Gut Microbial and Metabolic Mediators of Rotavirus Vaccine Response

摘要 轮状病毒(RV)感染会导致危及生命的脱水腹泻，是腹泻的主要原因。 5岁儿童死亡，尽管有疫苗可用。关键的是，口服疫苗效果较差。 在中低收入国家，与高收入国家相比，死亡人数不成比例地多 国家。解决疫苗效力方面的这种差异是一项主要的公共卫生优先事项。的相关性 目前还不存在保护措施，人类对轮状病毒的细胞反应仍不完全清楚。 越来越多的证据支持肠道微生物区系在调节体液和细胞免疫中的直接作用 对口服疫苗的反应，但对其实际作用机制知之甚少。在我们的初步研究中， 疫苗应答者的长双歧杆菌丰度明显更高， 与无反应者相比，肠道中与叶酸转化相关的微生物基因。这些数据 提示婴儿可能依赖诸如长杆菌等微生物来合成新的叶酸作为一种机制 用于轮状病毒特异性免疫细胞的扩增。我们假设由这样的微生物重新合成叶酸 由于长杆菌促进轮状病毒特异性免疫细胞扩增，而叶酸水平调节疫苗 免疫原性。我们建议对来自美国、巴拿马和秘鲁的330名婴儿进行研究，这些国家的疫苗效力是 已知分别为高、中和低，通过使用存储和预期收集的纵向 0至12个月婴儿的血液和粪便样本。我们设计了一款新颖的房车“巨型池” 免疫原肽用于确定RV疫苗接种后的细胞免疫反应 传统的轮状病毒免疫后血清特异性IgA和粪便轮状病毒脱落(目标1)。我们将描述Gut的特征 疫苗接种前多个时间点微生物组成和功能的元基因组测序 疫苗应答者和无应答者确定长杆菌的丰度和合成能力 叶酸预测疫苗的免疫原性(目标2)。我们将分析代谢副产物，以确定叶酸或 其他代谢物增强疫苗反应(目标3)。我们独特的疫苗、免疫学专家团队， 微生物学、生物化学和生物信息学将确保成功地综合分析和解释 这些免疫学和多组学数据。这项研究的完成将提供一个全面的 轮状病毒疫苗应答的微生物和代谢生物标志物的特征，为靶向铺平道路 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.