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

基本信息

  • 批准号:
    10737392
  • 负责人:
  • 金额:
    $ 78.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目概要/摘要 轮状病毒 (RV) 是幼儿腹泻相关发病率和死亡率的主要原因 全球超过五个。虽然 RV 疫苗大大降低了 RV 死亡率,但中低收入儿童 由于疫苗水平明显较低,收入国家仍面临危及生命的 RV 疾病的风险 与高收入国家相比的有效性。我们最近发现了肠道病毒 B (EV- B)感染降低口服RV疫苗(ORV)的性能。具体而言,EV-B 感染时 在一组来自加纳的婴儿中,接种疫苗与 ORV 血清转化缺乏有关。然而, 与这种干扰相关的信号传导途径和机制尚未确定。我们 假设 EV-B 诱导上皮源性抗病毒细胞因子来限制 ORV 复制和抗 RV 免疫反应。 确定 EV-B 介导的 ORV 干扰机制将利用 离体人类肠道类器官、体内小鼠模型和非侵入性粪便的补充分析 对接受 RV 疫苗的婴儿的人体临床试验队列进行分析。代表性 EV-B 株 与加纳婴儿队列中发现的一致,并且在疾病减少的国家中普遍存在 这些研究已选定疫苗功效。我们将探究先天的抗病毒信号通路 EV-B 感染诱导的病毒,并测试它们是否需要限制 ORV 或 RV 复制, 儿科人类类器官,包括关键先天免疫基因被敲除的同基因系,以及野生型 型、转基因或敲除小鼠系。 EV-B混合感染对适应性免疫发展的影响 还将在小鼠模型中评估对 RV 的反应。此外,来自正在进行的临床的粪便样本 评估 ORV 和非复制 RV 疫苗临床疗效的试验将用于验证 EV-B 干扰 与 ORV 一起使用,定义 EV-B 相关的抗病毒细胞因子,并评估 EV-B 是否也干扰非病毒 复制 RV 疫苗。我们组建了一支在实验方面拥有丰富专业知识的研究人员团队 定义潜在分子机制所需的 RV 系统、临床疫苗学和病毒组分析 低收入和中等收入国家 ORV 性能低下是重要且持续的临床挑战。 该提案的完成将为 EV-B 介导的 ORV 干扰提供重要见解 广泛涉及肠道环境中病毒与病毒的相互作用及其对肠道菌群发展的影响 免疫反应。通过确定调节疫苗反应性的关键因素,我们的目标是促进 开发和测试循证干预措施以提高 RV 疫苗的性能。

项目成果

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Megan T Baldridge其他文献

Megan T Baldridge的其他文献

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{{ truncateString('Megan T Baldridge', 18)}}的其他基金

Defining astrovirus-specific T cell responses
定义星状病毒特异性 T 细胞反应
  • 批准号:
    10667003
  • 财政年份:
    2023
  • 资助金额:
    $ 78.07万
  • 项目类别:
Norovirus regulation via bacterial modulation of interferon-lambda
通过细菌调节干扰素-λ来调节诺如病毒
  • 批准号:
    10754430
  • 财政年份:
    2019
  • 资助金额:
    $ 78.07万
  • 项目类别:
Norovirus regulation via bacterial modulation of interferon-lambda
通过细菌调节干扰素-λ来调节诺如病毒
  • 批准号:
    10797060
  • 财政年份:
    2019
  • 资助金额:
    $ 78.07万
  • 项目类别:
Norovirus regulation via bacterial modulation of interferon-lambda
通过细菌调节干扰素-λ来调节诺如病毒
  • 批准号:
    10574603
  • 财政年份:
    2019
  • 资助金额:
    $ 78.07万
  • 项目类别:
Norovirus regulation via bacterial modulation of interferon-lambda
通过细菌调节干扰素-λ来调节诺如病毒
  • 批准号:
    10356068
  • 财政年份:
    2019
  • 资助金额:
    $ 78.07万
  • 项目类别:
Norovirus regulation via bacterial modulation of interferon-lambda
通过细菌调节干扰素-λ来调节诺如病毒
  • 批准号:
    10112816
  • 财政年份:
    2019
  • 资助金额:
    $ 78.07万
  • 项目类别:
Microbiota-dependent regulation of primitive hematopoieses
原始造血的微生物依赖调节
  • 批准号:
    10053705
  • 财政年份:
    2018
  • 资助金额:
    $ 78.07万
  • 项目类别:
Microbiota-dependent regulation of primitive hematopoieses
原始造血的微生物依赖调节
  • 批准号:
    10293608
  • 财政年份:
    2018
  • 资助金额:
    $ 78.07万
  • 项目类别:
Microbiota-dependent regulation of primitive hematopoieses
原始造血的微生物依赖调节
  • 批准号:
    10515636
  • 财政年份:
    2018
  • 资助金额:
    $ 78.07万
  • 项目类别:
Impact of the Intestinal Microbiome on HIV/SIV Vaccines
肠道微生物组对 HIV/SIV 疫苗的影响
  • 批准号:
    10077897
  • 财政年份:
    2017
  • 资助金额:
    $ 78.07万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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