Role of the gut microbiota and cell-mediated immunity in vaccine-induced mucosal immunity to Polio Virus

肠道微生物群和细胞介导的免疫在疫苗诱导的脊髓灰质炎病毒粘膜免疫中的作用

• 批准号: 10706804
• 负责人: Jessica W. Crothers
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706804
• 关键词: Adjuvant; Adult; Antibody Response; Antigens; Area; Attenuated; Attenuated Vaccines; Bangladesh; Binding; CD8-Positive T-Lymphocytes; CD8B1 gene; Cellular Assay; Cellular Immunity; Childhood; Clinical; Clinical Trials; Data; Development; Disease; Disease Reservoirs; Dose; Evaluation; Exposure to; Feces; Flow Cytometry; Funding; Future; Goals; Human; Human Volunteers; Human poliovirus; Immune; Immune Targeting; Immune response; Immunity; Immunization; Immunologics; Individual; Infant; Infection; Infectious Diseases Research; Investigation; Lipopolysaccharide Biosynthesis Pathway; Lipopolysaccharides; Measures; Metagenomics; Methods; Mucosal Immunity; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Oral Poliovirus Vaccine; Outcome; Paralysed; Peptides; Peripheral Blood Mononuclear Cell; Placebos; Poliomyelitis; Poliovirus Vaccines; Population; Predisposition; Principal Investigator; Production; Regimen; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Strategic Planning; T-Lymphocyte; Toxin; Training; Vaccination; Vaccine Adjuvant; Vaccinee; Vaccines; Viral; Virus Shedding; Work; World Health Organization; cell mediated immune response; cohort; comparison group; cytokine; cytotoxic; cytotoxic CD8 T cells; enterotoxigenic Escherichia coli; fighting; gut microbiome; gut microbiota; human subject; indexing; insight; microbiota; mucosal vaccine; mutant; neurovirulence; novel; novel vaccines; pathogen; phenotypic biomarker; prevent; research clinical testing; response; transmission process; vaccination strategy; vaccine formulation; vaccine immunogenicity; vaccine strategy; viral transmission; virome; young adult

PROJECT SUMMARY: Jessica Crothers, MD, Research Project Leader (RPL) Paralytic Polio is a devastating cause of flaccid paralysis, and its eradication is a major initiative of the World Health Organization (WHO). Critical to eradication efforts is control of viral shedding and environmental transmission of poliovirus (PV). While live attenuated oral poliovirus vaccines (OPV) have been widely effective in establishing sterilizing mucosal immunity and limiting human to human transmission, viral strains used can revert to neurovirulence while being shed in the feces of vaccinees such that its use perpetuates the existence of an environmental reservoir of disease. Alternatively, inactivated polio vaccines (IPV) do little to establish mucosal immunity and limit viral shedding despite their ability to generate protective antibody responses. If polio eradication efforts are to be realized, new PV vaccine strategies and enhanced understanding of the immunologic mechanisms responsible for effective mucosal immunity to PV are critically needed. Dr. Crothers will maximize evaluation of existing data and biospecimens from key clinical PV vaccine-challenge studies to characterize the immunologic target profile of PV mucosal immunity and investigate whether leveraging immune-microbiota interactions, including through use of a novel mucosal vaccine adjuvant, offer a path forward in the fight to eradicate polio. In addition to protective immunity to prevent disease, mucosal immunity is an important vaccination goal to limit pathogen transmission. This project will seek to comprehensively characterize the immune responses of human subjects during PV challenge and compare those of individuals with and without effective mucosal immunity to identify immunologic target profiles associated with effective mucosal immunity to PV. The immunologic impact of a novel mucosal adjuvant (dmLT) combined with IPV will be evaluated to assess its ability to stimulate target immune profiles. Lastly, the impact of the gut microbiota on PV replication and transmission dynamics will be investigated during PV challenge. Altogether, this work will provide a critical step in understanding the role of adjuvants and the gut microbiome in the development of mucosal immunity to PV. This work aligns with the NIAID 2018 strategic plan on vaccine adjuvants which highlights development of mucosal adjuvants with an emphasis on maximizing evaluation of clinical trial data to enhance understanding of their mode of action.

项目总结：Jessica Crothers，MD，研究项目负责人（RPL） 麻痹性脊髓灰质炎是导致弛缓性麻痹的一种毁灭性原因，根除它是世界卫生组织的一项重大举措。 卫生组织（卫生组织）。根除工作的关键是控制病毒脱落和环境 脊髓灰质炎病毒（PV）的传播。虽然口服脊髓灰质炎减毒活疫苗（OPV）已广泛有效， 在建立杀菌粘膜免疫和限制人与人之间传播中，所用病毒株可 在疫苗接种者的粪便中脱落时恢复神经毒力， 疾病的环境储存库。另外，灭活脊髓灰质炎疫苗（IPV）对建立 尽管它们能够产生保护性抗体应答，但它们具有粘膜免疫性并限制病毒脱落。如果 根除脊髓灰质炎的努力有待实现，新的PV疫苗战略和加强对 非常需要负责对PV有效粘膜免疫的免疫机制。克罗瑟斯医生 将最大限度地评价关键临床PV疫苗攻毒研究的现有数据和生物标本， 描述PV粘膜免疫的免疫靶点特征，并研究是否利用 免疫-微生物群相互作用，包括通过使用新的粘膜疫苗佐剂，提供了一种途径， 在根除小儿麻痹症的斗争中向前迈进。 除了预防疾病的保护性免疫外，粘膜免疫也是一个重要的接种目标， 病原体传播该项目将寻求全面表征免疫反应， PV激发期间的人类受试者，并比较具有和不具有有效粘膜刺激的个体的那些 免疫，以确定与PV的有效粘膜免疫相关的免疫靶谱。的 将评价新型粘膜佐剂（dmLT）与IPV组合的免疫学影响，以评估其 刺激目标免疫特性的能力。最后，肠道微生物群对PV复制和 将在PV挑战期间研究传输动力学。总之，这项工作将提供一个关键的一步， 了解佐剂和肠道微生物组在PV粘膜免疫发展中的作用。 这项工作符合NIAID 2018年疫苗佐剂战略计划，该计划强调了 粘膜佐剂，重点是最大限度地评估临床试验数据，以提高理解 他们的行动方式。