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Principal Investigator: Hanping Feng
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2024
Award: $621,331
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Human norovirus (hNoV) and Clostridium difficile (CD) represent two leading causes of acute gastroenteritis
worldwide with significant morbidity and mortality. The two infections (one viral and one bacterial) share many of
the same characteristics of transmission; and concurrent infections are particularly prevalent in the US in high-
risk populations, such as aged patients undergoing antibiotic treatments, hospitalized patients, or patients
staying in long-term care facilities. Despite great efforts in the development of vaccines against both infections,
to date there is still no single vaccine available on the market. We have developed a novel platform technology
against enteric bacterial pathogens by engineering a probiotic yeast, Saccharomyces boulardii, to secrete multi-
specific single-domain (VHH) antibodies, directly targeting bacterial virulence factors at the intestinal site of
infection. We have successfully applied this technology to target Clostridium difficile. The overall objective of this
project is to generate Sb strains secreting mSdAbs against both CD toxins and hNoV, generate proof-of-principle
efficacy data in relevant animal disease models, and develop clinic-compatible formulations for drying and
encapsulating the Sb-mSdAb strains. We hypothesize that oral administration of Sb-mSdAb strains secreting
mSdAb against hNoV and CD toxins will prevent their individual or concurrent infections. To test this hypothesis,
we propose to accomplish the following 3 specific aims: 1) Engineer Sb-mSdAb strains (Sb-aNoVCd) secreting
VHH fusions against both CD toxins and hNoVs. 2) Determine preventive efficacy of Sb-aNoVCd strains against
infections with hNoV and CD in gnotobiotic pigs. 3) Develop a formulation supporting yeast spray drying and
encapsulation. With the completion of proposed translational activities, we will have generated lead Sb-aNoVCd
strains and evaluated in vivo characteristics in mice and in gnotobiotic pigs which is the most appropriate animal
model of hNoV infection and disease. Should the key proof-of-principle efficacy data generated, future scale-up
efforts will be justified to include additional VHHs for generating broadly efficacious lead immunoprophylactic
strains and eventual commercialization of the yeast products against CD and hNoV gastroenteritis for which we
currently have no prophylaxis or vaccines.
Terms: <Acute><Animal Disease Models><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Antibodies><Binding><Blood erythrocyte><Body Weight decreased><C diff><C difficile><C. diff><C. difficile><Capsules><Carbohydrates><Characteristics><Chromosomal Insertion><Clinic><Clinical><Clostridioides difficile><Clostridium difficile><Communicable Diseases><DNA cassette><Data><Development><Diarrhea><Disease><Disorder><Dose><Dried Yeast><Drug or chemical Tissue Distribution><Dryness><Encapsulated><Engineered Probiotics><Engineering><Enteral><Enteric><Erythrocytes><Erythrocytic><Excipients><Family suidae><Formulation><Future><GI microbiota><Gastroenteritis><Gastrointestinal microbiota><Genes><Genome><Gnotobiotic><Gnotobiotics><Goals><Hand><Health Facilities><Health care facility><Healthcare Facility><Hemagglutination><Hospital Admission><Hospitalization><Human><In Vitro><Individual><Infection><Infection prevention><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intestinal><Intestinal Secretions><Intestines><Lead><Long-Term Care><Marketing><Marrow erythrocyte><Mediating><Methods><Mice><Mice Mammals><Miscellaneous Antibiotic><Modern Man><Modified Probiotics><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><Murine><Mus><Norovirus><Norwalk-like Viruses><Nutritional Yeast><Oral><Oral Administration><Oral Drug Administration><Pathogenicity Factors><Patients><Pb element><Pigs><Prevent infection><Preventative strategy><Prevention strategy><Preventive><Preventive strategy><Probiotic Engineering><Probiotics><Process><Production><Prophylactic treatment><Prophylaxis><Red Blood Cells><Red Cell><Resistance to antibiotics><Resistant to antibiotics><Saccharomyces><Site><Suidae><Swine><Symptoms><Technology><Testing><Therapeutic><Tissue Distribution><Toxin><Transmission><Traveler's diarrhea><Vaccines><Variant><Variation><Viral><Viral Burden><Viral Load><Viral Load result><Virulence Factors><Virus-like particle><Weight Loss><Weight Reduction><Yeasts><access to vaccination><access to vaccines><aged><anti-toxin><antibiotic drug resistance><antibiotic resistant><antibiotic-associated diarrhea><bacteria pathogen><bacterial disease treatment><bacterial infectious disease treatment><bacterial pathogen><blood corpuscles><body weight loss><bowel><capsule><care facilities><commercialization><develop a vaccine><develop vaccines><development of a vaccine><developmental><enhancer cassette><enteral pathogen><enteric microbial community><enteric microbiota><enteric pathogen><enteropathogen><expression cassette><extended care><gastrointestinal microbial flora><gene cassette><genetic cassette><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><hands><heavy metal Pb><heavy metal lead><high risk group><high risk individual><high risk people><high risk population><human model><in vivo><integration cassette><intestinal flora><intestinal microbiota><intestinal microflora><intestinal pathogen><intestinal tract microflora><intestine pathogen><intraoral drug delivery><longterm care><microbial consortia><microbial flora><microbiome transplant><microbiome transplantation><microbiota><microbiota transplant><microbiota transplantation><microflora><model of animal><model of human><mortality><multispecies consortia><nanobodies><nanobody><novel><passive antibodies><pathogen><pathogenic bacteria><porcine><prevent><preventing><promoter cassette><reporter cassette><resistance cassette><scale up><sdAb><selectable cassette><selection cassette><single domain antibodies><stop cassette><suid><technology platform><technology system><tool><transcription cassette><transcriptional cassette><transgene cassette><transmission process><vaccination access><vaccination availability><vaccine access><vaccine availability><vaccine development><virus-like nanoparticles><viruslike particle><wt-loss>