Development of a Non-adjuvanted VLP Vaccine against Stealth H7N9 Influenza

针对隐形 H7N9 流感的无佐剂 VLP 疫苗的开发

基本信息

  • 批准号:
    9304958
  • 负责人:
  • 金额:
    $ 29.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-01 至 2020-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The avian-origin H7N9 influenza virus that emerged in humans in China in 2013 presents a unique challenge to vaccine development because it is poorly immunogenic. Neutralizing antibodies are not detected in acute-phase infection. Anti-H7 antibody responses are significantly delayed and exhibit low avidity, in comparison with antibodies generated following seasonal influenza vaccination and infection. Furthermore, unadjuvanted H7N9 vaccines developed using conventional approaches elicit weak hemagglutinin-inhibition (HAI) antibody titers in clinical trials. Adjuvanted formulations may overcome this limitation but present significant regulatory challenges because adverse effects have recently been associated with adjuvanted influenza vaccines. Alternative vaccine approaches are needed to redress the low immunogenicity of H7N9 and circumvent safety risks. Because HAI titers are directly related to effector CD4+ T cell frequencies induced by vaccination, we hypothesize that a vaccine strategy that enhances effector CD4+ T cell activation will improve H7N9 vaccine efficacy without requiring adjuvant formulation. In published studies, we observed that the T cell epitope content of H7N9 virus differs significantly from more immunogenic influenza subtypes. H7N9 contains fewer T cell epitopes and some epitopes stimulate regulatory T cells (Tregs) that may help the virus evade effector responses needed for protection. These findings suggest that H7N9 vaccine design that carefully addresses the T cell subsets primed by immunization will overcome limitations of conventional vaccine approaches. The goal of this research program is to produce an unadjuvanted, influenza H7N9 virus-like particle (VLP) vaccine that augments effector CD4+ T cell responses and diminishes Treg effects for enhanced protection against disease. This new SBIR program will apply cutting edge computational and experimental methods that EpiVax has successfully applied against influenza and other viral and bacterial pathogens, as well as deep experience in influenza VLP production and vaccine testing in collaboration with Dr. Ted Ross at the University of Georgia. Two different engineered VLP strategies will be tested: (i) addition of effector epitopes and (ii) removal of Treg epitopes. Using these prototype effector T cell epitope-enhanced VLP vaccines in the proof-of-concept program described here, we will evaluate the vaccines for immunogenicity and efficacy and move forward in a Phase II program to further optimize efficacy and complete safety/toxicity studies in the run up to clinical trial.
 描述(由申请方提供):2013年在中国人类中出现的禽源H7N9流感病毒对疫苗开发提出了独特的挑战,因为其免疫原性差。在急性期感染中未检测到中和抗体。与季节性流感疫苗接种和感染后产生的抗体相比,抗H7抗体应答显著延迟并表现出低亲合力。此外,使用常规方法开发的无佐剂H7N9疫苗在临床试验中引起弱的血凝素抑制(HAI)抗体滴度。佐剂制剂可以克服这一限制,但目前存在重大的监管挑战,因为最近与佐剂流感疫苗相关的不良反应。需要替代疫苗方法来纠正H7N9的低免疫原性并规避安全风险。由于HAI滴度与疫苗接种诱导的效应CD 4 + T细胞频率直接相关,因此我们假设增强效应CD 4 + T细胞活化的疫苗策略将改善H7N9疫苗效力而无需佐剂制剂。在已发表的研究中,我们观察到H7N9病毒的T细胞表位含量与更具免疫原性的流感亚型显著不同。H7N9含有较少的T细胞表位,并且一些表位刺激调节性T细胞(Tcells),这可能有助于病毒逃避保护所需的效应子反应。这些发现表明,仔细解决通过免疫引发的T细胞亚群的H7N9疫苗设计将克服传统疫苗方法的局限性。这项研究计划的目标是生产一种无佐剂的H7N9流感病毒样颗粒(VLP)疫苗,该疫苗可增强效应CD 4 + T细胞应答并减少Treg效应,以增强对疾病的保护。这项新的SBIR计划将采用EpiVax成功应用于流感和其他病毒和细菌病原体的尖端计算和实验方法,以及与格鲁吉亚大学的Ted Ross博士合作在流感VLP生产和疫苗测试方面的丰富经验。将测试两种不同的工程化VLP策略:(i)添加效应表位和(ii)去除Treg表位。在本文所述的概念验证计划中使用这些原型效应T细胞表位增强的VLP疫苗,我们将评估疫苗的免疫原性和有效性,并在II期计划中向前推进,以进一步优化有效性并在临床试验前完成安全性/毒性研究。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Novel H7N9 influenza immunogen design enhances mobilization of seasonal influenza T cell memory in H3N2 pre-immune mice.
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Anne Searls DeGroot其他文献

Anne Searls DeGroot的其他文献

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{{ truncateString('Anne Searls DeGroot', 18)}}的其他基金

ISPRI-HCP: CHO protein impurity immunogenicity risk prediction for improving biosimilar product development and assessing product interchangeability
ISPRI-HCP:CHO 蛋白杂质免疫原性风险预测,用于改进生物仿制药产品开发和评估产品互换性
  • 批准号:
    10620080
  • 财政年份:
    2022
  • 资助金额:
    $ 29.05万
  • 项目类别:
Structure-Guided Design of CD4 T cell Memory-Enhanced rHA H7N9 Influenza Vaccine
CD4 T细胞记忆增强rHA H7N9流感疫苗的结构引导设计
  • 批准号:
    10216952
  • 财政年份:
    2017
  • 资助金额:
    $ 29.05万
  • 项目类别:
Structure-Guided Design of CD4 T cell Memory-Enhanced rHA H7N9 Influenza Vaccine
CD4 T细胞记忆增强rHA H7N9流感疫苗的结构引导设计
  • 批准号:
    9362529
  • 财政年份:
    2017
  • 资助金额:
    $ 29.05万
  • 项目类别:
Structure-Guided Design of CD4 T cell Memory-Enhanced rHA H7N9 Influenza Vaccine
CD4 T细胞记忆增强rHA H7N9流感疫苗的结构引导设计
  • 批准号:
    9978692
  • 财政年份:
    2017
  • 资助金额:
    $ 29.05万
  • 项目类别:
Novel Antigen-Specific Immunomodulatory Tregitope-based Therapy to Address Autoimmune Pathogenesis in Graves' Disease
基于新型抗原特异性免疫调节 Tregitope 的疗法可解决格雷夫斯病的自身免疫发病机制
  • 批准号:
    9410057
  • 财政年份:
    2017
  • 资助金额:
    $ 29.05万
  • 项目类别:
Inducing Tolerance to Enzyme Replacement Therapy for Pompe Disease
诱导对庞贝病酶替代疗法的耐受性
  • 批准号:
    8394488
  • 财政年份:
    2012
  • 资助金额:
    $ 29.05万
  • 项目类别:
TRIAD Pilot Projects Core
TRIAD 试点项目核心
  • 批准号:
    8378749
  • 财政年份:
    2012
  • 资助金额:
    $ 29.05万
  • 项目类别:
Combined Factor VIII Replacement and Tolerance Therapy for Hemophilia A
A 型血友病联合因子 VIII 替代和耐受治疗
  • 批准号:
    8508305
  • 财政年份:
    2012
  • 资助金额:
    $ 29.05万
  • 项目类别:
Multi-intracellular Pathogen Epitope-based Vaccine
基于多细胞内病原体表位的疫苗
  • 批准号:
    8378738
  • 财政年份:
    2012
  • 资助金额:
    $ 29.05万
  • 项目类别:
Combined Factor VIII Replacement and Tolerance Therapy for Hemophilia A
A 型血友病联合因子 VIII 替代和耐受治疗
  • 批准号:
    8313747
  • 财政年份:
    2012
  • 资助金额:
    $ 29.05万
  • 项目类别:

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