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: 10081089
• 负责人: Andrew E. Levin
• 金额: $ 100万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081089
• 关键词: Acute; Address; Aedes; Affect; Africa; Agreement; Antibodies; Antigens; Arboviruses; Area; Authorization documentation; 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; Emergency Situation; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemic; Epidemiology; Epitopes; Event; Exposure to; Family; Female; Flavivirus; Freezing; Funding; Generations; Geography; Grant; Guillain-Barré Syndrome; Health; Human; Immunoglobulin G; Immunoglobulin M; In Vitro; 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; Serologic tests; Serological; 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; authority; base; clinical Diagnosis; clinical diagnostics; congenital zika syndrome; cross reactivity; design; diagnostic assay; disability; falls; 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.

项目摘要 寨卡病毒，直到最近一种来自非洲的不明蚊媒黄病毒，在2015 - 2016年迅速出现， 对西半球公众健康的一个主要威胁。在穿越太平洋后，它很快成为 在南美洲和中美洲、墨西哥和加勒比地区流行，由一种相容的伊蚊携带 病媒种群虽然寨卡病毒感染在急性期通常相对良性，但它已成为一种因果关系。 与先天性寨卡综合征（CZS）有关，例如受感染妇女所生婴儿的小头畸形，以及 格林-巴利综合征和脑膜炎除了通过蚊虫叮咬传播外，寨卡还可通过 通过性接触和输血世界卫生组织（WHO）宣布寨卡为 国际公共卫生紧急情况，美国疾病控制中心（CDC）和美国食品 美国食品和药物管理局（FDA）迅速加大了努力，准备和应对 寨卡病毒在美国因此，FDA建议暂时推迟有潜力的献血者， 波多黎各等流行地区的暴露，并批准了紧急使用授权（EUA）， 检测病毒RNA的研究性血液筛查试验。然而，病毒血症的持续时间很短， 大多数暴露于寨卡病毒的个体在检测病毒RNA时可能呈阴性， 在这种情况下，检测先前接触和相关健康风险的方法是通过抗体血清学试验 对病毒的反应由于寨卡病毒作为一种重大的人类健康威胁的出现是最近才出现的， 诊断检测仍处于早期阶段，第一代商业产品用于血清学检测 达不到理想的性能。一个主要的挑战是将寨卡病毒与登革热病毒区分开来 由于这两种病毒在遗传上密切相关，感染是由相同的蚊子媒介传播的， 并且在地方病流行的地区有地理重叠。很大一部分地方性人群携带IgG， 由于先前暴露而导致登革热，并且这种背景登革热IgG的存在使检测复杂化 寨卡病毒抗体在同一个人。虽然2015 - 2016年寨卡疫情已经消退，但 复发需要公共卫生做好准备，包括检测感染的准确化验。该项目涉及 迫切需要一种高度敏感和特异性的寨卡病毒感染血清学检测方法， 与登革热和其他病毒感染的反应性。临床上需要这种检测来识别孕妇， 由于早期暴露而导致的CZS风险，以及流行病学监测Zika暴露的程度， 由于检测病毒血症的时间限制，NAAT检测不切实际的可能爆发。同相 我们证明了寨卡病毒特异性原型检测的可行性，该检测可以准确区分人类 寨卡病毒的IgG和IgM抗体来自登革热病毒感染引起的那些。在第二阶段，我们计划改进 将该测定转化为商业产品，准备用于规模化生产，在临床前研究中对其进行验证， 准备用于研究用途的商业发布和随后用于体外诊断用途的监管申报。