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microbiota transplantation; mouse model; novel strategies; oral vaccine; prevent; public health relevance; response; unpublished works; vaccine efficacy; vaccine failure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 Furthermore, our unpublished work compellingly argues for a central role for gut microbiota composition in RV vaccine inefficacy.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