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.

项目概要 寨卡病毒直到最近还是一种来自非洲的不起眼的蚊媒黄病毒，在 2015 年至 2016 年迅速出现， 对西半球公共卫生的重大威胁。跨越太平洋后，它很快就成为 在南美洲和中美洲、墨西哥和加勒比海地区流行，由相容的伊蚊携带 向量人口。虽然寨卡病毒感染在急性阶段通常相对良性，但它已成为因果关系 与先天性寨卡综合症（CZS）有关，例如受感染妇女所生婴儿的小头畸形，以及 吉兰-巴利综合征和脑膜炎。除了通过蚊虫叮咬传播之外，寨卡病毒还可以传播 通过性接触和输血。世界卫生组织（WHO）宣布寨卡病毒为 国际公共卫生紧急事件、美国疾病控制中心 (CDC) 和美国食品和药物管理局 药品监督管理局 (FDA) 迅速加大力度，准备并应对病毒带来的威胁 寨卡在美国。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 的研究性血液筛查分析。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进行病毒 RNA 检测时可能呈阴性，而唯一 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血清学检测 到病毒。由于寨卡病毒作为对人类健康的重大威胁才刚刚出现，因此开发 诊断分析仍处于早期阶段，第一代商业产品用于血清学检测 达不到理想的表现。一个主要挑战是区分寨卡病毒和登革热病毒 鉴于这两种病毒在遗传上密切相关，因此感染是由相同的蚊子媒介携带的， 并且在流行地区地理上重叠。很大一部分流行人群携带 IgG 登革热是先前暴露的结果，并且这种背景登革热 IgG 的存在使检测变得复杂 同一个人体内有寨卡病毒抗体。虽然 2015-2016 年寨卡疫情已经平息，但 复发需要公共卫生准备，包括检测感染的准确检测。该项目地址 迫切需要针对寨卡病毒感染进行高度灵敏和特异的血清学检测，以避免交叉感染 与登革热和其他病毒感染的反应。临床上需要该测定来识别孕妇 由于早期暴露而导致 CZS 的风险，以及从流行病学角度监测寨卡病毒暴露程度 由于检测病毒血症的时间限制，NAAT 检测不切实际，因此可能爆发疫情。同相 I，我们证明了针对寨卡病毒的原型检测的可行性，该检测可以准确地区分人类 登革热病毒感染引起的寨卡病毒 IgG 和 IgM 抗体。在第二阶段，我们计划完善 将该测定转化为商业产品，准备扩大生产，在临床前研究中对其进行验证，并 准备用于研究用途的商业发布以及随后用于体外诊断用途的监管提交。