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Bifidobacterium infantis supplementation in early life to improve immunity in infants exposed to HIV: a randomized, placebo-controlled, double-blind trial

Award Number: R01HD109089
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: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Bifidobacterium infantis supplementation in early life to improve immunity in infants exposed to HIV: a randomized, placebo-controlled, double-blind trial - The early life microbiome plays a significant role in health and disease, including immune development and maturation, and maternal microbiota is a major determinant of infant microbiota. Infants who are exposed to HIV but uninfected (iHEU) are more vulnerable to disease, have stunted growth, altered gut microbiota and poorer immunity, even when they are not infected with HIV themselves. In iHEU and mice we found that higher relative abundances of Bifidobacterium longum subspecies infantis in the gut around time of Bacillus Calmette–Guérin (BCG) vaccination results in improved cellular immunity later in life, which was accompanied changes in gut metabolome, suggesting a link between B. infantis abundance or metabolites and T cell immunity. We hypothesize that B. infantis supplementation in early life offers a therapeutic avenue to improve immunity and subsequent health outcomes in iHEU. We thus propose to randomize 200 breastfed South African iHEU into a placebo-controlled, double-blinded trial of B. infantis ECV001 (a commercially available product with proven safety and health outcomes) versus placebo. The aims are to 1) compare gut microbial structure and function longitudinally in iHEU randomized to receive B. infantis versus placebo in early life and evaluate associations with stool metabolome. Infant stool will be analysed using shotgun metagenomics and metabolome using semi-targeted metabolomics. The microbiome composition and function will be compared between groups at birth, week 4, 7 and 36 of life, and correlated with stool metabolome at week 4. 2) To compare gut mucosal integrity and regulatory versus inflammatory T cell ratios in iHEU who received early life B. infantis versus placebo. At baseline, weeks 4, 7 and 36 markers of microbial translocation and systemic inflammation will be assessed by ELISA and T cell phenotyping conducted using multi-parameter flow cytometry. We will use an unsupervised self-assembly matching approach to compare T cell subsets and correlate findings with measurements systemic markers in infants who received B. infantis versus placebo. 3) To compare T cell responsiveness to BCG vaccination and linear growth in iHEU who received early life B. infantis versus placebo. BCG vaccine responses will be measured at week 7 and 36 using a whole-blood- assay and flow cytometry, and growth at week 36 using length for age Z scores, and compared cross- sectionally between groups. BCG vaccine responses will be correlated with B. infantis abundance at all time points. Finally, we will develop an integrative model on the effects of B. infantis supplementation on the health of iHEU using data generated from all aims. Determining whether B. infantis ECV001, a readily available intervention, is effective in improving gut health, inflammation, and immunity in iHEU, a growing and vulnerable pediatric population, could result in improved clinical management and health outcomes of iHEU. This proposal is highly relevant for sub-Saharan Africa, where up to 30% of infants are exposed to HIV.


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: 2026 ( Subtotal = $686,430 )
2026	2026	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	5	5/12/2026	NON-COMPETING CONTINUATION	$686,430
														Subtotal = $686,430

Issue Date FY: 2025 ( Subtotal = $843,813 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	002	4	8/11/2025	SUPPLEMENT FOR EXPANSION	$82,137
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	4	8/4/2025	NON-COMPETING CONTINUATION	$65,880
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	4	7/17/2025	NON-COMPETING CONTINUATION	$695,796
														Subtotal = $843,813

Issue Date FY: 2024 ( Subtotal = $760,095 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	3	5/1/2024	NON-COMPETING CONTINUATION	$752,494
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	3	6/5/2024	NON-COMPETING CONTINUATION	$7,601
														Subtotal = $760,095

Issue Date FY: 2023 ( Subtotal = $620,641 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	2	5/5/2023	NON-COMPETING CONTINUATION	$620,641
														Subtotal = $620,641

Issue Date FY: 2022 ( Subtotal = $631,835 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	1	6/1/2022	NEW	$631,835
														Subtotal = $631,835

Grand Total All Awards = $3,542,814

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Bifidobacterium infantis supplementation in early life to improve immunity in infants exposed to HIV: a randomized, placebo-controlled, double-blind trial

Award Number: R01HD109089

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: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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