Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Excivion Ltd., Cambridge, United Kingdom.
Front Immunol. 2021 Jul 23;12:703887. doi: 10.3389/fimmu.2021.703887. eCollection 2021.
The only licensed dengue vaccine, Dengvaxia, increases risk of severe dengue when given to individuals without prior dengue virus (DENV) infection but is protective against future disease in those with prior DENV immunity. The World Health Organization has recommended using rapid diagnostic tests (RDT) to determine history of prior DENV infection and suitability for vaccination. Dengue experts recommend that these assays be highly specific (≥98%) to avoid erroneously vaccinating individuals without prior DENV infection, as well as be sensitive enough (≥95%) to detect individuals with a single prior DENV infection. We evaluated one existing and two newly developed anti-flavivirus RDTs using samples collected >6 months post-infection from individuals in non-endemic and DENV and ZIKV endemic areas. We first evaluated the IgG component of the SD BIOLINE Dengue IgG/IgM RDT, which was developed to assist in confirming acute/recent DENV infections (n=93 samples). When evaluated following the manufacturer's instructions, the SD BIOLINE Dengue RDT had 100% specificity for both non-endemic and endemic samples but low sensitivity for detecting DENV seropositivity (0% non-endemic, 41% endemic). Sensitivity increased (53% non-endemic, 98% endemic) when tests were allowed to run beyond manufacturer recommendations (0.5 up to 3 hours), but specificity decreased in endemic samples (36%). When tests were evaluated using a quantitative reader, optimal specificity could be achieved (≥98%) while still retaining sensitivity at earlier timepoints in non-endemic (44-88%) and endemic samples (31-55%). We next evaluated novel dengue and Zika RDTs developed by Excivion to detect prior DENV or ZIKV infections and reduce cross-flavivirus reactivity (n=207 samples). When evaluated visually, the Excivion Dengue RDT had sensitivity and specificity values of 79%, but when evaluated with a quantitative reader, optimal specificity could be achieved (≥98%) while still maintaining moderate sensitivity (48-75%). The Excivion Zika RDT had high specificity (>98%) and sensitivity (>93%) when evaluated quantitatively, suggesting it may be used alongside dengue RDTs to minimize misclassification due to cross-reactivity. Our findings demonstrate the potential of RDTs to be used for dengue pre-vaccination screening to reduce vaccine-induced priming for severe dengue and show how assay design adaptations as well quantitative evaluation can further improve RDTs for this purpose.
唯一获得许可的登革热疫苗登革热疫苗（Dengvaxia）增加了未感染登革热病毒（DENV）个体发生重症登革热的风险，但对既往有 DENV 免疫力的个体具有预防未来疾病的作用。世界卫生组织建议使用快速诊断检测（RDT）来确定既往 DENV 感染史和疫苗接种的适用性。登革热专家建议这些检测应具有很高的特异性（≥98%），以避免错误地为没有既往 DENV 感染的个体接种疫苗，同时还应具有足够的敏感性（≥95%），以检测到仅有单次既往 DENV 感染的个体。我们使用在非流行区和登革热和寨卡病毒流行区采集的感染后>6 个月的样本，评估了一种现有的和两种新开发的抗黄病毒 RDT。我们首先评估了 SD BIOLINE 登革热 IgG/IgM RDT 的 IgG 成分，该 RDT 旨在协助确认急性/近期登革热感染（n=93 个样本）。按照制造商的说明进行评估时，SD BIOLINE 登革热 RDT 对非流行区和流行区样本的特异性均为 100%，但对检测 DENV 血清阳性的敏感性较低（非流行区为 0%，流行区为 41%）。当允许检测时间超过制造商建议的时间（0.5 至 3 小时）时，敏感性增加（非流行区为 53%，流行区为 98%），但在流行区样本中特异性降低（36%）。当使用定量读取器评估检测时，在非流行区（44-88%）和流行区样本（31-55%）中，可以在早期实现最佳特异性（≥98%），同时仍然保持敏感性。接下来，我们评估了由 Excivion 开发的用于检测既往 DENV 或 ZIKV 感染并减少交叉黄病毒反应性的新型登革热和寨卡病毒 RDT（n=207 个样本）。从视觉上评估时，Excivion 登革热 RDT 的敏感性和特异性值为 79%，但使用定量读取器评估时，最佳特异性（≥98%）可以实现，同时仍然保持中等敏感性（48-75%）。Excivion 寨卡病毒 RDT 的定量评估显示出很高的特异性（>98%）和敏感性（>93%），表明它可以与登革热 RDT 一起使用，以最大程度地减少由于交叉反应性引起的错误分类。我们的研究结果表明 RDT 具有用于登革热疫苗接种前筛查的潜力，可以减少疫苗引起的重症登革热的引发作用，并表明检测设计的适应性和定量评估如何进一步提高 RDT 的这一用途。
