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Gut microbial and metabolic mediators of rotavirus vaccine response

Award Number: R01HD100542
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Gut microbial and metabolic mediators of rotavirus vaccine response - Abstract Rotavirus (RV) infection causes life-threatening, dehydrating diarrhea and is the leading cause of diarrheal deaths among children <5 years old despite availability of a vaccine. Critically, the oral vaccine is less effective in middle- and low-income countries where disproportionately more deaths occur compared to high-income countries. Addressing this disparity in vaccine effectiveness is a major public health priority. Correlates of protection do not exist, and cellular responses against RV in humans remain incompletely understood. Mounting evidence supports a direct role for the gut microbiota in modulating humoral and cellular immune responses to oral vaccines, but little is known about their actual mechanism of action. In our pilot study, vaccine responders had a significantly greater abundance of Bifidobacterium longum and higher content of microbial genes associated with folate transformation in their gut compared to nonresponders. These data suggest that infants may depend on microbes such as B. longum to synthesize folate de novo as a mechanism for RV-specific immune cell expansion. We hypothesize that de novo folate synthesis by microbes such as B. longum facilitates RV-specific immune cell expansion, and that levels of folate modulate vaccine immunogenicity. We propose to study 330 infants from the US, Panama, and Peru where vaccine efficacy is known to be high, medium and low, respectively, by using both stored and prospectively collected longitudinal samples of blood and stool from infants 0 to 12 months of age. We have designed a novel RV “megapool” of immunogenic peptides to define cellular immune responses to RV vaccination in addition to assessing traditional serum RV-specific IgA and stool RV shedding after immunization (Aim 1). We will characterize gut microbial composition and function using metagenomic sequencing at multiple pre-vaccination time points in vaccine responders and nonresponders to determine if the abundance of B. longum and capacity to synthesize folate predict vaccine immunogenicity (Aim 2). We will analyze the metabolic byproducts to identify if folate or other metabolites enhance vaccine response (Aim 3). Our unique team of experts in vaccinology, immunology, microbiology, biochemistry, and bioinformatics will ensure successful integrative analysis and interpretation of these immunologic and multi-omics data. Completion of the study will provide a comprehensive characterization of microbial and metabolic biomarkers of RV vaccine responses, paving the way for targeted immune augmentation strategies.


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: 2025 ( Subtotal = $0 )
2025	2023	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	4	12/3/2024	NON-COMPETING CONTINUATION	-$88,923
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	002	5	12/3/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$397,484
2025	2022	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	3	12/3/2024	NON-COMPETING CONTINUATION	-$308,561
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $574,822 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	002	6	5/29/2024	NON-COMPETING CONTINUATION	$614,942
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	001	5	2/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$551,221
2024	2023	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	2/23/2024	NON-COMPETING CONTINUATION	-$591,341
														Subtotal = $574,822

Issue Date FY: 2023 ( Subtotal = $680,264 )
2023	2023	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	4/7/2023	NON-COMPETING CONTINUATION	$680,264
														Subtotal = $680,264

Issue Date FY: 2022 ( Subtotal = $696,500 )
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	3	5/5/2022	NON-COMPETING CONTINUATION	$696,500
														Subtotal = $696,500

Issue Date FY: 2021 ( Subtotal = $644,656 )
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	3/17/2021	NON-COMPETING CONTINUATION	$644,656
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	2	9/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $644,656

Issue Date FY: 2020 ( Subtotal = $681,780 )
2020	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	1	5/31/2020	NEW	$681,780
														Subtotal = $681,780

Grand Total All Awards = $3,278,022

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Gut microbial and metabolic mediators of rotavirus vaccine response

Award Number: R01HD100542

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/07/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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