Abstract
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.
Highlights
Dengue viruses 1 to 4 (DENV1-4) are mosquito-borne flaviviruses that cause about 105 million infections globally each year [1]
We evaluated a commonly used dengue RDT (SD BIOLINE Dengue IgG/IgM) and report for the first time the evaluation of new dengue and Zika RDTs developed by Excivion, which use a modified E antigen to distinguish previous DENV and Zika virus (ZIKV) immunity
We found quantitative evaluation can improve RDT performance, especially for the Excivion Zika RDT, but the SD BIOLINE Dengue IgG/IgM and Excivion Dengue RDT still require further development to be used as optimal dengue pre-vaccination screening assays
Summary
Dengue viruses 1 to 4 (DENV1-4) are mosquito-borne flaviviruses that cause about 105 million infections globally each year [1]. Primary infection with one DENV serotype induces long-term immunological protection against that specific serotype but can increase the risk of developing severe dengue disease during secondary infection by one of the other three serotypes [6, 7]. After recovering from a secondary DENV infection, individuals are much less likely to develop severe dengue disease upon subsequent infection [8]. This has led researchers to conclude that having sequential DENV infections with two distinct serotypes can induce enduring immunological cross-protection against all four DENV serotypes [9]
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