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microbiota transplantation; mouse model; novel strategies; oral vaccine; prevent; public health relevance; response; unpublished works; vaccine efficacy; vaccine failure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 Furthermore, our unpublished work compellingly argues for a central role for gut microbiota composition in RV vaccine inefficacy.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

项目摘要 通过减毒轮状病毒（RV）疫苗感染肠上皮细胞用于每年保护数百万人的生命。是 越来越多的人认识到，肠道微生物群，它塑造了轮状病毒遇到病毒的环境， 上皮是轮状病毒疫苗效力的关键决定因素。事实上，RV疫苗已经被证明是非常有效的。 在发展中国家效果较差，因为这些国家的肠道微生物群组成存在明显差异。 我们发表的工作表明，微生物群既可以直接影响RV，也可以影响肠道 上皮细胞，以防止其进入和复制。此外，我们未发表的工作令人信服地认为， 肠道微生物群组成在RV疫苗无效中的核心作用。具体来说，我们发现， 来自非RV疫苗应答儿童的微生物群赋予微生物群依赖性非应答者表型。 此外，在生物反应器连续培养系统中培养婴儿粪便样品产生上清液， 差异抑制RV疫苗的体外复制。因此，本建议的中心目标是确定和 分离导致RV疫苗在人体中无效微生物群成分，并确定 他们行动。这项工作的发现将推进我们对细菌-病毒相互作用的基础知识， 肠道，机械地启发微生物群如何影响复制和对活的减毒口服 疫苗，并可能有助于开发新的战略，以减少肠道病毒感染的负担。