Universal room temperature stable influenza nanovaccine
通用型室温稳定流感纳米疫苗
基本信息
- 批准号:10079019
- 负责人:
- 金额:$ 104.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-24 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAntibodiesAntibody titer measurementAntigensAppearanceAreaAvian Influenza A VirusB-LymphocytesCellular ImmunityCessation of lifeClinical TrialsCold ChainsDevice or Instrument DevelopmentDevicesDoseEconomicsEnsureEpidemicEpitopesEquus caballusFerretsFormulationFutureGoalsH5 hemagglutininHeadHemagglutininHospitalizationHumanHumoral ImmunitiesImmunityImmunizationInfectionInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A Virus, H3N2 SubtypeInfluenza A Virus, H5N1 SubtypeInfluenza A virusLeadLegal patentLifeLungMaintenanceMedical Care CostsMembrane ProteinsMemoryMemory B-LymphocyteMicellesModelingMorbidity - disease rateMusNational Institute of Allergy and Infectious DiseasePolyanhydridesPolymersProcessProductivityProtein FragmentProteinsPublic HealthRecombinantsRefrigerationSafetySerotypingSeverity of illnessStructure of mucous membrane of noseStructure of parenchyma of lungT cell responseT memory cellT-LymphocyteTechnologyTemperatureTissuesToxicologyTranslatingUnited StatesVaccinationVaccinesVariantViralViral AntigensViral Load resultViral ProteinsVirusVirus Diseasesbasecombatcopolymercost effectivecytotoxic CD8 T cellsdesigneconomic costimprovedinfluenza virus straininnovationmanufacturing processmortalitynanoparticlenanovaccineneutralizing antibodynovelpandemic diseaserespiratoryresponsestemuniversal vaccine
项目摘要
PROJECT SUMMARY / ABSTRACT
Influenza A virus (IAV) is a major cause of serious respiratory illness and has been responsible for significant
morbidity and mortality in humans worldwide. The virus leads to approximately 200,000 hospitalizations and
36,000 deaths annually in the U.S. during non-pandemic years. Given the disease severity, the associated
economic costs and the recent appearance of novel IAV strains and/or variants, there is an urgent need to
develop novel and efficacious “universal” vaccines to combat this significant global public health threat. Current
IAV vaccines are limited by the need to account for viral antigen drift/shift, the slow manufacturing process, low
to moderate efficacy rates, and the inability to induce lung resident memory T and B cells that occur during
natural IAV infections. The most efficacious universal vaccine may need to target conserved epitopes within
both the head and the stem regions of the IAV hemagglutinin (HA) and include conserved proteins that drive T
cell immunity. Immunizations that generate local tissue-resident memory T and B memory cells and systemic
immunity offer the greatest protection against future IAV encounters. Thus, our long-term goal is to develop a
universal IAV vaccine that will induce broadly neutralizing antibodies (bnAb) and durable, IAV-specific, lung-
resident T and B cell immunity, protect against group 1 and 2 IAV strains, and not require a cold chain. To this
end, we have discovered a novel immunogen based on equine recombinant HA3 (rHA3) that elicits Ab in
multiple species and protects across influenza groups by targeting both the HA head and stem regions. We
have also developed two promising polymeric nanovaccine platforms that have been shown to increase Ab
titer, improve T cell immunity, and prolong antigen release after vaccination. One is comprised of
biodegradable polyanhydride nanoparticles and the other is based on pentablock copolymer micelles. We have
shown that both platforms induced protective immunity with reduced viral load upon vaccination. The IAV
nanovaccine showed promising efficacy in protection against homologous and heterologous IAV infections and
induced T and B cell responses in the lungs. This proposal will use the combined expertise of our team to
determine if a nanovaccine approach will induce both bnAb and durable, lung-resident T and B cell immunity
and lead to universal protection using the following specific aims: 1) synthesize and characterize rHA3
nanovaccines;; 2) establish the safety and toxicological profile of rHA3 nanovaccine in mice and ferrets;; 3)
determine rHA3 nanovaccine formulation(s) that will elicit the most appropriate and sustained response to IAV
following a single-dose vaccination;; 4) design multivalent rHA3 nanovaccines that increase bnAb and CMI to
diverse strains of IAV;; and 5) develop GLP-compliant process for synthesis of identified lead universal
nanovaccine and evaluate its shelf life in delivery devices. The proposed studies with tightly bound milestones
and decision points will lead to a final product that will meet NIAID’s characterization of a protective universal
IAV vaccine and provide important first steps for translating our findings to human clinical trials.
项目摘要://摘要:
甲型流感病毒(IAV)是一种严重的呼吸系统疾病的主要致病因素,一直以来都是造成这种重大疾病的主要原因。
在世界范围内,人类的发病率和死亡率都在上升。这种病毒导致大约20万人住院和死亡。
在非大流行的几年里,美国东部每年有3.6万人死亡。考虑到这种疾病的严重性,以及与之相关的疾病。
经济成本很高,而且最近出现了一种新型的IAV毒株和/或变种,但目前还没有一个迫切的需求需要解决。
开发一种新型的、高效的、“通用”的疫苗,以进一步抗击这一重大的全球公共卫生威胁。
IAV疫苗的发展受到以下因素的限制:他们需要解决病毒抗原漂移/漂移的问题,因为制造过程非常缓慢,而且很低。
为了保持适度的疗效,预防和减少在治疗期间经常发生的不能诱导肺、居民记忆T细胞和B细胞死亡的情况。
天然的IAV感染。作为最有效和最通用的疫苗,可能需要在未来几年内寻找目标,以保护其保守的抗原表位。
IAV血凝素(HA)基因的主要部分和主干都包括一些保守的蛋白质,这些蛋白质可以驱动T细胞。
细胞免疫。免疫可产生局部免疫组织驻留的T细胞和B细胞的记忆,以及全身免疫。
豁免权提供了对未来IAV成员遭遇的最大保护。因此,我们的长期目标是更好地发展IAV。
万能的IAV疫苗说,它将不会通过中和抗体(BNab)而广泛地诱导肺炎,并且耐用,而且是IAV特异性的,用于肺部。
居民T细胞和B细胞的免疫,以保护他们免受第1群和第2群IAV毒株的侵袭,他们和他们不需要一个更好的冷藏链。
最后,我们还发现了一种基于马重组HA3蛋白(RHA3)的新型免疫原,它能在体内诱导抗体产生。
多种禽流感病毒通过同时针对医管局负责人和疫区的目标来保护所有流感病毒群体的健康。
他们还开发了两个很有前途的聚合物纳米疫苗新平台,这些平台已经被证明可以增加抗体。
滴度,提高T细胞免疫力,延长疫苗接种后T细胞抗原的释放时间。一种疫苗由多种成分组成。
可生物降解的聚酸酐纳米粒子和其他材料都是基于五嵌段共聚物胶束的。
研究表明,这两个平台在接种疫苗后都诱导了保护性免疫应答,并降低了病毒载量。
纳米疫苗在预防同源病毒和异种病毒感染方面显示出良好的疗效。
诱导T细胞和B细胞在肺中的反应。这项新的提案将不会使用我们的团队的最新的专业知识。
确定一种新的纳米疫苗接种方法是否会同时诱导bNab抗体和持久的、居住在肺部的T细胞和B细胞的免疫。
并将领导人们通过使用以下具体目标来实现普遍的卫生保护:(1)合成和表征rHA3。
纳米疫苗;;(2)建立在小鼠和雪貂身上使用的纳米疫苗的安全标准和毒理学模型;HA3)。
确定HA3和纳米疫苗的配方(S):这将引发对IAV的最适当的反应和可持续的反应。
继单剂疫苗接种之后;;(4)设计了多价rHA3纳米疫苗,使bNab和CMI值增加到2.5%。
;的不同毒株将开发符合GLP的新工艺,以合成已确定的铅和通用铅。
纳米疫苗在其递送设备中测试和评估其最新的保质期和寿命。该公司提出了一项与紧密绑定的技术里程碑相关的研究。
这一决定将导致我们最终推出一款新的产品,该产品将不会满足NIAID对全球保护性和普惠性的描述。
IAV疫苗研发为将我们的研究结果转化为人类临床试验提供了重要的第一步。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Balaji Narasimhan其他文献
Balaji Narasimhan的其他文献
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{{ truncateString('Balaji Narasimhan', 18)}}的其他基金
Universal room temperature stable influenza nanovaccine
通用型室温稳定流感纳米疫苗
- 批准号:
10320415 - 财政年份:2019
- 资助金额:
$ 104.76万 - 项目类别:
Universal room temperature stable influenza nanovaccine
通用型室温稳定流感纳米疫苗
- 批准号:
10539285 - 财政年份:2019
- 资助金额:
$ 104.76万 - 项目类别:
Enhanced Shelf-life Nanovaccine Formulation for Immunity to Biodefense Pathogens
延长保质期的纳米疫苗配方,可增强对生物防御病原体的免疫力
- 批准号:
8694579 - 财政年份:2014
- 资助金额:
$ 104.76万 - 项目类别:
Enhanced Shelf-life Nanovaccine Formulation for Immunity to Biodefense Pathogens
延长保质期的纳米疫苗配方,可增强对生物防御病原体的免疫力
- 批准号:
9120299 - 财政年份:2014
- 资助金额:
$ 104.76万 - 项目类别:
Impact of polymer adjuvant chemistry on adaptive immune mechanisms
聚合物佐剂化学对适应性免疫机制的影响
- 批准号:
8132630 - 财政年份:2010
- 资助金额:
$ 104.76万 - 项目类别:
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