Intestinal microbiota-mediated rotavirus vaccine failure

肠道微生物介导的轮状病毒疫苗失败

• 批准号: 10586698
• 负责人: Andrew T Gewirtz
• 金额: $ 77.25万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586698
• 关键词: Antibodies; Antibody titer measurement; Antigens; Attenuated; Attenuated Vaccines; Automobile Driving; Bacteria; Bioreactors; Cessation of life; Child; Childhood; Developing Countries; Development; Disease; Distress; Dose; Enterocytes; Epithelial; Epithelial Cells; Exposure to; Failure; Feces; Goals; Health; Heterogeneity; Human; Immunity; In Vitro; Incidence; Infant; Infection; Interferons; Intestines; Knowledge; Mediating; Microbe; Modeling; Mucosal Immune Responses; Mus; Oral; Organoids; Outcome; Oxygen; Pediatric cohort; Phenotype; Prevention; Public Health; Publishing; Research; Resistance; Role; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Sampling; Scourge; Shapes; System; Testing; Transplantation; Vaccination; Vaccinee; Vaccines; Viral; Viral Vaccines; Virulent; Work; adaptive immunity; base; cohort; enteric virus infection; fecal transplantation; gastrointestinal epithelium; gut microbiome; gut microbiota; human microbiota; microbial; microbial community; microbiome research; microbiota; microbiota transplantation; mouse model; novel strategies; oral vaccine; prevent; public health relevance; response; unpublished works; vaccine efficacy; vaccine failure

PROJECT SUMMARY Infection of gut epithelia by attenuated rotavirus (RV) vaccines serves to protect millions of lives annually. It is increasingly appreciated that gut microbiota, which shape the milieu in which rotaviruses encounter the epithelium is a pivotal determinant of rotavirus vaccine efficacy. Indeed, RV vaccines have proven to be much less effective in developing countries which are known to have stark differences in gut microbiota composition. Our published work demonstrates that microbiota can both directly impact RV and, moreover, impact gut epithelia to prevent against its entry and replication. Furthermore, our unpublished work compellingly argues for a central role for gut microbiota composition in RV vaccine inefficacy. Specifically, we find that transplant of microbiota from non-RV vaccine responding children confers a microbiota-dependent non-responder phenotype. In addition, culturing infant fecal samples in bioreactor continuous culture systems yields supernatants that differentially inhibit RV vaccine replication in vitro. Hence, the central goals of this proposal are to identify and isolate microbiota constituents that drive RV vaccine inefficacy in humans and determine mechanisms by which they act. Findings from this work will advance our fundamental knowledge on bacterial-viral interactions in the gut, mechanistically enlighten how microbiota can impact replication and response to live, attenuated oral vaccines and potentially aid in the development of novel strategies to reduce the burden of enteric viral infections.

项目概要 减毒轮状病毒 (RV) 疫苗感染肠道上皮细胞每年可以保护数百万人的生命。这是 人们越来越认识到肠道微生物群塑造了轮状病毒遇到的环境 上皮细胞是轮状病毒疫苗功效的关键决定因素。事实上，RV 疫苗已被证明有很多作用。 在发展中国家效果较差，因为众所周知，这些国家的肠道微生物群组成存在明显差异。 我们发表的研究表明，微生物群不仅可以直接影响 RV，而且还可以影响肠道 上皮细胞以防止其进入和复制。此外，我们未发表的作品有力地论证了 肠道微生物群组成在 RV 疫苗无效中发挥着核心作用。具体来说，我们发现移植 来自对 RV 疫苗无反应的儿童的微生物群赋予微生物群依赖的非反应者表型。 此外，在生物反应器连续培养系统中培养婴儿粪便样本产生的上清液 差异性抑制 RV 疫苗体外复制。因此，该提案的中心目标是确定和 分离导致人类 RV 疫苗无效的微生物群成分，并确定其机制 他们行动了。这项工作的发现将增进我们对细菌-病毒相互作用的基础知识 肠道，从机制上揭示微生物群如何影响复制和对活的、减毒的口腔的反应 疫苗并可能有助于制定减少肠道病毒感染负担的新策略。