Simultaneous Diagnosis of Dengue and Prognosis of Severe Dengue with a Single Point-of-Care Test

通过单点护理测试同时诊断登革热和严重登革热的预后

基本信息

批准号：
10475305
负责人：
Michael F Marusich
金额：
$ 29.99万
依托单位：
MABDX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-25 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475305
关键词：
Affect Antibodies Antibody-Dependent Enhancement Antigens Biological Assay Biological Markers Caring Clinical Cross Infection Data Decision Making Dengue Dengue Fever Dengue Infection Dengue Virus Detection Development Diagnosis Disease Drops Economic Burden Economics Epitopes Fatality rate Health Care Costs Hospitals Hour Human Immunity Individual Infection Life Ligands Monoclonal Antibodies Morbidity - disease rate Neutralization Tests Nucleic Acid Amplification Tests Patient Triage Patients Performance Phase Primary Infection Prognosis Proteins Publishing Reagent Reporter Resource-limited setting Resources Risk Risk Factors Serotyping Serum Specificity Supportive care Symptoms Testing Time Virus Diseases Visual antibody detection antigen detection base care outcomes clinical care clinical practice cross reactivity detection limit innovation lateral flow assay mortality mosquito-borne neutralizing antibody point of care point of care testing prognostic prognostic assays response secondary infection severe dengue

项目摘要

Dengue is the most common mosquito-borne viral disease and the cause of tremendous morbidity, mortality and economic burden. Yearly, there are an estimated 390 million (M) Dengue virus (DENV) infections, 96M symptomatic cases of Dengue Fever, and 0.5M cases of Severe Dengue. Untreated Severe Dengue has a fatality rate of 20-40%, but the fatality rate drops to less than 1% with timely in-hospital care. Unfortunately, Severe Dengue is now detected only by skillful observation of clinical warning signs, and progression to severe disease can occur within hours, making effective care difficult. Therefore, there is an urgent need for prognostic tests that can identify patients most likely to progress to Severe Dengue. There are four serotypes of DENV and infection with any one serotype generates strong, potentially life-long immunity to reinfection by that same serotype, due to development of neutralizing antibodies against serotype-specific epitopes. However, most antibodies induced by first infections are cross-reactive and non-neutralizing, and paradoxically can increase the risk of Severe Dengue in patients who suffer a later infection with a different serotype, due to a phenomenon termed Antibody-Dependent Enhancement (ADE). Heterotypic secondary infection is the major accepted risk factor for Severe Dengue but heterotypic secondary infections cannot now be identified within the time available for decision making to impact clinical care and outcome. We propose to create a simple, inexpensive, Point-of-Care (POC) test with visual plus/minus readout that will not only diagnose DENV infections early, but also be prognostic for Severe Dengue by quickly identifying patients who have secondary heterotypic infections. Phase I will create key biomarker detection reagents and incorporate them into two sets of serotype-specific Lateral Flow Assays (LFAs): 1) antigen LFAs to diagnose and serotype current infections (by detecting DENV- NS1 made during active infections), and 2) antibody LFAs to diagnose and serotype past infections (by detecting anti-DENV-antibodies made by patients in response to previous infections). Phase II will combine the individual assays in a single dual reporter LFA and then generate analytical and clinical performance data to support applications for CE Mark and FDA 510(k) clearance as a POC IVD. Innovation: The proposal creatively combines a well-established clinical observation (heterotypic secondary infection is the major risk factor for Severe Dengue), with two significant technical advances:1) rapid serotyping of current infections, and 2) rapid serotyping of past infections. With this combination we will develop a first-in- class POC test for DENV diagnosis and Severe Dengue prognosis that will change clinical practice. Impact: A simple, inexpensive POC test that provides timely prognostic results even in resource-limited settings would enable dramatic reductions in Dengue morbidity and mortality while reducing health care costs by allowing clinicians to focus resources effectively and efficiently on patients who may need them most.

登革热是最常见的蚊媒病毒性疾病，是造成巨大发病率和死亡率的原因和经济负担。每年估计有 3.9 亿 (M) 登革热病毒 (DENV) 感染，9600 万有症状的登革热病例和 50 万严重登革热病例。未经治疗的严重登革热有死亡率为20-40%，但通过及时的住院治疗，死亡率可降至1%以下。很遗憾，现在只能通过熟练观察临床警告信号以及进展为严重登革热来发现疾病可能在数小时内发生，使得有效的护理变得困难。因此，迫切需要预后测试可以识别最有可能发展为严重登革热的患者。有四种血清型 DENV 和任何一种血清型的感染都会产生强大的、可能终生的再感染免疫力由于针对血清型特异性表位的中和抗体的发展，具有相同的血清型。然而，大多数由首次感染引起的抗体是交叉反应性的且非中和性的，并且矛盾的是可能会增加后来感染不同血清型的患者患严重登革热的风险，因为这种现象被称为抗体依赖性增强（ADE）。异型继发感染是严重登革热的主要公认危险因素，但目前无法确定异型继发感染在可用于影响临床护理和结果的决策的时间内。我们建议创建一个简单、廉价的护理点 (POC) 测试，并带有视觉正/负读数这不仅可以早期诊断登革热病毒感染，还可以快速预测严重登革热识别继发异型感染的患者。第一阶段将创建关键的生物标志物检测试剂，并将其纳入两套血清型特异性试剂中侧向层析检测 (LFA)：1) 抗原 LFA 用于诊断当前感染并对其进行血清分型（通过检测 DENV- NS1 在活动性感染期间产生），以及 2）抗体 LFA 用于诊断过去的感染并对其进行血清分型（通过检测患者针对先前感染产生的抗 DENV 抗体）。第二阶段将合并在单个双报告器 LFA 中进行单独测定，然后生成分析和临床性能数据支持作为 POC IVD 申请 CE 标志和 FDA 510(k) 许可。创新：该提案创造性地结合了成熟的临床观察（异型二次感染是严重登革热的主要危险因素），具有两项重大技术进步：1）快速血清分型当前感染的情况，以及 2) 对过去感染的快速血清分型。通过这种组合，我们将开发出首创的用于 DENV 诊断和严重登革热预后的 POC 测试将改变临床实践。影响：一种简单、廉价的 POC 测试，即使在资源有限的情况下也能提供及时的预后结果环境将能够大幅降低登革热发病率和死亡率，同时降低医疗保健成本让临床医生能够有效地将资源集中在最需要的患者身上。