Gut Microbial and Metabolic Mediators of Rotavirus Vaccine Response

摘要 轮状病毒（RV）感染导致危及生命的脱水性腹泻，是腹泻的主要原因 5岁以下儿童死亡，尽管有疫苗。重要的是，口服疫苗的效果 与高收入国家相比，中低收入国家的死亡率高得不成比例， 国家解决疫苗有效性的这种差异是一个主要的公共卫生优先事项。Correlates of 保护并不存在，并且人类中针对RV的细胞应答仍然不完全清楚。 越来越多的证据支持肠道微生物群在调节体液和细胞免疫中的直接作用。 口服疫苗的反应，但对它们的实际作用机制知之甚少。在我们的试点研究中， 疫苗应答者的长双歧杆菌丰度显著更高， 与无应答者相比，与肠道中叶酸转化相关的微生物基因。这些数据 表明婴儿可能依赖于B等微生物。longum重新合成叶酸的机制 用于RV特异性免疫细胞扩增。我们假设，微生物的叶酸从头合成， 作为B。longum促进RV特异性免疫细胞扩增，且叶酸水平调节疫苗 免疫原性我们计划研究来自美国、巴拿马和秘鲁的330名婴儿，这些国家的疫苗效力不高， 通过使用储存的和预期收集的纵向数据， 0至12个月婴儿的血液和粪便样本。我们设计了一个新颖的RV“megapool”， 免疫原性肽来定义对RV疫苗接种的细胞免疫应答， 传统的血清RV特异性伊加和免疫后粪便RV脱落（目的1）。我们将描述肠道 在多个接种前时间点使用宏基因组测序的微生物组成和功能， 疫苗应答者和无应答者，以确定是否存在B.长度和合成能力 叶酸预测疫苗免疫原性（目的2）。我们将分析代谢副产物，以确定是否叶酸或 其它代谢物增强疫苗应答（目的3）。我们独特的疫苗学，免疫学， 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， 这些免疫学和多组学数据。研究完成后， RV疫苗反应的微生物和代谢生物标志物的表征，为靶向 免疫增强策略。

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.