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Preventing norovirus and Clostridium difficile gastroenteritis by engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies

Award Number: R01AI148357
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Preventing norovirus and Clostridium difficile gastroenteritis by engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $621,331 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	5	12/14/2023	NON-COMPETING CONTINUATION	$559,198
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	5	5/20/2024	NON-COMPETING CONTINUATION	$62,133
														Subtotal = $621,331

Issue Date FY: 2023 ( Subtotal = $611,307 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	4	12/6/2022	NON-COMPETING CONTINUATION	$611,307
														Subtotal = $611,307

Issue Date FY: 2022 ( Subtotal = $608,573 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	12/13/2021	NON-COMPETING CONTINUATION	$608,573
														Subtotal = $608,573

Issue Date FY: 2021 ( Subtotal = $600,213 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	2	12/21/2020	NON-COMPETING CONTINUATION	$600,213
														Subtotal = $600,213

Issue Date FY: 2020 ( Subtotal = $647,849 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	1/23/2020	NEW	$647,849
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	1	2/4/2020	NEW	$0
														Subtotal = $647,849

Grand Total All Awards = $3,089,273

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Preventing norovirus and Clostridium difficile gastroenteritis by engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies

Award Number: R01AI148357

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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