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

生命早期补充婴儿双歧杆菌可提高感染 HIV 的婴儿的免疫力：一项随机、安慰剂对照、双盲试验

• 批准号: 10632103
• 负责人: Heather Beryl Jaspan
• 金额: $ 62.06万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632103
• 关键词: Address; Africa South of the Sahara; African; Age; Antibiotic Prophylaxis; BCG Live; BCG Vaccine; Bacille Calmette-Guerin vaccination; Bacteria; Bifidobacterium; Biological Assay; Birth; Blood Cells; Breast Feeding; Breastfed infant; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Childhood; Clinical Management; Collecting Cell; Country; Data; Development; Disease; Enrollment; Enzyme-Linked Immunosorbent Assay; Exhibits; Exposure to; Feces; Flow Cytometry; Gastrointestinal tract structure; Germ-Free; Growth; Gut Mucosa; HIV; Health; Human Microbiome; Human Milk; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Infant; Infant Health; Inflammation; Inflammatory; Intervention; LCN2 gene; Length; Life; Link; Measurement; Measures; Memory; Metagenomics; Modeling; Mothers; Mucous Membrane; Mus; Nature; Neonatal; Oligosaccharides; Organism; Outcome; Phenotype; Placebos; Play; Population; Randomized; Regulatory T-Lymphocyte; Role; Safety; Sampling; Secondary to; Shapes; Shotguns; South Africa; South African; Structure; Supplementation; Systems Development; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Vaccination; Vaccines; Vulnerable Populations; Whole Blood; Woman; arm; bacterial community; cohort; commensal bacteria; double-blind placebo controlled trial; feeding; gastrointestinal epithelium; gut health; gut microbiome; gut microbiota; immune activation; improved; infancy; infant outcome; intestinal fatty acid binding protein; lipopolysaccharide-binding protein; maternal microbiota; metabolome; metabolomics; microbial; microbial composition; microbiome; microbiome composition; microbiota; peripheral blood; post intervention; prevent; prototype; response; self assembly; systemic inflammatory response; transmission process; vaccination outcome; vaccine response; vaginal microbiome

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.

早期生命微生物组在健康和疾病中发挥着重要作用，包括免疫发育和 母亲微生物群是婴儿微生物群的主要决定因素。暴露于 未感染艾滋病毒（iHEU）的人更容易患病，生长发育迟缓，肠道微生物群改变， 免疫力较差，即使他们自己没有感染艾滋病毒。在iHEU和小鼠中，我们发现， 长双歧杆菌各亚种在肠道中的相对丰度 卡介苗（BCG）疫苗接种可改善生命后期的细胞免疫力， 肠道代谢组的变化，表明B。代谢产物丰度和T细胞 免疫力我们假设B.在生命早期补充维生素B12提供了一种治疗途径，以改善 免疫和随后的健康结果。因此，我们建议随机选择200名母乳喂养的南方 非洲iHEU进入B的安慰剂对照双盲试验。ECV 001（市售可得的 产品的安全性和健康结果）与安慰剂相比。目的是1）比较肠道微生物 随机接受B iHEU纵向结构和功能。与安慰剂相比， 评估与粪便代谢组的相关性。婴儿粪便将使用鸟枪宏基因组学进行分析， 使用半靶向代谢组学的代谢组学。将比较微生物组的组成和功能 出生时、出生后第4、7和36周的组间差异，并与出生后第4周的粪便代谢组相关。2)到 比较早期接受iHEU治疗的患者的肠道粘膜完整性和调节性T细胞与炎症性T细胞的比率 B。与安慰剂相比。在基线、第4、7和36周时，微生物易位和全身性 将通过ELISA和使用多参数流式细胞术进行的T细胞表型分析来评估炎症 细胞仪我们将使用无监督的自组装匹配方法来比较T细胞亚群， 将结果与接受B的婴儿的全身标志物测量结果相关联。婴儿与安慰剂。第三章 比较接受早期生活B的iHEU中T细胞对BCG疫苗接种的反应性和线性生长。 婴儿与安慰剂。BCG疫苗应答将在第7周和第36周使用全血- 分析和流式细胞术，并在第36周使用年龄Z评分的长度生长，并比较交叉- 组之间的分段。BCG疫苗反应将与B相关。在任何时候都是富足的 点最后，我们将发展一个关于B效应的综合模型。对健康的补充 使用所有目标产生的数据来评估iHEU。确定B. ECV 001是一种现成的 干预，可有效改善iHEU的肠道健康、炎症和免疫力，iHEU是一个不断增长且脆弱的群体 儿童人群，可能会导致改善iHEU的临床管理和健康结果。这项建议 在撒哈拉以南非洲，高达30%的婴儿暴露于艾滋病毒。