Multiplex serological assays to support arbovirus diagnosis, surveillance and vaccines

多重血清学检测支持虫媒病毒诊断、监测和疫苗开发

基本信息

批准号：
10611391
负责人：
Aravinda M. DeSilva
金额：
$ 41.36万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-05-11 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611391
关键词：
Acute Aedes Africa Alphavirus Americas Antibodies Antibody Response Antigens Arbovirus Infections Arboviruses Area Arthropods Asia Biological Assay Blood Central America Chikungunya virus Child Clinical Research Clinical Trials Cohort Studies Consumption Culicidae Dengue Dengue Infection Dengue Vaccine Dengue Virus Detection Development Diagnosis Disease Drops Ecology Environment Epidemic Epitopes Exposure to Far East Fever Flavivirus Flavivirus Infections Fluorescence Human Immune Immunity Individual Infection Laboratories Latin America Length Location Mayaro virus Measures Methods Microspheres Monitor Newly Diagnosed North Carolina Performance Persons Phase III Clinical Trials Population Proteins Recombinants Recording of previous events Risk Safety Sampling Serology Serology test Serotyping Serum Specificity Specimen Technology Testing Ticks Time Undifferentiated United States National Institutes of Health Urbanization Vaccines Viral Proteins Virion Virus Yellow fever virus Zika Virus Zika virus vaccine accurate diagnosis cross reactivity detection assay experience feeding minimally invasive multiplex assay neutralizing antibody novel predicting response programs sample collection severe dengue transmission process urban setting vaccine candidate vaccine development vaccine efficacy vaccine safety vaccine trial vaccine-induced antibodies viral detection viral transmission

项目摘要

Abstract At a global level, ongoing ecological, environmental and demographic changes favor the survival and expansion of several mosquito and tick species that transmit arboviruses. Aedes mosquito species that thrive in urban environments created by humans are responsible for epidemics of several flaviviruses [dengue virus (DENV) serotypes 1, 2, 3, 4; Zika virus (ZIKV); yellow fever virus (YFV)] and alphaviruses [chikungunya virus (CHIKV) and Mayaro virus (MAYV)]. Laboratory-based diagnosis and surveillance for arboviruses is difficult because most infected individuals are asymptomatic or develop a mild undifferentiated febrile illness. Serological assays have been developed for the detection of recent or past arboviral infections, but the utility of these assays is severely limited by antibody cross reactivity between related viruses. For example, when ZIKV emerged in many regions of the Americas where greater than 80% of the population was dengue-immune, with current serological assays, it was difficult, if not impossible, to identify infected individuals or monitor the spread of ZIKV at a population level, and likewise to now detect new DENV infections in areas that experienced intense ZIKV epidemics. Our studies over the past 10 years demonstrate that people exposed to flavivirus infections reliably develop antibodies to epitopes that are unique to each flavivirus as well as cross-reactive antibodies. Using our discoveries about the location of immunodominant virus type-specific epitopes, we have produced novel recombinant antigens and demonstrated their utility for the type-specific diagnosis of arboviruses. Under Specific Aim 1 of this proposal, we will build on these discoveries to develop a sample-sparing, microsphere bead-based multiplex assay for the type-specific and sensitive detection of recent or past arbovirus infections. Our initial studies will focus on 8 arboviruses transmitted by Aedes aegypti and Aedes albopictus mosquitos because these viruses share a similar ecology and co-circulate in the same human populations. At a second stage, we will expand the coverage of the assay to detect infections with other arboviruses transmitted by other mosquito species and ticks. Several tetravalent DENV and ZIKV vaccines are currently being evaluated in human clinical trials. While vaccine developers have relied on neutralizing antibodies as a correlate of protection, recent results from clinical trials demonstrate that neutralizing antibodies alone are a poor correlate of vaccine safety and efficacy. We have identified flavivirus type- and epitope-specific antibody responses that are better predictors than neutralizing antibodies of vaccine safety and efficacy. Under Specific aim 2 of this proposal, we will develop a sample-sparing microsphere-based assay for the detection of epitope-specific vaccine-induced antibody responses that are correlated with protective immunity to each of the DENV serotypes and ZIKV. The technological advances and products from this proposal will enhance our ability to efficiently monitor arbovirus infections at the individual and population levels and also support the development of arbovirus vaccines.

抽象的在全球范围内，持续的生态、环境和人口变化有利于生存和扩张几种传播虫媒病毒的蚊子和蜱虫。在城市中繁衍生息的伊蚊种类人类创造的环境导致多种黄病毒[登革热病毒（DENV）]的流行血清型1、2、3、4；寨卡病毒（ZIKV）；黄热病病毒（YFV）]和甲病毒[基孔肯雅病毒（CHIKV）和马亚罗病毒（MAYV）]。基于实验室的虫媒病毒诊断和监测很困难，因为大多数感染者没有症状或出现轻微的未分化发热性疾病。血清学检测已被开发用于检测最近或过去的虫媒病毒感染，但这些测定的实用性是受到相关病毒之间抗体交叉反应的严重限制。例如，当 ZIKV 在许多国家出现时在美洲地区，超过 80% 的人口对登革热免疫，目前的血清学检测中，即使不是不可能，也很难识别感染者或监测 ZIKV 的传播。人口水平，同样现在可以在 ZIKV 严重的地区检测新的 DENV 感染流行病。我们过去 10 年的研究表明，接触黄病毒感染的人可靠开发针对每种黄病毒独特表位的抗体以及交叉反应抗体。使用我们的关于免疫显性病毒类型特异性表位位置的发现，我们产生了新的重组抗原并证明了它们在虫媒病毒类型特异性诊断中的实用性。在下面该提案的具体目标 1，我们将在这些发现的基础上开发一种保留样本的、基于微球珠的多重检测，用于近期或过去的类型特异性和灵敏检测虫媒病毒感染。我们的初步研究将集中于由埃及伊蚊和伊蚊传播的 8 种虫媒病毒白纹伊蚊，因为这些病毒具有相似的生态并在同一人类体内共同传播人口。在第二阶段，我们将扩大检测的覆盖范围，以检测其他感染由其他蚊子和蜱传播的虫媒病毒。几种四价 DENV 和 ZIKV 疫苗目前正在人体临床试验中进行评估。虽然疫苗开发商依赖于中和抗体作为保护的相关性，最近的临床试验结果表明，中和抗体单独来看，疫苗安全性和有效性的相关性很差。我们已经确定了黄病毒类型和表位特异性抗体反应比中和抗体更能预测疫苗的安全性和有效性。在下面该提案的具体目标 2 是，我们将开发一种基于微球的样本保留检测方法，用于检测与保护性相关的表位特异性疫苗诱导的抗体反应对每种 DENV 血清型和 ZIKV 都有免疫力。由此产生的技术进步和产品该提案将增强我们在个人和群体层面有效监测虫媒病毒感染的能力并支持虫媒病毒疫苗的开发。