R01HD109089

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. 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 the time of Bacillus Calmette-Guérin (BCG) vaccination results in improved cellular immunity later in life. This improvement was accompanied by 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 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:

1) To 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 analyzed 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 of 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.

Seattle Children's Hospital

NOT APPLICABLE

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Seattle, Washington 981053901 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 461% from $631,835 to $3,542,814.