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: 10481469
• 负责人: Heather Beryl Jaspan
• 金额: $ 63.18万
• 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/10481469
• 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; Country; Data; Development; Disease; Double-blind trial; 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; Placebo Control; 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; base; cohort; commensal bacteria; 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; 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.

生命早期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 成熟，母体微生物群是婴儿微生物群的主要决定因素。 未感染 HIV 的人 (iHEU) 更容易患病，生长发育迟缓，肠道微生物群和 免疫力较差，即使它们本身没有感染艾滋病毒，我们发现在 iHEU 和小鼠中，免疫力较高。 芽孢杆菌出现前后肠道中长双歧杆菌婴儿亚种的相对丰度 卡介苗 (BCG) 疫苗接种可改善晚年的细胞免疫力，并伴随 肠道代谢组的变化，表明婴儿双歧杆菌丰度或代谢物与 T 细胞之间存在联系 我们认为，在生命早期补充婴儿双歧杆菌提供了一种改善免疫力的治疗途径。 因此，我们建议对 200 名母乳喂养的南方人进行随机分组。 非洲 iHEU 对婴儿双歧杆菌 ECV001（一种市售药物）进行安慰剂对照、双盲试验 具有经过验证的安全性和健康结果的产品）与安慰剂相比，目的是 1）比较肠道微生物。 iHEU 的结构和功能纵向随机接受婴儿双歧杆菌与安慰剂在生命早期和 将使用鸟枪法宏基因组学来分析婴儿粪便与粪便代谢组的关联。 使用半靶向代谢组学对微生物组的组成和功能进行比较。 出生时、生命第 4、7 和 36 周时各组之间的差异，并与第 4 周时的粪便代谢组相关。2) 比较接受早期生命的 iHEU 的肠粘膜完整性以及调节性 T 细胞与炎症性 T 细胞的比率 婴儿双歧杆菌与安慰剂相比，在基线、第 4、7 和 36 周的微生物易位和全身标记。 将通过 ELISA 和使用多参数流进行的 T 细胞表型分析来评估炎症 我们将使用无监督的自组装匹配方法来比较 T 细胞亚群和 将接受婴儿双歧杆菌与安慰剂的婴儿的研究结果与测量系统标记物相关联 3)。 比较接受早期生命 B 的 iHEU 中 T 细胞对 BCG 疫苗接种的反应和线性生长。 婴儿与安慰剂的反应将在第 7 周和第 36 周使用全血进行测量。 测定和流式细胞术，以及使用年龄 Z 评分的长度在第 36 周时的生长，并比较了交叉 各组之间的 BCG 疫苗反应始终与婴儿双歧杆菌丰度相关。 最后，我们将开发一个关于婴儿双歧杆菌补充剂对健康影响的综合模型。 iHEU 使用所有目标生成的数据确定是否是婴儿双歧杆菌 ECV001（一种现成的药物）。 干预可有效改善 iHEU 的肠道健康、炎症和免疫力，iHEU 是一个正在成长且脆弱的群体 儿科人群，可能会改善 iHEU 的临床管理和健康结果。 与撒哈拉以南非洲地区高度相关，那里高达 30% 的婴儿接触艾滋病毒。