SELECTION OF VACCINE ANTIGENS FOR PROTECTION FROM HEPATITIS C VIRUS INFECTION
选择预防丙型肝炎病毒感染的疫苗抗原
基本信息
- 批准号:10608965
- 负责人:
- 金额:$ 34.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:Active immunityAdjuvantAntigen-Presenting CellsAntigensB-LymphocytesBinding SitesCD4 Positive T LymphocytesCD81 geneCell Culture TechniquesCell physiologyCellsChronic Hepatitis CCountryDevelopmentEncapsulatedEnvironmentEvaluationGenerationsGenomic SegmentGenotypeGlycoproteinsHealthHealth BenefitHelper-Inducer T-LymphocyteHepatitis CHepatitis C IncidenceHepatitis C VaccineHepatitis C ViremiaHepatitis C virusHumanImmuneImmune responseImmunizationImmunizeImmunocompetentImpairmentInfectionInterruptionLiteratureLiver diseasesMF59MacrophageMacrophage ActivationMessenger RNAMusMutateNatural Killer CellsNatureNucleosidesPatientsPeptidesPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhasePhenotypePoint MutationPopulations at RiskPreventive vaccineProteinsPublic HealthRecombinantsRegimenResearchResistanceResource-limited settingRiskRoleSafetyT cell responseT-LymphocyteT-Lymphocyte EpitopesTestingVaccinatedVaccine AdjuvantVaccine AntigenVaccinesVaccinia virusViralViral AntigensViral ProteinsVirus DiseasesWorkanti-hepatitis Ccomparativecost effectivecross reactivityend stage liver diseaseexperimental studyglobal healthhealthy volunteerimmune functionimmunogenicityimmunoregulationimprovedlipid nanoparticlelow socioeconomic statusmouse modelmutantnanoparticleneutralizing antibodynovel vaccinespathogenpreclinical studyprogression riskprotective efficacyrational designresponsestemtransmission processvaccine candidatevaccine deliveryvaccine developmentvaccine efficacyvaccine evaluationvaccine platformvaccine strategyviral RNAvirus envelopevolunteer
项目摘要
Abstract
Chronic hepatitis C virus (HCV) infection often causes end stage liver disease. Although current anti-HCV
drugs are successful in eliminating viral RNA load, they do not prevent reinfection. In addition, eliminating
HCV RNA load does not reduce the risk for progression to end stage liver disease. Therefore, the urgent
need for the development of a comprehensive strategy to control HCV infection must include a vaccine. HCV
envelope glycoproteins are the key components for the initiation of viral infection. Our phase I safety and
immunogenicity trial of a recombinant HCV envelope glycoprotein candidate vaccine did not induce a strong
immune response in most vaccinated volunteers. Subsequent studies indicated that purified HCV E2 has an
immunoregulatory role and biases primary macrophage activation toward the M2 phenotype (via E2-CD81
interactions), impairs DC/CD4+T cell functions, and leads to an environment for a muted response to
antigen. Nevertheless, HCV E2 still contains strong cross-genotype specific B- and T-cell epitopes vital to
an active immunity. We hypothesize that modifying E2 by discrete point mutations to inhibit interaction with
CD81 will improve immune functions and induce robust protective responses in combination with other HCV
regions as candidate vaccine, and will generate stronger protective efficacy. Outstanding abilities of
nucleoside modified mRNA-lipid nanoparticle (LNP) to elicit potent immune responses against pathogens
makes it a viable new cost-effective platform for vaccine development. The incorporation of modified
nucleosides in the mRNA will offer advantages for generation of modified antigens to induce a broad effective
immune response. The premise and rigor of the study stems from our own work, and information in the
literature. Thus, the use of nanoparticle encapsulated mRNA of modified E2 for stronger immunogenicity
together with other viral antigens (E1 and non-structural (NS) genomic regions) for prime and boost with
proteins/peptides as a candidate vaccine for HCV cross protective efficacy will generate robust B- and T- cell
responses for protection against HCV. The results from our study will advance vaccine development against
persistent HCV infection.
摘要
慢性丙型肝炎病毒(HCV)感染往往会导致终末期肝病。虽然目前抗HCV
药物成功地消除了病毒RNA载量,但它们不能防止再感染。此外,消除
HCV RNA载量不会降低进展为终末期肝病的风险。因此,紧急
发展控制HCV感染的综合策略的需要必须包括疫苗。HCV
包膜糖蛋白是启动病毒感染的关键成分。我们的第一阶段安全和
重组HCV包膜糖蛋白候选疫苗免疫原性试验未诱导强烈的
大多数接种疫苗的志愿者的免疫反应。随后的研究表明,纯化的HCV E2具有
免疫调节作用,并使初级巨噬细胞活化偏向M2表型(通过E2-CD 81
相互作用),损害DC/CD 4 +T细胞功能,并导致对
抗原的尽管如此,HCV E2仍然含有强的跨基因型特异性B和T细胞表位,
主动免疫我们假设,通过离散点突变来修饰E2以抑制与E2的相互作用,
CD 81将与其他HCV结合,改善免疫功能并诱导强大的保护性应答
区域作为候选疫苗,并将产生更强的保护效力。杰出的能力
核苷修饰的mRNA-脂质纳米颗粒(LNP),以引发针对病原体的有效免疫应答
使其成为疫苗开发的可行的新的成本效益平台。修改后的合并
mRNA中的核苷将为产生修饰的抗原提供优势,以诱导广泛的有效免疫应答。
免疫反应这项研究的前提和严谨性源于我们自己的工作,
文学因此,使用纳米颗粒包封的修饰的E2的mRNA用于更强的免疫原性,
与其他病毒抗原(E1和非结构(NS)基因组区域)一起用于初免和加强,
作为HCV交叉保护效力的候选疫苗的蛋白质/肽将产生稳健的B-和T-细胞
针对HCV的保护反应。我们的研究结果将促进疫苗的开发,
持续性HCV感染。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hepatitis C virus E1 and modified E2 delivered from an mRNA vaccine induces protective immunity.
从mRNA疫苗传递的丙型肝炎病毒E1和修饰的E2可诱导保护性免疫。
- DOI:10.1038/s41541-023-00635-9
- 发表时间:2023-03-18
- 期刊:
- 影响因子:9.2
- 作者:
- 通讯作者:
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Ranjit Ray其他文献
Ranjit Ray的其他文献
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{{ truncateString('Ranjit Ray', 18)}}的其他基金
SELECTION OF VACCINE ANTIGENS FOR PROTECTION FROM HEPATITIS C VIRUS INFECTION
选择预防丙型肝炎病毒感染的疫苗抗原
- 批准号:
10207624 - 财政年份:2020
- 资助金额:
$ 34.09万 - 项目类别:
SELECTION OF VACCINE ANTIGENS FOR PROTECTION FROM HEPATITIS C VIRUS INFECTION
选择预防丙型肝炎病毒感染的疫苗抗原
- 批准号:
10397662 - 财政年份:2020
- 资助金额:
$ 34.09万 - 项目类别:
Hepatitis C virus infection and mechanism of liver disease progression
丙型肝炎病毒感染及肝病进展机制
- 批准号:
9891052 - 财政年份:2017
- 资助金额:
$ 34.09万 - 项目类别:
Hepatitis C virus infection and mechanism of liver disease progression
丙型肝炎病毒感染及肝病进展机制
- 批准号:
9323675 - 财政年份:2017
- 资助金额:
$ 34.09万 - 项目类别:
Hepatitis C virus escape mechanisms from innate immunity
丙型肝炎病毒逃避先天免疫的机制
- 批准号:
8234942 - 财政年份:2011
- 资助金额:
$ 34.09万 - 项目类别:
Mechanisms of Liver Disease Progression by Hepatitis C Virus
丙型肝炎病毒导致肝病进展的机制
- 批准号:
7900335 - 财政年份:2009
- 资助金额:
$ 34.09万 - 项目类别:
Mechanisms of Liver Disease Progression by Hepatitis C Virus
丙型肝炎病毒导致肝病进展的机制
- 批准号:
7735483 - 财政年份:2009
- 资助金额:
$ 34.09万 - 项目类别:
Mechanisms of Liver Disease Progression by Hepatitis C Virus
丙型肝炎病毒导致肝病进展的机制
- 批准号:
8299564 - 财政年份:2009
- 资助金额:
$ 34.09万 - 项目类别:
Mechanisms of Liver Disease Progression by Hepatitis C Virus
丙型肝炎病毒导致肝病进展的机制
- 批准号:
8516026 - 财政年份:2009
- 资助金额:
$ 34.09万 - 项目类别:
Hepatitis C virus escape mechanisms from innate immunity
丙型肝炎病毒逃避先天免疫的机制
- 批准号:
7672150 - 财政年份:2009
- 资助金额:
$ 34.09万 - 项目类别:
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