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Principal Investigator: DREW WEISSMAN
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $301,171
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY- PROJECT 1 (VACCINE DEVELOPMENT)
Clostridioides difficile is a gram negative spore forming pathogen that causes mild to severe gastrointestinal
disorders and death in the elderly, immune compromised individuals and those exposed to systemic antibiotics.
Increased recurrence and difficulties treating the disease following antibiotic administration highlight the need to
develop novel therapeutic and prophylactic strategies. To date, vaccines against C. difficile demonstrated
promising results but failed to meet primary outcome criteria to mitigate/reduce primary infections. Therefore,
novel and innovative strategies/approaches are required. Our objective is to develop a clinically relevant
highly effective multivalent mRNA-LNP vaccine to prevent colonization and treat C. difficile infection.
Our strategy relies on our extensive experience with the nucleoside-modified mRNA and mRNA-LNP platforms,
large libraries of ionizable lipids, and a multipronged approach to vaccine development and novel target
discovery, as well as the unique multidisciplinary expertise and resources available to us. We hypothesize that
multivalent targeting of disease causing toxins and bacterial proteins (e.g., surface proteins) will 1)
mitigate primary infection in healthy individuals, and 2) prevent disease and promote decolonization in
infected individuals. Improving mucosal immunity following intramuscular administration of mRNA-LNP
through ligand and charge mediated tropism, oral delivery of mRNA-LNP vaccines capsulated in hydrogels
and/or the addition of immune modulators will improve the efficacy of the multivalent vaccine to decolonize C.
difficile in the gut lumen. Insight from the proposed multi-omic approach for target discovery (Project 2 and Core
B), and a better understanding of human immune responses to C difficile (Project 3 and Core C) will support a
translational workflow that leverages fundamental science and knowledge based approach for the discovery and
rational design of novel vaccine targets to treat and prevent C. difficile.
Terms: <Adhesions><Adjuvant><Alginates><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibodies><Antigens><Artificial nano particles><Artificial nanoparticles><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bacterial Gene Products><Bacterial Gene Proteins><Bacterial Proteins><Bone-Derived Transforming Growth Factor><C diff><C difficile><C. diff><C. difficile><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cell Body><Cell Wall><Cells><Cessation of life><Charge><Chemistry><Children's Hospital><Chitosan><Clinical><Clostridioides difficile><Clostridium difficile><Cohort Studies><Collaborations><Concurrent Studies><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Death><Disease><Disorder><Economic Burden><Elderly><Encapsulated><Engineering><Epithelial Cells><Exposure to><Ferritin><Filament><Formulation><Gastrointestinal Diseases><Genes><Genomics><Gut Mucosa><HPGF><Hepatocyte-Stimulating Factor><Homing><Human><Hybridoma Growth Factor><Hydrogels><IFN-beta 2><IFNB2><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-22><IL-23><IL-6><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL6 Protein><IgA><Immune><Immune Evasion><Immune Targeting><Immune response><Immunes><Immunoglobulin A><Immunological response><Immunology><Immunomodulation><Immunomodulators><Individual><Infection><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Interleukin-6><Intestinal><Intestinal Mucosa><Intestines><Intramuscular><LPAM-1 adhesion molecule><Laboratories><Libraries><Life Cycle><Life Cycle Stages><Ligands><Lipids><MAdCAM-1><MGI-2><Maleimides><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mercaptans><Mercapto Compounds><Messenger RNA><Mice><Mice Mammals><Microbeads><Microspheres><Milk Growth Factor><Miscellaneous Antibiotic><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Immune Responses><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><Murine><Mus><Myeloid Differentiation-Inducing Protein><Nucleosides><Oral><Organ><Pediatric Hospitals><Penetration><Philadelphia><Plasmacytoma Growth Factor><Platelet Transforming Growth Factor><Poliglusam><Primary Infection><Production><Property><Proteins><RNA vaccine><RNA-based vaccine><Recurrence><Recurrent><Reproduction spores><Research Resources><Resources><Science><Severity of illness><Spores><Stomach><Sulfhydryl Compounds><Surface><Surface Proteins><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic><Thiols><Time><Toxin><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Tropism><Vaccines><Work><advanced age><alpha(4)beta(7) integrin><bowel><clinical relevance><clinically relevant><cytokine><design><designing><develop a vaccine><develop vaccines><development of a vaccine><disease severity><elders><engineered nano particle><engineered nanoparticle><experience><gastric><gastrointestinal disorder><geriatric><host response><immune evasive><immune modulation><immune modulators><immune regulation><immune system response><immunogen><immunogenicity><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><improved outcome><infection recurrence><inhibitor><innovate><innovation><innovative><insight><integrin alpha4beta7><integrin α4β7><interferon beta 2><interleukin-22><interleukin-23><intestinal homing receptor alpha4beta7><knowledge base><late life><later life><life course><lipid based nanoparticle><lipid nanoparticle><lymphocyte-Peyer's patch adhesion molecule><mRNA><mRNA delivery><mRNA vaccine><mRNA-based vaccine><microbial consortia><microbial flora><microbiota><microflora><model of animal><mortality><mucosal addressin cell adhesion molecule-1><mucosal vaccination><multidisciplinary><multiomics><multiple omics><multispecies consortia><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><new vaccines><next generation therapeutics><next generation vaccines><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><novel vaccines><older adult><older person><pathogen><prevent><preventing><primary outcome><prophylactic><rational design><recurrent infection><recurring infection><response><secondary infection><senior citizen><success><sulfhydryl group><vaccination study><vaccination trial><vaccine development><vaccine efficacy><vaccine platform><vaccine response><vaccine responsiveness><vaccine study><vaccine trial><vaccine-induced response>