of collaboration and complementary
expertise in vaccinology, immunology, biochemistry, innate cell receptor biology, adjuvants, and bioinformatics.
We will deliver a novel, efficacious combination of innate cytoplasmic PRR adjuvants with rASP-1 that
promotes protective long-lived adaptive responses and boosts efficacy of vaccines in aged populations.
Terms: <21+ years old><ASP-1><Adjuvant><Adult><Adult Human><Agonist><Alpha-Beta-Omega Interferon Receptor-1><Anti-viral Response><Antibody Response><Antigens><Antiviral Protein Alpha Type><Asparaginase II><Asparagine Deaminase><Assay><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bio-Informatics><Bioassay><Biochemistry><Bioinformatics><Biological Assay><Biological Chemistry><Biology><Blood monocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><CD183><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><CKR-L2><CMKAR3><CRG-2><CRISPR><CRISPR/Cas system><CSIF><CSIF-10><CXCL10><CXCL10 gene><CXCR3><CXCR3 gene><Cell Body><Cell Communication and Signaling><Cell Mediated Immunology><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Immunity><Cellular Immunology><Chemokine (C-X-C Motif) Receptor 3><Clustered Regularly Interspaced Short Palindromic Repeats><Colaspase><Collaborations><Communicable Diseases><Cytokine Synthesis Inhibitory Factor><Cytoplasm><Data><Dendritic Cells><Elspar><Engineered Gene><Engineering><Ensure><G Protein-Coupled Receptor 9><GPR9><Genes><Germinal Center><Goals><Helminths><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><History><HuIFN-Alpha-Rec><Human><IFI10><IFN><IFNBR><IFRC><IL-10><IL10><IL10A><INP10><IP-10><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><Immune Cell Activation><Immune response><Immune signaling><Immune system><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Immunomodulation><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection prevention><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza Vaccines><Interferon Alpha-Beta Receptor Alpha Chain><Interferon Type I><Interferons><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Kidrolase><L asparagine amidohydrolase><L-ASP><L-Asparaginase><LYT3><Lcf-ASP><Lead><Ligands><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><MOB-1><Marrow monocyte><Measures><Memory><Mice><Mice Mammals><Mig Receptor><Mig-R><MigR><Modeling><Modern Man><Molecular Fingerprinting><Molecular Profiling><Morbidity><Morbidity - disease rate><Murine><Mus><Nature><Older Population><Onchocerca volvulus><Parasites><Parasitic Worms><Pathway interactions><Pattern recognition receptor><Pb element><Peptides><Prevent infection><Proteins><Receptor Cell><Recording of previous events><Regulatory Pathway><SCYB10><Serasa><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Societies><Structure of germinal center of lymph node><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TLR7><TLR7 gene><Testing><Toll-Like Receptor 7><Up-Regulation><Upregulation><Vaccination><Vaccines><Veiled Cells><adulthood><age associated><age correlated><age dependent><age linked><age related><age specific><aged><aged group><aged groups><aged individual><aged individuals><aged mice><aged mouse><aged people><aged person><aged persons><aged population><aged populations><aging associated><aging population><aging related><asparaginase><biological signal transduction><clinical efficacy><driving><elderly mice><flu infection><flu vaccine><flu virus infection><flu virus vaccine><gIP-10><healthy aging><healthy human aging><heavy metal Pb><heavy metal lead><histories><host response><human model><iPS><iPSC><iPSCs><ifnar1 gene product><immune activation><immune modulation><immune regulation><immune response to vaccination><immune response to vaccines><immune senescence><immune system response><immunogen><immunogenicity><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosenescence><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenza virus vaccine><knockout gene><lymph gland><lymph nodes><lymphnodes><microbial><model of human><molecular profile><molecular signature><monocyte><mortality><mouse model><murine model><new approaches><novel><novel approaches><novel strategies><novel strategy><old mice><older groups><older individuals><older person><pathogen><pathway><population aging><recruit><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><synergism><thymus derived lymphocyte><transcriptomics><type I IFN receptor><type I interferon receptor><vaccine against flu><vaccine against influenza><vaccine associated immune response><vaccine efficacy><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccinology>