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Principal Investigator: Siyuan Ding
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $155,500
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Diarrheal diseases account for 1 in 10 child deaths worldwide. Rotavirus (RV) and enterotoxigenic
Escherichia coli (ETEC) are major etiological causes of acute gastroenteritis and severe diarrhea worldwide,
together resulting in approximately 300,000 deaths each year, mostly in children under the age of five. Current
RV vaccines have limited efficacy in endemic countries and no direct antivirals are available. No vaccine is
licensed for ETEC. Our overall objectives are to better understand the biology of RV and ETEC and to use that
information to develop therapeutic interventions to alleviate diarrhea and sequelae.
In preliminary studies, we utilized an improved RV reverse genetics system developed by our lab and
generated a recombinant murine RV that encodes the protruding domain of the human norovirus VP1 protein.
We found that this RV-based viral vector induces a robust antigen-specific serum IgG and fecal IgA responses
in inoculated mouse pups. Based on these data, we constructed several new recombinant RVs that express
ETEC heat-labile and heat-stable toxins. We hypothesize that one or more novel RV-ETEC dual vaccine
candidates will induce a protective humoral immune response in mice and reduce pathogen burden
and pathogenesis from subsequent RV and ETEC infections.
To test this hypothesis, we have developed a highly tractable murine RV reverse genetics method, disease
relevant neonatal and adult mouse models, and several innovative primary human small bowel organoid
cultures, which will provide an unprecedented resolution of understanding of the immunogenicity and protective
efficacy of our vaccine candidates. In Aim 1, we will characterize RV replication and define the immunological
responses of our dual vaccines in neonatal mice. In Aim 2, we will examine the efficacy of the recombinant RV-
ETEC dual vaccines in protecting immunized mice from RV and ETEC challenges in adult mice. Collectively,
we expect our proof-of-principle study to start to establish the utility of RVs as an innovative live-attenuated
mucosal vaccine platform to encode foreign antigens and broadly protect against common enteric pathogens.
Terms: <0-11 years old><21+ years old><3'5'-cyclic ester of AMP><7S Gamma Globulin><AIDS><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acute><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adult><Adult Human><Affect><Age><Animal Model><Animal Models and Related Studies><Anti-viral Agents><Antibodies><Antibody Response><Antigens><Assay><Astrovirus><Atrophic><Atrophy><Attenuated><Automobile Driving><Bioassay><Biological Assay><Biology><Blood Serum><Body Tissues><Body Weight decreased><Body Weights and Measures><Causality><Cessation of life><Child><Child Youth><Children (0-21)><Clonogenic Cell Assay><Colony-Forming Units Assay><Country><Cryptosporidium><Cyclic AMP><Cyclic GMP><Data><Death><Development><Diarrhea><Disease><Disorder><Double-Stranded RNA><E coli Infections><E. coli Infections><ELISA><ETEC><Enteral><Enteric><Enterotoxins><Enzyme-Linked Immunosorbent Assay><Equilibrium><Escherichia coli Infections><Etiology><Future><Gastroenteritis><Generalized Growth><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genome><Goals><Growth><Guanosine Cyclic Monophosphate><H-D Antigens><Hanganutziu-Deicher Antigens><Harvest><Heteroantigens><Heterogenetic Antigens><Heterologous Antigens><Heterophil Antigens><Heterophile Antigens><Human><IgA><IgG><Immune response><Immunity><Immunize><Immunofluorescence><Immunofluorescence Immunologic><Immunoglobulin A><Immunoglobulin G><Immunological response><Infant><Infant Mortality><Infant Mortality Total><Infection><Intestinal><Intestines><Laboratories><Licensing><Malaria><Measles><Measures><Medical><Methods><Mice><Mice Mammals><Modern Man><Monitor><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Neonatal><Norovirus><Norwalk-like Viruses><Oral><Organoids><Outcome><Paludism><Pathogenesis><Paul-Bunnell Antigens><Plaque Assay><Plasmodium Infections><RNA vaccine><RNA-based vaccine><Recombinant DNA Technology><Recombinants><Reporter><Research Specimen><Resolution><Rotavirus><Rotavirus Infections><Rotavirus VP6 protein><Rotavirus Vaccines><Rotavirus viral outer coat protein VP6><Rubeola><Series><Serum><Shigella><Small Intestines><Specimen><Spinal Column><Spine><System><Testing><Therapeutic Intervention><Tissue Growth><Tissues><Toxic effect><Toxicities><Toxin><Toxoids><VIVIPAROUS1 protein><Vaccinated><Vaccination><Vaccines><Vertebral column><Villus><Viral><Viral Vector><Virulence><Virulent><Virus><Virus Replication><Viviparous-1 protein><Vp1 protein><Weight Loss><Weight Reduction><Xenoantigens><Xenogeneic Antigens><Xenogenic Antigens><adenosine 3'5' monophosphate><adulthood><ages><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><attenuate><attenuates><backbone><balance><balance function><body weight loss><bowel><cAMP><cGMP><causation><co-infection><cognitive development><coinfection><death among infants><death in first year of life><death in infancy><death in infants><design><designing><determine efficacy><developmental><diarrheal disease><diarrheal illness><disease causation><driving><dsRNA><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><enteral infection><enteral pathogen><enteric infection><enteric pathogen><enteric pathogen infection><enteropathogen><enteropathogen infection><enteropathogenic infection><enterotoxigenic E coli><enterotoxigenic E. coli><enterotoxigenic E.coli><enterotoxigenic Escherichia coli><enzyme linked immunoassay><evaluate efficacy><examine efficacy><genetically engineered><host response><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><improved><infant death><infant demise><infantile death><infected with enteropathogen><innovate><innovation><innovative><intervention therapy><intestinal infection><intestinal pathogen><intestine infection><intestine pathogen><kids><mRNA vaccine><mRNA-based vaccine><model of animal><morbilli><mortality><mortality in infants><mouse model><mucosal vaccine><murine model><mutant><nano-luciferase><nanoluciferase><neonatal mice><neutralizing antibody><novel><ontogeny><pathogen><plasmid vaccine><prevent><preventing><protective efficacy><pup><rational design><resolutions><response><reverse genetics><small bowel><suckling><tissue culture><vaccine candidate><vaccine efficacy><vaccine platform><vector><vector induced><vector vaccine><viral multiplication><viral replication><virus multiplication><wt-loss><youngster>