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.

早期生命微生物组在健康和疾病中起着重要作用，包括免疫发展和 成熟和母体菌群是婴儿菌群的主要决定。暴露于 艾滋病毒但未感染的（iheu）更容易受到疾病的影响，发育不良，肠道菌群改变和 免疫力较差，即使他们没有感染艾滋病毒本身。在Iheu和老鼠中，我们发现更高 芽孢杆菌中双歧杆菌长杆菌的相对丰度在芽孢 Calmette -Guérin（BCG）疫苗接种可改善生命后来的细胞免疫学，这已完成 肠道代谢组的变化表明，芽孢杆菌抽象或代谢物与T细胞之间有联系 免疫。我们假设早期的婴儿芽孢杆菌补充剂提供了一种治疗途径来改善 IHEU的免疫力和随后的健康状况。因此，我们建议将200个母乳喂养的南方随机 非洲iheu进入安慰剂对照，双盲iftantis ecv001的试验（可获得的商业可用 具有可靠安全和健康结果的产品）与安慰剂。目的是1）比较肠道微生物 在IHEU中，结构和功能在早期的IHEU中随机接收婴儿芽孢杆菌与安慰剂的结构和功能 评估与粪便代谢组的关联。婴儿粪便将使用shot弹枪宏基因组学和 使用半靶向代谢组学的代谢组。将比较微生物组组成和功能 在出生时，生命的第4、7和36周之间，与粪便代谢组相关，在第4周。2） 比较接受早期生命的IHEU中肠粘膜完整性和调节性与炎症T细胞比率 B. Infantis与安慰剂。在基线时，第4、7和36周的微生物易位和全身标记 炎症将通过使用多参数流进行的ELISA和T细胞表型评估 细胞仪。我们将使用无监督的自组装匹配方法来比较T细胞子集和 与接受芽孢杆菌与安慰剂的婴儿的测量结果相关的发现系统标记。 3） 比较接受早期生命B的IHEU的T细胞反应性与BCG疫苗接种和线性生长。 婴儿与安慰剂。 BCG疫苗反应将在第7和36周使用全血疫苗。 测定和流式细胞仪，以及第36周的生长，使用长度为z年龄的长度，并比较了跨 组之间的部分。 BCG疫苗的反应将与infantis Ampractance有关 点。最后，我们将开发一个关于补充芽孢杆菌对健康的影响的综合模型 使用所有目标生成的数据。确定B. iftantis ecv001是否可用 干预，有效地改善了IHEU的肠道健康，感染和免疫力，这是一个成长且脆弱的 儿科人群可能会改善IHEU的临床管理和健康结果。这个建议 与撒哈拉以南非洲高度相关，那里的基础设施中有30％暴露于艾滋病毒。