Dengue virus (DENV) is the most significant cause of arthropod-borne viral disease in humans, resulting in an estimated 50 million cases of dengue fever and over 450,000 cases of life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) each year. DENV has spread alarmingly across the globe over the past few decades, resulting in a dramatic increase in the number of dengue cases. As a result, DENV is now classified as a Category A pathogen of interest to the NIH. An effective dengue vaccine is critically needed, but has proven a significant challenge to develop because low affinity or low concentration antibodies that do not neutralize DENV can instead enhance infection. Thus, a vaccine that does not confer persistent protection against all four serotypes of the virus is potentially dangerous to recipients if they are subsequently infected. Large-scale human trials of several tetravalent dengue vaccines are imminent, but reliable, high- throughput tools for measuring protective humoral immunity in these trials are still lacking. The primary assay for detecting neutralizing antibodies in human serum is the plaque reduction neutralization test (PRNT). PRNT is poorly suited for measuring the magnitude, persistence, and specificity of the humoral response in large- scale vaccine trials. Analysis of large numbers of serum samples would be greatly facilitated by the availability of a new, quality-controlled, automated method to test for neutralizing antibodies specific for each DENV serotype. In response to this need, we developed the dengue reporter virus particle (DENV RVP) which can be used to monitor infection of cells in culture and to detect the presence of neutralizing antibodies in a test sample. We expect commercial DENV RVPs to be used in vaccine trials, clinical studies, and basic dengue research. To complete the development and validation of the DENV RVP, our Specific Aims are: Validate RVPs for use in clinical studies Verify suitability of RVPs for use in dengue vaccine trials Develop advanced production, quality control, and modifications of RVPs for clinical and research applications The global distribution of dengue virus is spreading rapidly - there are already 3 billion people (50% of the world's population) living at risk of infection, resulting in more than 50 million cases of illness each year, making it the most significant arthropod-borne viral pathogen of humans. Vaccine development and epidemiological surveillance and control programs are hampered by the lack of a rapid, easy method for measuring protective humoral immunity. The product that will result from this proposal, a kit containing the dengue reporter virus particle (DENV RVP), will be the first safe, high-throughput, standardized assay of DENV neutralizing antibodies, and the most immediate public health impact of its use by customers will be accelerating tetravalent vaccine efficacy trials.
| Katzelnick, Leah C; Ben-Shachar, Rotem; Mercado, Juan Carlos et al. (2018) Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua. Proc Natl Acad Sci U S A 115:10762-10767 |
| Biswas, Hope H; Gordon, Aubree; Nuñez, Andrea et al. (2015) Lower Low-Density Lipoprotein Cholesterol Levels Are Associated with Severe Dengue Outcome. PLoS Negl Trop Dis 9:e0003904 |
| Lau, Louis; Green, Angela M; Balmaseda, Angel et al. (2015) Antibody avidity following secondary dengue virus type 2 infection across a range of disease severity. J Clin Virol 69:63-7 |
| Christian, Elizabeth A; Kahle, Kristen M; Mattia, Kimberly et al. (2013) Atomic-level functional model of dengue virus Envelope protein infectivity. Proc Natl Acad Sci U S A 110:18662-7 |
| Parameswaran, Poornima; Liu, Yi; Roskin, Krishna M et al. (2013) Convergent antibody signatures in human dengue. Cell Host Microbe 13:691-700 |
| Zompi, Simona; Montoya, Magelda; Pohl, Marie O et al. (2012) Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans. PLoS Negl Trop Dis 6:e1568 |
| Parameswaran, Poornima; Charlebois, Patrick; Tellez, Yolanda et al. (2012) Genome-wide patterns of intrahuman dengue virus diversity reveal associations with viral phylogenetic clade and interhost diversity. J Virol 86:8546-58 |
| OhAinle, Molly; Balmaseda, Angel; Macalalad, Alexander R et al. (2011) Dynamics of dengue disease severity determined by the interplay between viral genetics and serotype-specific immunity. Sci Transl Med 3:114ra128 |
| Narvaez, Federico; Gutierrez, Gamaliel; Perez, Maria Angeles et al. (2011) Evaluation of the traditional and revised WHO classifications of Dengue disease severity. PLoS Negl Trop Dis 5:e1397 |
| Mattia, Kimberly; Puffer, Bridget A; Williams, Katherine L et al. (2011) Dengue reporter virus particles for measuring neutralizing antibodies against each of the four dengue serotypes. PLoS One 6:e27252 |
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