Optimization of a Self-Adjuvanting Particle System for Delivering Respiratory Syncytial Virus Prefusion Protein
用于输送呼吸道合胞病毒预融合蛋白的自我辅助颗粒系统的优化
基本信息
- 批准号:10666079
- 负责人:
- 金额:$ 22.67万
- 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:2023-02-02 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:5 year oldAcuteAdjuvantAdultAlveolar MacrophagesAntibodiesAntibody FormationAntibody-mediated protectionAntigen-Presenting CellsAntigensAvidinBiotinBiotinylationBreast FeedingCD8-Positive T-LymphocytesCD8B1 geneChildChildhoodChimeric ProteinsClinical TrialsCollaborationsCommunitiesCouplingDataDendritic CellsDiseaseDoseDrug Delivery SystemsDyesEnsureEnvironmentEquilibriumExhibitsFamilyFlow CytometryFormulationFrequenciesGenerationsGlycolatesHalf-LifeHospital ChargesHospitalizationImmune responseImmunityImmunizationImmunizeImmunoglobulin AImmunoglobulin GInbred BALB C MiceInfantInfectionInflammationInjectionsInterferon Type IIInterleukin-12IntramuscularIntranasal AdministrationKineticsLabelLeadLettersLicensingLifeLipidsLower Respiratory Tract InfectionLungMaternal antibodyMethodsMolecularMolecular ConformationMorbidity - disease rateMothersMucous MembraneMucous body substanceMusNaturePharmacy (field)PhasePopulationPredispositionPreventionProductionPropertyProtein ConformationProtein EngineeringProteinsQuality of lifeResearch PersonnelRespiratory DiseaseRespiratory Syncytial Virus InfectionsRespiratory Syncytial Virus VaccinesRespiratory syncytial virusRisk ReductionSafetySeveritiesSiteSolventsStructureSurfaceSystemT cell responseTeenagersTestingTimeVaccinationVaccinesVariantViralViral AntigensWheezingaluminum sulfateburden of illnessclinical developmentclinically relevantcytokinedesignimmune activationimmune activatorimmunogenicityimprovedin vivoinnovationinsightmanufacturematernal outcomemortalitymouse modelnanoparticlenanovaccineneutralizing antibodynovelnovel vaccinesparticlepathogenpre-clinicalpreservationprototyperesponsetissue resident memory T celluptakevaccine candidatevaccine deliveryvaccine developmentvaccine formulationvaccine platform
项目摘要
In the US, RSV infects nearly 100% of children, and total associated hospital charges are estimated at
approximately $2.5 billion dollars. Infants are most susceptible to severe RSV-related disease in the first six
months of life. During this time, infants mount poorly protective antibody-mediated immunity on their own upon
RSV infection or vaccination. Rather they veer toward Th2-type responses, which can cause disease- or vaccine-
enhanced severity upon re-infection, and subsequent wheezing throughout childhood and into their teens. In
recent years, promising maternal RSV vaccine candidates have progressed to clinical trials, but the window of
protection to the infant remains limited to the half-life of the maternally-derived antibody (~1 month) or moderately
longer if the mother is breast feeding. An RSV vaccine that protects infants beyond the first month of life or
ameliorates the course of their respiratory disease, will (i) reduce the frequency of infant hospitalizations, (ii)
improve the quality of life for infants, families, communities, and populations, and (iii) lessen disease burden on
the US economy.
In this multiple PI project, we seek to optimize and characterize a nanoparticle-based intranasal RSV vaccine
platform with intrinsic adjuvant properties. The biodegradable biotin-nanoparticle system (referred to as bNP)
functions as an antigen carrier and immune activator. Coupling antigen delivery and adjuvant properties into a
single physical entity will enhance the capacity to overcome the inherent immunosuppressive environment of
mucosal tissues. The particle system has a tunable design in which the dose of the antigen can be varied without
remanufacturing. To ensure a Th-1 type response, we will use a variant RSV prefusion protein (preF) engineered
to lock in the native conformation as the cargo antigen.
We hypothesize that preF sterically stabilized on bNP (preF-bNP) will activate antigen-presenting cells to induce
important correlates of protection, including RSV-specific Th1-dominant T cell response, CD8 resident memory T
cells, and neutralizing antibody. Three specific aims are proposed. In Aim 1 we will optimize display of preF on
bNP and capacity of the formulation to activate antigen presenting cells. In Aim 2 we will determine preF-bNP
uptake kinetics into antigen presenting cells and preF-bNP-induced immunity in vivo, including resident memory T
cells. In Aim 3 we will establish the safety and efficacy of intranasal preF-bNP in an RSV mouse model.
Successful completion of the studies will lead pave the way for advancing a novel RSV vaccine formulation for
generating safe and protective RSV immunity in young children.
在美国,RSV感染几乎100%的儿童,相关的医院费用估计为
大约25亿美元。婴儿最容易患上前六种严重的RSV相关疾病
几个月的生活。在这段时间里,婴儿依靠自身抗体介导的免疫力,
RSV感染或接种疫苗。相反,他们转向Th 2型反应,这可能导致疾病或疫苗,
在再次感染时严重性增加,随后在整个儿童期和青少年期出现喘息。在
近年来,有希望的母体RSV疫苗候选物已进展到临床试验,但
对婴儿的保护仍然限于母源性抗体的半衰期(约1个月)或中度
如果母亲是母乳喂养的话。RSV疫苗可保护出生后第一个月以上的婴儿,
改善其呼吸道疾病的病程,将(i)减少婴儿住院的频率,(ii)
改善婴儿、家庭、社区和人口的生活质量,以及(iii)减轻
美国经济。
在这个多PI项目中,我们寻求优化和表征基于纳米颗粒的鼻内RSV疫苗
具有内在佐剂性质的平台。生物素-纳米粒子系统(简称bNP)
作为抗原载体和免疫激活剂。将抗原递送和佐剂性质偶联到一个
单一的物理实体将增强克服固有的免疫抑制环境的能力,
粘膜组织粒子系统具有可调的设计,其中抗原的剂量可以变化,而不需要改变。
再制造为了确保Th-1型应答,我们将使用工程化的变体RSV融合前蛋白(preF),
以锁定天然构象作为货物抗原。
我们假设空间稳定在bNP上的preF(preF-bNP)将激活抗原呈递细胞,诱导
保护的重要相关因素,包括RSV特异性Th 1-显性T细胞应答,CD 8驻留记忆T细胞,
细胞和中和抗体。提出了三个具体目标。在目标1中,我们将优化preF在
bNP和制剂活化抗原呈递细胞的能力。在目标2中,我们将确定preF-bNP
体内抗原呈递细胞的摄取动力学和preF-bNP诱导的免疫,包括驻留记忆T细胞
细胞在目标3中,我们将在RSV小鼠模型中确定鼻内preF-bNP的安全性和有效性。
这些研究的成功完成将为开发新型RSV疫苗制剂铺平道路,
在幼儿中产生安全和保护性RSV免疫。
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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Kerry McGarr Empey其他文献
Kerry McGarr Empey的其他文献
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{{ truncateString('Kerry McGarr Empey', 18)}}的其他基金
Immature Infant Alveloar Macrophage Clearance of Cell Debris During RSV Infection
RSV 感染期间未成熟婴儿肺泡巨噬细胞清除细胞碎片
- 批准号:
9015445 - 财政年份:2015
- 资助金额:
$ 22.67万 - 项目类别:
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