Serologic assays for detection of Zika virus antibodies for clinical diagnosis and blood donor counseling

用于检测寨卡病毒抗体的血清学检测，用于临床诊断和献血者咨询

• 批准号: 10221519
• 负责人: Andrew E. Levin
• 金额: $ 98.93万
• 依托单位: KEPHERA DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221519
• 关键词: Acute; Address; Aedes; Affect; Africa; Agreement; Antibodies; Antigens; Arboviruses; Area; Awareness; Benign; Biological Assay; Birth; Bite; Blood; Blood Donations; Blood Screening; Blood Transfusion; Blood donor; Caribbean region; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Central America; Clinical; Clinical Research; Collection; Counseling; Culicidae; Dengue; Dengue Infection; Dengue Virus; Detection; Development; Diagnostic; Discrimination; Disease Outbreaks; Early Diagnosis; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemic; Epidemiology; Epitopes; Event; Exposure to; FDA Emergency Use Authorization; Family; Female; Flavivirus; Freezing; Funding; Generations; Geography; Grant; Guillain Barré Syndrome; Health; Human; Immunoglobulin G; Immunoglobulin M; Individual; Infant; Infection; International; Investigation; Japanese Encephalitis; Laboratories; Life; Link; Meningitis; Mexico; Microcephaly; Monitor; Mutation; Neurologic; Neutralization Tests; Nucleic Acid Amplification Tests; Nucleic Acids; Performance; Phase; Plasma; Population; Pregnant Women; Preparation; Procedures; Product Approvals; Production; Protocols documentation; Public Health; Puerto Rico; Ramp; Readiness; Recombinants; Recurrence; Reproducibility; Research; Research Design; Research Institute; Risk; Sampling; Serology; Serology test; Serum; Sexual Transmission; South America; Specificity; Spottings; Techniques; Testing; Time; Translating; Translations; Travel; United States; United States Food and Drug Administration; Vascular blood supply; Viral; Viremia; Virus; Virus Diseases; West Nile virus; Woman; World Health Organization; Yellow Fever; ZIKA; ZIKV infection; Zika Virus; adverse outcome; antibody test; authority; base; clinical Diagnosis; clinical diagnostics; congenital zika syndrome; cross reactivity; design; detection assay; detection sensitivity; diagnostic assay; disability; falls; in-vitro diagnostics; manufacturing scale-up; mosquito-borne; pathogenic virus; pre-clinical; preclinical study; prototype; public health emergency; research and development; scale up; secondary infection; seroconversion; stoichiometry; transmission process; validation studies; vector mosquito; viral RNA

PROJECT SUMMARY Zika virus, until recently an obscure mosquito-borne flavivirus from Africa, emerged rapidly in 2015-2016 to pose a major threat to public health in the Western Hemisphere. Having traveled across the Pacific, it quickly became endemic in South and Central America, Mexico and the Caribbean, carried by a compatible Aedes mosquito vector population. While Zika virus infection is typically relatively benign in the acute stage, it is has been causally linked to Congenital Zika Syndrome (CZS) exemplified by microcephaly in infants born to infected women, and to Guillain-Barré syndrome and meningitis. In addition to transmission by mosquito bite, Zika can be transmitted by sexual contact and through blood transfusions. The World Health Organization (WHO) declared Zika to be an international public health emergency, and the U.S. Centers for Disease Control (CDC) and the U.S. Food and Drug Administration (FDA) promptly ramped up efforts to prepare for and respond to the threat posed by Zika in the United States. Accordingly, FDA advised the temporary deferral of blood donors who had potential exposure in endemic areas such as Puerto Rico, and approved the Emergency Use Authorization (EUA) of investigational blood screening assays detecting viral RNA. However, the duration of viremia is very short, such that most individuals exposed to Zika virus are likely to be negative when tested for viral RNA, and the only means to detect prior exposure and associated health risks in such cases is through serologic tests for antibodies to the virus. As the emergence of Zika as a significant human health threat is quite recent, the development of diagnostic assays is still at an early stage, with the first generation of commercial products for serologic testing falling short of ideal performance. A major challenge has been the differentiation of Zika from Dengue virus infection, given that the two viruses are genetically closely related, are carried by the same mosquito vectors, and overlap geographically in regions of endemicity. A large fraction of the endemic population carries IgG to Dengue as a result of prior exposure, and the presence of this background Dengue IgG complicates the detection of Zika antibodies in the same individuals. While the 2015-2016 Zika outbreak has subsided, the potential for a recurrence requires public health readiness, including accurate assays to detect infection. This project addresses the critical need for a highly sensitive and specific serological assay for Zika virus infection that avoids cross- reactivity with Dengue and other viral infections. This assay is needed clinically to identify pregnant women at risk of CZS due to an earlier exposure, as well as epidemiologically to monitor the extent of Zika exposure in a possible outbreak where NAAT testing is impractical due to the time limitations for detection of viremia. In Phase I, we demonstrated feasibility of a prototype assay specific for the Zika virus that accurately distinguished human IgG and IgM antibodies to Zika virus from those elicited by Dengue virus infection. In Phase II, we plan to refine this assay into a commercial product ready for scaled up manufacture, validate it in preclinical studies and prepare for commercial launch for research use and subsequent regulatory submissions for vitro diagnostic use.

项目总结 寨卡病毒，直到最近还是一种来自非洲的鲜为人知的蚊媒黄病毒，在2015-2016年间迅速出现， 这是对西半球公共卫生的主要威胁。在横渡太平洋之后，它很快就变成了 在中南美洲、墨西哥和加勒比海地区流行，由相容的伊蚊携带 媒介种群。虽然寨卡病毒感染在急性期通常是相对良性的，但它一直是因果关系 与先天性寨卡病毒综合症(CZS)有关，例如受感染妇女所生婴儿的小头畸形症，以及 格林-巴利综合征和脑膜炎。除了通过蚊子叮咬传播外，寨卡病毒还可以传播 通过性接触和输血。世界卫生组织(WHO)宣布寨卡病毒 国际突发公共卫生事件，以及美国疾病控制中心(CDC)和美国食品和药物管理局 美国食品和药物管理局(FDA)迅速加大力度，准备和应对由 寨卡病毒在美国。因此，FDA建议暂时推迟那些有潜力的献血者 在波多黎各等流行区暴露，并批准了 调查性血液筛查检测病毒RNA。然而，病毒血症的持续时间很短，例如 大多数接触寨卡病毒的人在病毒RNA检测中可能是阴性的，而且唯一的 在这种情况下，检测先前接触和相关健康风险的手段是通过抗体的血清学测试。 对病毒来说。由于寨卡病毒作为对人类健康的重大威胁是最近才出现的， 诊断化验仍处于早期阶段，第一代用于血清学检测的商业产品 没有达到理想的表现。一项重大挑战是区分寨卡病毒和登革热病毒 鉴于这两种病毒在基因上关系密切，感染是由相同的蚊子媒介携带的， 并在特有区域内地理上重叠。很大一部分地方性人群携带有免疫球蛋白 登革热是先前接触的结果，这种背景登革热免疫球蛋白的存在使检测变得复杂 同一个人体内的寨卡病毒抗体。虽然2015-2016年寨卡病毒爆发已经消退，但潜在的 复发需要公共卫生准备，包括检测感染的准确化验。本项目致力于 迫切需要一种高度敏感和特异的寨卡病毒感染血清学检测方法，以避免交叉检测 对登革热和其他病毒感染的反应性。这个测试是临床上需要的，以确定孕妇在 早期接触寨卡病毒的风险，以及流行病学监测寨卡病毒感染的程度。 由于检测病毒血症的时间限制，NAAT检测不切实际的情况下可能爆发。同相 I，我们证明了一种针对寨卡病毒的原型检测的可行性，这种检测方法可以准确地区分人类 登革病毒感染者血清中抗寨卡病毒抗体的检测。在第二阶段，我们计划完善 将该分析转化为商业化产品，准备扩大生产，在临床前研究中验证它，并 为用于研究的商业发布和随后用于体外诊断的监管提交做好准备。