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Development of Nanoparticle Dengue Diagnostic Tests


Background: Dengue is a major public health problem in global tropical and subtropical areas. Primary prevention of this mosquito vector-borne (transmitted) disease is limited because vaccines are only in the late-stage development phase and vector control has been thus far unsuccessful. Dengue presents as an acute febrile illness often without signs or symptoms that differentiate it from other common diseases such as influenza and leptospirosis. Some patients progress to severe dengue near the end of their febrile period, which can result in death. Good clinical management, early in the course of dengue, prevents excess morbidity and mortality. Yet, early clinical management requires accurate laboratory diagnosis to differentiate dengue from other similar presenting diseases (e.g., influenza, leptospirosis). Until recently, dengue diagnostic testing was problematic because most patients present during the first days after onset of fever. Dengue virus (DENV) detection in serum is the only way to make the diagnosis, but anti-DENV IgM levels usually do not reach measurable levels until the critical phase. While molecular testing identifies most persons with dengue, this method is not widely available in developing countries where the disease is endemic. In addition, a soluble non-structural antigen (NS1) can be detected by immunoassay during this period, but is not as sensitive as molecular tests. Nanoparticle-based technology significantly increases the sensitivity of antigen and antibody detection tests and can be used for molecular diagnostics and in multiplex formats. Microresonator constructs and nanowire-based field effect transistors allow this technology to detect biolytes at low femtomolar concentrations. Surface enhanced Raman scattering (SERS) and extrinsic Raman labels (ERLs) have been used with metal nanoparticles (gold, silver) organic reporter molecules to magnify the Raman response by ~106, which surpasses fluorescence. Project Goal: To develop prototype dengue diagnostic tests that identify DENV by either molecular or immuno-detector systems (e.g., DENV specific nucleic acid, NS1 and E antigen) using nanoparticle-based technology that includes but is not limited to SERS and ERLs. The prototype test(s) should be developed as a biochip with a product profile that is amenable to a short-turn-around diagnostic result for use in resource constrained settings. Prototype test(s) would be judged as ‘acceptable’ if they detect a high proportion of dengue cases during the early phase of the febrile illness across all DENV serotypes, in primary and secondary infections and do not cross-react or misdiagnose other flavivirus infections or infections due to other causes of febrile illness that present with signs and symptoms similar to dengue. Impact: The availability of dengue diagnostic tests with high sensitivity and specificity that detect DENV infection soon after the onset of fever would greatly change the public health impact of current secondary prevention activities by improving clinical outcomes, and would provide the basis for evaluation of dengue vaccines following introduction. The market for dengue diagnostic tests has not been estimated, however, it is estimated that 40-60% of the world’s population reside in dengue endemic areas of the world (i.e., 100% cases of dengue are reported annually). Thus, one would expect there would be a many-fold great market for these tests each year.
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