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microbiota transplantation; mouse model; novel strategies; oral vaccine; prevent; public health relevance; response; unpublished works; vaccine efficacy; vaccine failure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 Furthermore, our unpublished work compellingly argues for a central role for gut microbiota composition in RV vaccine inefficacy.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.

项目总结 用减毒轮状病毒(RV)疫苗感染肠道上皮细胞每年可保护数百万人的生命。它是 越来越多的人意识到肠道微生物区系，它塑造了轮状病毒遇到 上皮细胞是轮状病毒疫苗效果的关键决定因素。事实上，轮状病毒疫苗已经被证明有很大的作用 在已知肠道微生物区系组成有明显差异的发展中国家，效果较差。 我们发表的工作表明，微生物区系不仅可以直接影响RV，而且还可以影响肠道 上皮细胞防止其进入和复制。此外，我们未发表的作品令人信服地主张 肠道微生物区系组成在轮状病毒疫苗无效中的核心作用。具体地说，我们发现移植了 来自无RV疫苗应答儿童的微生物区系赋予了一种微生物区系依赖的无应答者表型。 此外，在生物反应器连续培养系统中培养婴儿粪便样本会产生 差异性抑制轮状病毒疫苗体外复制。因此，这项提案的中心目标是确定和 分离导致轮状病毒疫苗在人类中无效的微生物区系成分，并确定其机制 他们采取行动。这项工作的发现将促进我们对细菌-病毒相互作用的基础知识 肠道，机械地启发微生物区系如何影响复制和对活的减毒口腔的反应 疫苗，并有可能有助于开发新的战略，以减轻肠道病毒感染的负担。