Gut Microbial and Metabolic Mediators of Rotavirus Vaccine Response

轮状病毒疫苗反应的肠道微生物和代谢介质

• 批准号: 10618197
• 负责人: Pia S Pannaraj
• 金额: $ 8.89万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618197
• 关键词: 5 year old; Address; Age Months; Antibodies; Antibody titer measurement; Bacteria; Bifidobacterium; Biochemistry; Bioinformatics; Biological Markers; Birth; Blood; Blood specimen; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; Child; Country; Data; Dehydration; Detection; Development; Diarrhea; Disparity; Enrollment; Ensure; Feces; Folic Acid; Folic Acid Deficiency; Genes; Human; Immune; Immune Targeting; Immune response; Immunization; Immunoglobulin A; Immunologics; Immunology; Income; Infant; Infection; Intervention; Intestines; Life; Literature; Lymphocyte; Maintenance; Mediator; Memory; Metabolic; Metabolic Biotransformation; Metabolism; Methods; Microbe; Microbiology; Multiomic Data; Mus; Nutrient; Oncogenes; Oral; Panama; Pathway interactions; Peptides; Peru; Peruvian; Pilot Projects; Population; Production; Public Health; Recommendation; Regulatory T-Lymphocyte; Role; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Sample Size; Sampling; Serum; Shotguns; Specificity; T cell response; T memory cell; T-Cell Proliferation; Therapeutic Intervention; Time; Vaccination; Vaccines; Vitamins; cell growth; design; folic acid supplementation; gut microbiome; gut microbiota; health disparity; immune function; immunogenic; immunoregulation; improved; low and middle-income countries; low income country; metabolic profile; metabolomics; metagenomic sequencing; microbial; microbiome; novel; oral vaccine; prevent; preventive intervention; prospective; public health priorities; responders and non-responders; response; sample collection; socioeconomics; statistical and machine learning; stool sample; vaccine access; vaccine effectiveness; vaccine efficacy; vaccine immunogenicity; vaccine response; vaccine-induced antibodies; vaccinology; 5 year old; Address; Age Months; Antibodies; Antibody titer measurement; Bacteria; Bifidobacterium; Biochemistry; Bioinformatics; Biological Markers; Birth; Blood; Blood specimen; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; Child; Country; Data; Dehydration; Detection; Development; Diarrhea; Disparity; Enrollment; Ensure; Feces; Folic Acid; Folic Acid Deficiency; Genes; Human; Immune; Immune Targeting; Immune response; Immunization; Immunoglobulin A; Immunologics; Immunology; Income; Infant; Infection; Intervention; Intestines; Life; Literature; Lymphocyte; Maintenance; Mediator; Memory; Metabolic; Metabolic Biotransformation; Metabolism; Methods; Microbe; Microbiology; Multiomic Data; Mus; Nutrient; Oncogenes; Oral; Panama; Pathway interactions; Peptides; Peru; Peruvian; Pilot Projects; Population; Production; Public Health; Recommendation; Regulatory T-Lymphocyte; Role; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Sample Size; Sampling; Serum; Shotguns; Specificity; T cell response; T memory cell; T-Cell Proliferation; Therapeutic Intervention; Time; Vaccination; Vaccines; Vitamins; cell growth; design; folic acid supplementation; gut microbiome; gut microbiota; health disparity; immune function; immunogenic; immunoregulation; improved; low and middle-income countries; low income country; metabolic profile; metabolomics; metagenomic sequencing; microbial; microbiome; novel; oral vaccine; prevent; preventive intervention; prospective; public health priorities; responders and non-responders; response; sample collection; socioeconomics; statistical and machine learning; stool sample; vaccine access; vaccine effectiveness; vaccine efficacy; vaccine immunogenicity; vaccine response; vaccine-induced antibodies; vaccinology

Abstract Rotavirus (RV) infection causes life-threatening, dehydrating diarrhea and is the leading cause of diarrheal deaths among children <5 years old despite availability of a vaccine. Critically, the oral vaccine is less effective in middle- and low-income countries where disproportionately more deaths occur compared to high-income countries. Addressing this disparity in vaccine effectiveness is a major public health priority. Correlates of protection do not exist, and cellular responses against RV in humans remain incompletely understood. Mounting evidence supports a direct role for the gut microbiota in modulating humoral and cellular immune responses to oral vaccines, but little is known about their actual mechanism of action. In our pilot study, vaccine responders had a significantly greater abundance of Bifidobacterium longum and higher content of microbial genes associated with folate transformation in their gut compared to nonresponders. These data suggest that infants may depend on microbes such as B. longum to synthesize folate de novo as a mechanism for RV-specific immune cell expansion. We hypothesize that de novo folate synthesis by microbes such as B. longum facilitates RV-specific immune cell expansion, and that levels of folate modulate vaccine immunogenicity. We propose to study 330 infants from the US, Panama, and Peru where vaccine efficacy is known to be high, medium and low, respectively, by using both stored and prospectively collected longitudinal samples of blood and stool from infants 0 to 12 months of age. We have designed a novel RV “megapool” of immunogenic peptides to define cellular immune responses to RV vaccination in addition to assessing traditional serum RV-specific IgA and stool RV shedding after immunization (Aim 1). We will characterize gut microbial composition and function using metagenomic sequencing at multiple pre-vaccination time points in vaccine responders and nonresponders to determine if the abundance of B. longum and capacity to synthesize folate predict vaccine immunogenicity (Aim 2). We will analyze the metabolic byproducts to identify if folate or other metabolites enhance vaccine response (Aim 3). Our unique team of experts in vaccinology, immunology, microbiology, biochemistry, and bioinformatics will ensure successful integrative analysis and interpretation of these immunologic and multi-omics data. Completion of the study will provide a comprehensive characterization of microbial and metabolic biomarkers of RV vaccine responses, paving the way for targeted immune augmentation strategies.

抽象的 轮状病毒（RV）感染会导致威胁生命，脱水腹泻，是腹泻的主要原因 5岁儿童的死亡人数疫苗的可用性。至关重要的是，口服疫苗的效率较低 在中低收入国家，与高收入相比，死亡人数不成比例不成比例 国家。解决疫苗有效性方面的这种差异是一个主要的公共卫生优先事项。相关 保护不存在，对人类中RV的细胞反应仍然不完全理解。 安装证据支持肠道菌群在调节体液和细胞免疫中的直接作用 对口服疫苗的反应，但对其实际作用机理知之甚少。在我们的试点研究中 疫苗反应者的双歧杆菌长度明显更大，含量更高 与非应答者相比，与叶酸的叶酸转化相关的微生物基因。这些数据 表明婴儿可能依靠微生物（例如长芽孢杆菌）将叶酸从头综合为一种机制 用于RV特异性免疫细胞膨胀。我们假设微生物从头叶酸合成 作为长芽孢杆菌的收藏夹RV特异性免疫球膨胀，叶酸调节疫苗的水平 免疫原性。我们建议研究疫苗效率的330名来自美国，巴拿马和秘鲁的婴儿 已知通过使用纵向和前瞻性收集的纵向，分别是高，中和低的 婴儿的血液和粪便样本为0至12个月大。我们设计了一种新颖的RV“ Megapool” 免疫原性促进了除了评估外，以将细胞免疫复杂定义为RV疫苗接种 免疫后传统的血清RV特异性IgA和粪便RV脱落（AIM 1）。我们将描述肠道 在多个疫苗接种时间点上使用宏基因组测序的微生物组成和功能 疫苗响应者和无反应者，以确定长芽孢杆菌的抽象和合成的能力是否 叶酸预测疫苗免疫原性（AIM 2）。我们将分析代谢副产品，以确定是叶酸还是 其他代谢物增强了疫苗反应（AIM 3）。我们独特的疫苗科学专家团队，免疫学专家， 微生物学，生物化学和生物信息学将确保成功的综合分析和解释 这些免疫学和多词数据。研究的完成将提供全面的 RV疫苗反应的微生物和代谢生物标志物的表征，为目标铺平道路 免疫增强策略。