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，非洲晦涩难懂 西半球对公共卫生的主要威胁。穿越太平洋后，它很快就变成了 墨西哥和加勒比海的南美内部人体，由兼容的伊德斯蚊子携带 载体人口。虽然寨卡病毒感染通常是急性阶段相对良性的，但它一直是因果 与先天性寨卡综合症（CZS）相关的小头畸形，在受感染妇女出生的婴儿和 到Guillain-Barré综合征和脑膜炎。除了通过蚊子叮咬传播，还可以传播Zika 通过性接触和通过输血。世界卫生组织（WHO）宣布Zika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 药物管理局（FDA）迅速加强了为准备和回应威胁的努力 寨卡在美国。根据FDA的说法，FDA建议有潜力的献血者 在波多黎各等内人体区域的接触，并批准了紧急使用授权（EUA） 研究性血液筛查测定检测病毒RNA。但是，病毒血症的持续时间很短，这样 在对病毒RNA进行测试时，大多数暴露于寨卡病毒的人可能是阴性的，唯一 在这种情况下检测先前暴露和相关健康风险的方法是通过抗体的血清学测试 到病毒。随着寨卡作为人类健康威胁的重大威胁的出现， 诊断测定仍处于早期阶段，第一代用于血清学测试的商业产品 缺乏理想的表现。一个主要的挑战是Zika与登革热病毒的区分 鉴于这两种病毒通常密切相关，感染是由同一蚊子向量携带的， 并在内在地区的地理上重叠。大部分的内在人群都带有IgG 登革热是由于先前的暴露而导致的，而这种背景IgG的存在使检测复杂化 同一个个体中的Zika抗体。虽然2015-2016寨卡爆发已经消退，但有可能 复发需要公共卫生准备就绪，包括准确的测定以检测感染。该项目解决 对寨卡病毒感染的高度敏感和特异性的血清学测定的迫切需求，避免了交叉 与登革热和其他病毒感染的反应性。需要在临床上进行此测定以识别 CZ因较早的暴露而发生的CZ风险以及流行病学以监测Zika暴露的程度 由于检测病毒血症的时间限制，因此NAAT测试是不切实际的可能爆发。在阶段 i，我们证明了针对寨卡病毒特有的原型测定的可行性 来自登革热病毒感染引起的Zika病毒的IgG和IgM抗体。在第二阶段，我们计划完善 该测定方法是准备扩大生产的商业产品，在临床前研究中进行验证 为研究使用和随后的监管提交准备的商业启动准备，以供体外诊断使用。