Enterovirus interference with rotavirus vaccine replication and immunity

肠道病毒干扰轮状病毒疫苗的复制和免疫

• 批准号: 10737392
• 负责人: Megan T Baldridge
• 金额: $ 78.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737392
• 关键词: Adult; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Country; Coxsackie Viruses; Data; Development; Diarrhea; Enteral; Enterovirus; Enterovirus Infections; Environment; Epithelial Cells; Epithelium; Evidence based intervention; Family Picornaviridae; Ghana; Goals; Hospitalization; Human; Immune; Immune response; Immunity; Income; Infant; Infection; Innate Immune Response; Integration Host Factors; Interferons; Intestines; Knockout Mice; Life; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Oral; Oral Poliovirus Vaccine; Organoids; Outcome; Pathway interactions; Performance; RNA Viruses; Research Personnel; Risk; Role; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Rotavirus disease; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; System; TNF gene; Testing; Time; Transgenic Organisms; Vaccination; Vaccines; Variant; Viral; Viral Interference; Work; Zambia; adaptive immune response; adaptive immunity; clinical efficacy; co-infection; cohort; compare effectiveness; cytokine; gastrointestinal epithelium; immunogenicity; immunoregulation; improved; in vivo; innate immune pathways; insight; knockout gene; low and middle-income countries; mortality; mouse model; oral vaccine; prevent; seroconversion; vaccine effectiveness; vaccine efficacy; vaccine immunogenicity; vaccine response; vaccine trial; vaccinology; virome; virus virus interaction

PROJECT SUMMARY/ABSTRACT Rotavirus (RV) is the leading cause of diarrhea-associated morbidity and mortality in children younger than five worldwide. While RV vaccines have substantially decreased RV deaths, children in low- and middle- income countries remain at risk of life-threatening RV disease because of significantly lower vaccine effectiveness compared to high-income countries. We recently identified a potential role for Enterovirus B (EV- B) infection in reducing oral RV vaccine (ORV) performance. Specifically, EV-B infection at the time of vaccination is associated with a lack of seroconversion to ORV in a cohort of infants from Ghana. However, the signaling pathways and mechanisms associated with this interference have not yet been defined. We hypothesize that EV-Bs induce epithelial-derived antiviral cytokines to limit both ORV replication and anti-RV immune responses. Determination of the mechanisms underlying EV-B-mediated interference with ORV will leverage complementary analyses in ex vivo human intestinal organoids, in vivo mouse models, and non-invasive fecal analyses from a human clinical trial cohort of infants receiving RV vaccines. Representative EV-B strains consistent with those identified in the Ghanaian infant cohort and which are prevalent in countries with reduced vaccine efficacy have been selected for these studies. We will interrogate the innate antiviral signaling pathways induced by EV-B infection, as well as test whether they are required to limit ORV or RV replication, in both pediatric human organoids, including isogenic lines where key innate immune genes are knocked-out, and wild- type, transgenic or knock-out mouse lines. EV-B co-infection effects on development of adaptive immune responses to RV will also be evaluated in murine models. Additionally, fecal samples from an ongoing clinical trial evaluating ORV and non-replicating RV vaccine clinical efficacy will be used to validate EV-B interference with ORV, define EV-B-associated antiviral cytokines, and assess whether EV-B also interferes with non- replicating RV vaccines. We have assembled a team of investigators with extensive expertise in the experimental RV systems, clinical vaccinology, and virome analyses required to define the molecular mechanisms underlying the important and persistent clinical challenge of low ORV performance in low- and middle-income countries. Completion of this proposal will provide key insights into EV-B-mediated interference with ORV, as well as broadly into virus-virus interactions in the intestinal environment and their consequences for development of immune responses. By identifying key factors that regulate vaccine responsiveness, we aim to facilitate development and testing of evidence-based interventions to improve RV vaccine performance.

项目总结/摘要 轮状病毒（RV）是婴幼儿腹泻相关发病和死亡的主要原因 全世界5个以上。虽然RV疫苗大大降低了RV死亡率，但低水平和中等水平的儿童 收入国家由于疫苗接种率低， 与高收入国家相比。我们最近确定了肠道病毒B（EV- B）感染降低口服RV疫苗（ORV）性能。具体而言，EV-B感染时， 在来自加纳的一组婴儿中，疫苗接种与缺乏ORV血清转化相关。但 与这种干扰相关的信号通路和机制尚未确定。我们 假设EV-B诱导上皮来源抗病毒细胞因子以限制ORV复制和抗RV 免疫反应。 确定EV-B介导的ORV干扰的潜在机制将利用 在离体人肠类器官、体内小鼠模型和非侵入性粪便中的互补分析 来自接受RV疫苗的婴儿的人类临床试验队列的分析。代表性EV-B毒株 与加纳婴儿队列中确定的情况一致， 这些研究选择了疫苗效力。我们将研究先天的抗病毒信号通路 诱导的EV-B感染，以及测试它们是否需要限制ORV或RV复制，在这两个 儿科人类类器官，包括关键先天免疫基因被敲除的等基因系，以及野生型 型、转基因或敲除小鼠品系。EV-B共感染对获得性免疫的影响 还将在鼠模型中评价对RV的应答。此外，来自正在进行的临床试验的粪便样本 评价ORV和非复制型RV疫苗临床疗效的试验将用于验证EV-B干扰 与ORV，定义EV-B相关的抗病毒细胞因子，并评估EV-B是否也干扰非 复制RV疫苗。我们已经组建了一个调查小组，他们在实验方面具有广泛的专业知识， RV系统，临床疫苗学和病毒组分析需要确定潜在的分子机制 在低收入和中等收入国家，ORV性能低是一个重要而持久的临床挑战。 该提案的完成也将为EV-B介导的ORV干扰提供关键见解， 广泛地研究了肠道环境中的病毒-病毒相互作用及其对发展的影响， 免疫反应。通过确定调节疫苗反应性的关键因素，我们旨在促进 开发和测试基于证据的干预措施，以提高RV疫苗的性能。