VACCINE DEVELOPMENT FOR ALPHAVIRUSES

甲病毒疫苗的开发

• 批准号: 8358111
• 负责人: CHAD J. ROY
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358111
• 关键词: Alphavirus; Animals; Antibodies; Attenuated; Biological Assay; Chikungunya virus; Clinical; Culicidae; Development; Disease; Dose; Electrocardiogram; Family Picornaviridae; Funding; Grant; Heart Rate; Human; Immunity; Implant; Infection; Measurement; Measures; Modeling; Monitor; Morbidity - disease rate; National Center for Research Resources; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Route; Saline; Sampling; Site; Source; Structural Protein; Syndrome; System; Telemetry; Temperature; Testing; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Viremia; Virus; Virus Diseases; base; chikungunya; cost; efficacy testing; immunogenic; immunogenicity; neutralizing antibody; nonhuman primate; prevent; promoter; research study; respiratory; response; subcutaneous; vaccine candidate; vaccine development

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Chikungunya (CHIK) is a vectorborne viral disease caused by chikungunya virus, a pathogenic alphavirus. Initially we recapitulated the viral disease in an experimental nonhuman primate model (M. fascicularis) (n=3). This morbidity model emulated the clinical syndrome and showed the hallmarks of natural disease noted in human infections. The model was established to provide an advanced monitoring system for testing the efficacy of candidate vaccines developed against CHIK. The CHIK vaccines under development are based upon constructs containing a picornavirus internal ribosomal entry site (IRES) to replace the subgenomic promoter for expression of the CHIK virus (CHIKV) structural proteins. This approach highly attenuates the virus and prevents mosquito infection, but preserves immunogenicity. The CHIK nonhuman primate model was used to test two versions of the vaccine (CHIK/IRESv1, v2) in separate experiments. Animals were implanted with remote radiotelemetry for continuous monitoring of clinical signs (core temperature, respiratory rate, heart rate, ECG) and samples were taken for viremia, antibody, and viremia assays following vaccination and after challenge. Groups of four animals (N=16) prime vaccinated with a single dose of 5.5^log by either the subcutaneous (SQ; CHIK/IRESv1) or intradermal (ID; CHIK/IRESv2) route, or sham vaccinated with saline. Approximately 45 days postvaccination, all animals were challenged SQ with 6.0log of wild-type CHIKV. The highest neutralizing antibody titers were generated by the CHIK/IRESv2 vaccine group, with slightly lower mean titers by CHIK/IRESv1 (ID) and CHIK/IRESv1 (SQ) groups. Little or no virema was noted after vaccination, and clinical response after vaccination as measured by implantable telemetry was unremarkable. Upon challenge with WT CHIKV, no vaccinated animals developed viremia, elevation in core temperature, or any other clinical hallmarks indicative of CHIK disease up to +45 days postinfection. In contrast, sham-vaccinated controls developed viremia acutely (+1-3d PI) and showed dramatic changes in core temperature, heart rate, and electrocardiogram measurements. The CHIK/IRES vaccine candidates are safe, highly immunogenic, and protect nonhuman primates from a robust experimental challenge model using WT CHIKV. Refinements in vaccine dose, as well as route of vaccination may be explored to evaluate the long term immunity associated with this vaccine product.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 基孔肯雅热 (CHIK) 是一种由基孔肯雅病毒（一种致病性甲病毒）引起的媒介传播病毒性疾病。 最初，我们在实验性非人类灵长类动物模型（束状支原体）（n = 3）中重现了病毒性疾病。 这种发病模型模拟了临床综合症，并显示了人类感染中自然疾病的特征。 该模型的建立是为了提供先进的监测系统，用于测试针对 CHIK 开发的候选疫苗的功效。 正在开发的 CHIK 疫苗基于含有小核糖核酸病毒内部核糖体进入位点 (IRES) 的构建体，以取代表达 CHIK 病毒 (CHIKV) 结构蛋白的亚基因组启动子。这种方法可以高度减弱病毒并防止蚊子感染，但保留免疫原性。 CHIK 非人灵长类动物模型用于在单独的实验中测试两种版本的疫苗（CHIK/IRESv1、v2）。 动物被植入远程无线电遥测技术，以连续监测临床体征（核心温度、呼吸频率、心率、心电图），并在疫苗接种后和攻击后采集样本进行病毒血症、抗体和病毒血症测定。 四只动物组 (N=16) 通过皮下 (SQ;CHIK/IRESv1) 或皮内 (ID;CHIK/IRESv2) 途径进行单剂量 5.5^log 初次疫苗接种，或用盐水进行假疫苗接种。 疫苗接种后大约 45 天，所有动物均用 6.0log 的野生型 CHIKV 攻击 SQ。 CHIK/IRESv2 疫苗组产生最高的中和抗体滴度，CHIK/IRESv1 (ID) 和 CHIK/IRESv1 (SQ) 组的平均滴度略低。 疫苗接种后几乎没有或没有观察到病毒瘤，并且通过植入式遥测技术测量的疫苗接种后的临床反应并不显着。 在用 WT CHIKV 攻击后，在感染后 45 天以内，没有接种疫苗的动物出现病毒血症、核心温度升高或指示 CHIK 疾病的任何其他临床特征。 相比之下，假接种疫苗的对照组则急性出现病毒血症（感染后 1-3 天），并且核心温度、心率和心电图测量结果显示出显着变化。 CHIK/IRES 候选疫苗安全、具有高免疫原性，可保护非人灵长类动物免受使用 WT CHIKV 的稳健实验挑战模型的影响。 可以探索疫苗剂量和疫苗接种途径的改进，以评估与该疫苗产品相关的长期免疫力。