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Neglected Disease Pipeline > Diseases > Dengue fever Background Global Burden | Causative Agent & Transmission | Pathogenesis | Current Control Strategy | Existing Products | Get Involved What is Dengue Fever? Dengue fever (DF) is a viral disease transmitted by infected mosquitoes. DF causes severe, flu-like symptoms with high fever and extreme muscle and joint pain. Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are less common but more severe forms of the disease. DHF/DSS initially presents with very similar symptoms to DF. The disease then progresses to a stage where the blood vessels become permeable, or “leaky,” causing a breakdown of the circulatory system, fluid loss, and possibly death. Global Burden Dengue is common in the tropical and sub-tropical countries of Southeast Asia, the Pacific, and the Americas and is also found in Africa and the Eastern Mediterranean. In 2002, a record high of 69 countries reported dengue cases.1 The World Health Organization (WHO) estimates that 2.5 billion people are at risk for dengue infection. Approximately 50 million infections (1 million confirmed) occur each year resulting in 500,000 hospitalizations and 20,000 deaths.2 Countries with areas of dengue risk (WHO, 2008) The economic burden of dengue in India alone is estimated to be US$29.3 million.2 Based on a study of eight endemic countries, the estimated total economic burden of dengue is on the order of US$587 million annually. However, known underreporting of dengue infection could increase this estimate to nearly US$1.8 billion. Back to Top Causative Agent and Transmission Dengue is a positive strand RNA virus and a member of the genus Flavivirus. This genus also includes the viruses that cause West Nile and yellow fever. Dengue virus enters the human body through the saliva of an infected mosquito, invades immature dendritic cells in the skin, and is transported to lymph nodes where viral antigens activate the host immune response. In addition to dendritic cells, the virus replicates in the cytosol of macrophages, lymphocytes, and liver cells. Dengue is transmitted through the bite of the female mosquito of the genus Aedes (usually Aedes aegypti, the vector for dengue (photo: CDC/James Gathany/Frank Collins) A. aegypti, but occasionally by other species such as A. albopictus). A mosquito becomes infected with dengue virus upon taking a blood meal from an infected person. The virus can replicate in the mosquito and is transmitted to the next human host when the mosquito takes another blood meal. Dengue is unusual among arthropod-borne viruses in that it does not require an animal reservoir, and is instead maintained through human-mosquito-human transmission.3 Unlike many other disease vectors, A. aegypti is primarily associated with urban areas. This is attributed to its tendency to reproduce in small water pools, such as collect in tires, buckets, or uncovered water storage containers, which are common in populated settings. The eggs of the A. aegypti mosquito are extremely resilient, increasing the difficulty of vector control. Pathogenesis Dengue infection leads to multiple non-specific symptoms such as high fever, rash, and joint pain. It is unclear why, but a small percentage of dengue patients progress to DHF, which is further classified as DSS in its most advanced stages. The majority of DHF/DSS cases occur in children under the age of 15. DHF and DSS are both classified by increased permeability of the blood vessels resulting in a loss of plasma. Symptoms such as bleeding, profuse sweating, and shock are common; death due to dehydration from plasma loss can follow. As syndromes, dengue fever, DHF, and DSS express considerable symptom overlap and are often difficult to distinguish.4 Plans are underway to standardize case descriptions and, ideally, uncover ways of predicting which patients will progress to severe disease. The fact that the virus has generally been cleared from the body by the time DHF/DSS appear complicates the application of potential antivirals to patients presenting with the most serious symptoms.3 There are four distinct serotypes of dengue, DEN-1, DEN-2, DEN-3, and DEN-4. The prevalence of these strains traditionally varied geographically, but now all four serotypes are circulating in most endemic countries. If a patient is infected with one dengue serotype, they will be immune against subsequent infection by that same serotype. However, secondary infection with a new serotype greatly increases the risk of severe disease. There are at least two immunological phenomena that may contribute to the more severe outcome of secondary infection: 1. Antibody dependent enhancement (ADE): ADE is a phenomenon whereby sub-optimal levels of antibodies enhance viral spread rather than clearing the infection. Antibodies specific for a particular dengue serotype are produced during primary infection or acquired by infants from an immune mother. During a second infection with a distinct serotype, these antibodies bind to the new virus but are not sufficient to neutralize the particles. Cell types that naturally engulf immune complexes through “Fcg” receptors take up the bound virus. Increased viral replication and exacerbated inflammatory responses resulting from access to Fcg receptor-bearing cell types are thought to lead to severe disease. 2. “Original antigenic sin”: Original antigenic sin was a term first coined in the 1960s to describe a phenomenon observed for influenza virus whereby the human immune system works against itself when trying to mount a response. When the body has been infected before, it can undergo a memory immune response upon seeing the agent again. In the case of original antigenic sin, the body mistakenly mounts a memory response to a similar, previously seen pathogen rather than to the current infection –- for example against the primary, rather than secondary, dengue serotype. Because the memory response is dominant, the body cannot properly fight the new infection. Original antigenic sin can impact both humoral and cellular immune responses. ADE and original antigenic sin have implications for public health and for dengue vaccine design. If an immune response to one dengue serotype can worsen the outcome of infection with a distinct serotype, a vaccine that does not provide robust, long-lasting protection against all four serotypes could potentially increase disease severity for the non-vaccine strain(s) or as immunity wanes. Back to Top Current Control Strategy As there are no drugs or vaccines for the treatment or prevention of dengue, control programs focus on: 1. Integrated vector control (i.e., combined use of environmental modification and chemical or biology interventions to interrupt mosquito reproduction) 2. Active disease surveillance 3. Outbreak response preparedness 4. Training to improve diagnosis and patient management Existing Products Drugs There are currently no drugs approved for the treatment of dengue. Treatment instead focuses on palliative care to manage fever and prevent dehydration, especially for patients with severe disease. Treatment of dehydration associated with plasma loss in DHF can significantly improve patient outcomes, reducing case fatality from 20% down to <1% for DHF.5 Drugs in development for dengue are discussed in the next section. Vaccines There is currently no vaccine approved for the prevention of dengue. Vaccines in development are discussed in the next section. Diagnostics There are numerous diagnostic assays available for dengue based on a wide range of technologies: 1. Virus isolation 2. Serological testing (including IgM antibody capture ELISA, IgG ELISA, neutralization assays, and lateral flow device for NS1-specific antibodies) 3. Nucleic acid amplification (RT-PCR, real time RT-PCR, and nucleic acid-sequence based amplification assays) 4. Antigen detection (NS1 antigen detected by antigen capture ELISA) The gold standard for dengue diagnosis is viral isolation as this allows for the most specific characterization of the dengue virus. However, advanced laboratory facilities are required for this technique, limiting its application in the developing world. Serological assays are the most commonly used diagnostics for dengue. There are over 50 commercial kits available based on the IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) developed by the Armed Forces Research Institute of Medical Sciences. A rapid diagnostic test (RDT) for detection of antibodies specific to the dengue NS1 protein is also available. However, the RDT cannot distinguish between dengue virus serotypes. The WHO's Special Programme for Training and Research in Tropical Diseases (TDR) conducts laboratory-based evaluations of existing dengue virus diagnostics to ensure quality-control. Back to Top References 1. Guzman MG et al. (2010) “Dengue: a continuing global health threat.” Nature Reviews Microbiology 8: S7-S16. 2. WHO (2010) First WHO report on neglected tropical diseases 2010: working to overcome the global impact of neglected tropical diseases. 3. Whitehead SS et al. (2007) “Prospects for a dengue virus vaccine.” Nature Reviews Microbiology 5: 518-28. 4. Deen JL et al. (2006) “The WHO dengue classification and case definitions: time for a reassessment.” The Lancet 368: 170–173. 5. WHO Dengue and Dengue Hemorrhagic Fever Fact Sheet. Get Involved To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at [email protected]. Pipeline & Analysis Drugs | Vaccines | Diagnostics | Get Involved Drugs PIPELINE Product/Research Program Developers Discovery Pre-clinical Phase I Phase II Phase III ASB010 Autoimmune Technologies LLC CB5300 Canopus BioPharma PYN-18 Phynova Onconase® (Ranpirnase), Natural P31, and Recombinant Amphinase 2 National Institute of Allergy and Infectious Diseases Tamir Biotechnology DengueCide NanoViricides, Inc. NS3 protease inhibitors Janssen Pharmaceutica Medivir Novartis dengue drug discovery program Novartis Institute for Tropical Diseases Siga dengue drug discovery program Siga Technologies, Inc. NanoViricides dengue drug discovery program NanoViricides, Inc. Virion Dengue Biotron Anti-viral discovery program Emory Institute for Drug Discovery Zirus Neugene dengue antisense compound AVI BioPharma On Hold ANALYSIS There are currently no drugs in clinical stage development for the treatment of dengue. However, the increasing prevalence of dengue and the more recent re-emergence of dengue in Puerto Rico and the southern United States are raising interest in the development of new dengue treatments. There are currently nine pre-clinical or discovery stage projects including RNAi therapeutics and natural products (see Targets/Technologies). These programs are too preliminary to provide detailed analysis at this time. Back to Top Vaccines PIPELINE Product/Research Program Developers ChimeriVax™ Tetravalent Dengue Vaccine Sanofi Pasteur T-DEN GlaxoSmithKline Walter Reed Army Institute of Research DENVax Centers for Disease Control and Prevention InViragen, Inc. TetraVax-DV Johns Hopkins Bloomberg School of Public Health National Institute of Allergy and Infectious Diseases DEN1-80E Merck & Co., Inc. Subunit recombinant antigen (domain III) vaccine Cuban Center for Genetic Engineering and Biotechnology Pedro Kouri Tropical Medicine Institute Live attenuated chimeric YF-DEN vaccine Oswaldo Cruz Foundation Tetravalent DNA vaccine GenPhar Naval Medical Research Center Purified inactivated tetravalent vaccine GlaxoSmithKline Walter Reed Army Institute of Research AltraDENV Altravax AVI 6006 AVI BioPharma Live attenuated dengue vaccine Arbovax St. Kitts Biomedical Research Foundation Walter Reed Army Institute of Research Quadravalent dengue vaccine Inovio Pharmaceuticals, Inc. Discovery Pre-clinical Phase I Phase II Phase III ANALYSIS The vaccine development pipeline for dengue is primarily focused on the development of tetravalent live attenuated vaccines. The most advanced vaccine is the ChimeriVax Dengue vaccine that is being developed by Sanofi Pasteur. The ChimeriVax system is a live, attenuated recombinant virus constructed from an attenuated yellow fever virus in which the envelope protein genes of yellow fever are replaced with those of dengue virus. Sanofi Pasteur is using a similar approach to build vaccines for West Nile virus and Japanese encephalitis. The vaccine is designed to protect against all four dengue serotypes and is currently in phase III clinical trials. There are three additional tetravalent live attenuated vaccines in phase I and II trials. Additional vaccines in development include recombinant protein, DNA, and inactivated whole cell vaccines. Of these other technologies, only one recombinant protein-based vaccine is in clinical development. Strengths Weaknesses Opportunities Risks Live attenuated Serogroup targeted: DENV1-4 Most advanced clinical product Result of incomplete or short-term seroconversion is unknown (potential to worsen disease) Combination vaccine with other ChimeriVax-based flavivirus vaccines Long term follow-up of vaccinated patients will be needed to confirm ADE/original antigenic sin are not induced Published results for pre-clinical studies of non-human primates showed good protection using DEN2-80E and tetravalent vaccine Phase I using only 1 serotype rather than tetravalent Development of tetravalent vaccine Long term follow-up of vaccinated patients will be needed to confirm ADE/original antigenic sin are not induced Most advanced program: ChimeriVax, Phase III Recombinant protein Serotypes targeted: DENV1 (DENV2 and tetravalent have been evaluated in pre-clinical studies) Most advanced program: DEN1-80E, Phase I May be cheaper to produce and/or deliver than live attenuated vaccine Phase III product likely to be available many years in advance of this product Back to Top Diagnostics There are numerous diagnostic assays already available for dengue virus. An RDT that would diagnose dengue using saliva is in development as a means of expediting dengue diagnosis and treatment. However, while new tests, such as RDTs that can distinguish viral serotypes, would be useful for epidemiological purposes, vaccines and treatments are a higher priority for investment in dengue research and development. Get Involved To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at [email protected]. Tools Drugs | Vaccines | Diagnostics | Get Involved The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for dengue. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The tools for dengue are generally well developed. Drug Development Tools Basic Research: Target Identification Target Validation Genome: Sequenced (all four serotypes) Gene knock-outs: Yes, using infectious clones. Key databases: EBI 2can Support Portal Conditional gene knock-outs: Yes, temperature-sensitive mutants In vitro culture: Clinical isolates propagate poorly in vitro. Several infectious laboratory strains are available that grow in mosquito and mammalian cell cultures. Cell culture-infectious molecular clones available for all four serotypes. Transposon mutagenesis: Possible RNAi: Yes, by utilizing machinery of host cell Screening: Hit/Lead Identification Optimization Whole-cell screening assays: Yes, replicons Enzymatic screening assays: Yes, for protease (NS3), helicase (NS3), polymerase (NS5), methyltransferase (NS5) Other antisense technology: Yes, antisense oligonucleotides and ribozymes; DNAzymes possible for related flavivirus. Clinical Validation Pre-clinical Validation Animal models: Yes Wild-type mice relatively resistant so severely immune-compromized models using non-physiologic infection routes, adapted dengue strains, or engraftment of human cells are used Rhesus macaques and chimpanzees most consistently reproduce symptoms of dengue fever or DHF/DSS Miniature swine model is in development Monitoring treatment efficacy: Yes Availability of endpoints: Yes, viral clearance Availability of surrogate endpoints: No Access to clinical trial patients / sites: Yes Viability assays: Yes Transcription microarrays: Yes, of infected cells Proteomics: Yes Crystal structures: Yes Back to Top Vaccine Development Tools Basic Research: Immune Response Characterization Clinical Validation Antigen Identification See drug development tools above Predictive animal models: Animal models available but limited predictive value due to immunodeficiency and/or inability to mimic human disease states Detection of endogenous antigen specific response in clinical samples: Yes, neutralizing antibodies against E protein provide lifelong protection against homologous strains Surrogate markers of protection: Yes, neutralizing antibodies can be detected by plaque reduction neutralization technique (PRNT) Challenge studies possible: No Natural immunity well characterized: Natural immunity is well understood for repeated infection with a single viral strain, but still subject of study for heterotypic infections Diagnostic Development Tools Basic Research: Biomarker Identification See drug development tools above Biomarker Validation Biomarkers known: Yes, viral RNA, proteins, and antibodies detectable Access to clinical samples: Yes Clinical Validation Access to clinical trial patients/sites: Yes Treatment available if diagnosed: No specific antivirals, supportive and rehydration therapy is standard Possible sample types: Serum, plasma, blood, saliva, urine Back to Top Get Involved To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at [email protected]. Product Details ACA-ELISA Synonyms: Antigen-capture anti-dengue ELISA ACA-ELISA Notes: Disease: Dengue fever Technology: Immunoassay Specific Indication: Secondary dengue infection Sample of Type: Saliva Portability: Peripheral laboratory Training Required: Moderate Clinical Trials: Publications: 9574674 21572982 AltraDENV Synonyms: AltraDENV Dengue Tetravalent Vaccine Disease: Dengue fever Target/Technology: DNA vaccines Specific Indication: Preventive Mechanism of Action: Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: Anti-viral discovery program Synonyms: Anti-viral discovery program Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: Host cell-targeted therapy Product Type: Drug PRV Elegible? Yes Notes: Clinical Trials: Molecule Class: Administration Route: Publications: ASB010 Synonyms: ASB010 Disease: Dengue fever Target/Technology: Natural products Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: AVI 6006 Synonyms: AVI 6006 Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: CB5300 Synonyms: CB5300 Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: ChimeriVax™ Tetravalent Dengue Vaccine Synonyms: CYD Dengue vaccine ChimeriVax™ Tetravalent Dengue Vaccine Disease: Dengue fever Target/Technology: Viral vector vaccines Specific Indication: Mechanism of Action: Preventive, serotypes 1, 2, 3, and 4 Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: NCT01134263 NCT00993447 NCT01064141 NCT00880893 NCT01187433 NCT00740155 NCT00617344 NCT00875524 NCT00842530 NCT00788151 DEN1-80E Synonyms: DEN1-80E HBV-001 D1 Recombinant E subunit vaccine Disease: Dengue fever Target/Technology: Recombinant/purified protein vaccines Specific Indication: Preventive, serotype 1 Mechanism of Action: Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: NCT00936429 20097152 DengueCide Synonyms: DengueCide Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: DENVax Synonyms: DENVax Disease: Dengue fever Target/Technology: Live attenuated vaccines Specific Indication: Preventive, serotypes 1, 2, 3, and 4 Mechanism of Action: Product Type: Vaccine Administration Route: Molecule Class: PRV Elegible? Yes Notes: Clinical Trials: Publications: NCT01224639 21633037 Live attenuated chimeric YF-DEN vaccine Synonyms: Live attenuated chimeric YF-DEN vaccine Disease: Dengue fever Target/Technology: Live attenuated vaccines Specific Indication: Mechanism of Action: Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? No Notes: Clinical Trials: Publications: 21079655 Live attenuated dengue vaccine Synonyms: Live attenuated dengue vaccine Disease: Dengue fever Target/Technology: Live attenuated vaccines Specific Indication: Mechanism of Action: deletion of genes encoding viral envelope glycoproteins Product Type: Vaccine PRV Elegible? Yes Notes: Clinical Trials: NanoViricides dengue drug discovery program Molecule Class: Administration Route: Publications: Synonyms: NanoViricides dengue drug discovery program Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: Neugene dengue antisense compound Synonyms: Neugene dengue antisense compound Disease: Dengue fever Target/Technology: RNAi therapeutic Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: Novartis dengue drug discovery program Synonyms: Novartis dengue drug discovery program Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: NS3 protease inhibitors Synonyms: NS3 protease inhibitors Disease: Dengue fever Target/Technology: Proteases Specific Indication: Mechanism of Action: Product Type: Molecule Class: Drug Administration Route: PRV Elegible? No Notes: Clinical Trials: Publications: Onconase® (Ranpirnase), Natural P31, and Recombinant Amphinase 2 Synonyms: Onconase® (Ranpirnase), Natural P31, and Recombinant Amphinase 2 Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: RNase (triggers apoptosis) Product Type: Drug PRV Elegible? Yes Notes: Clinical Trials: Molecule Class: Administration Route: Publications: Purified inactivated tetravalent vaccine Synonyms: Purified inactivated tetravalent vaccine Disease: Dengue fever Target/Technology: Inactivated vaccines Specific Indication: Preventive Mechanism of Action: Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? No Notes: Clinical Trials: Publications: 21079655 PYN-18 Synonyms: PYN-18 Disease: Dengue fever Target/Technology: Natural products Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: PRV Elegible? Yes Administration Route: Notes: Clinical Trials: Publications: Quadravalent dengue vaccine Synonyms: Quadravalent dengue vaccine Disease: Dengue fever Target/Technology: DNA vaccines Specific Indication: Preventive, all four serotypes Mechanism of Action: Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: Siga dengue drug discovery program Synonyms: Siga dengue drug discovery program Disease: Dengue fever Target/Technology: Unknown Specific Indication: Mechanism of Action: Product Type: Drug Molecule Class: Administration Route: PRV Elegible? Yes Notes: Clinical Trials: Publications: Subunit recombinant antigen (domain III) vaccine Synonyms: Subunit recombinant antigen (domain III) vaccine Disease: Dengue fever Target/Technology: Recombinant/purified protein vaccines Specific Indication: Preventive Mechanism of Action: Chimeric domain III protein fused to p64k of Neisseria meningitidis Product Type: Vaccine PRV Elegible? No Notes: Clinical Trials: Molecule Class: Administration Route: Publications: 21079655 T-DEN Synonyms: T-DEN Disease: Dengue fever Target/Technology: Live attenuated vaccines Specific Indication: Preventive, serotypes 1, 2, 3, and 4 Mechanism of Action: Product Type: Vaccine Administration Route: Molecule Class: PRV Elegible? Yes Notes: Clinical Trials: Publications: NCT00239577 NCT00468858 NCT00350337 NCT00384670 NCT00370682 NCT00322049 Tetravalent DNA vaccine Synonyms: Tetravalent DNA vaccine Disease: Dengue fever Target/Technology: DNA vaccines Specific Indication: Preventive Mechanism of Action: Product Type: Vaccine Molecule Class: Administration Route: PRV Elegible? No Notes: Clinical Trials: Publications: 21079655 TetraVax-DV Synonyms: TetraVax-DV Disease: Dengue fever Target/Technology: Live attenuated vaccines Specific Indication: Preventive, serotypes 1, 2, 3, and 4 Mechanism of Action: Product Type: Vaccine Administration Route: Molecule Class: PRV Elegible? Yes Notes: Clinical Trials: Publications: NCT01072786 Virion Dengue Synonyms: Virion Dengue Disease: Dengue fever Target/Technology: Ion channels Specific Indication: Mechanism of Action: M protein inhibitor; blocks the ion channel activity of viroporins Product Type: Drug PRV Elegible? No Notes: Clinical Trials: Molecule Class: Administration Route: Publications: Developer Details Janssen Pharmaceutica (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever NS3 protease inhibitors Discovery Medivir (Sweden) Type Disease Product/Research Program Current Phase Drug Dengue fever NS3 protease inhibitors Discovery Pedro Kouri Tropical Medicine Institute (Cuba) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Subunit recombinant antigen (domain III) vaccine Pre-clinical Cuban Center for Genetic Engineering and Biotechnology (Cuba) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Subunit recombinant antigen (domain III) vaccine Pre-clinical Oswaldo Cruz Foundation (Brazil) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Live attenuated chimeric YF-DEN vaccine Pre-clinical Naval Medical Research Center (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Tetravalent DNA vaccine Pre-clinical GenPhar (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Tetravalent DNA vaccine Pre-clinical Walter Reed Army Institute of Research (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Purified inactivated tetravalent vaccine Pre-clinical Walter Reed Army Institute of Research (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever T-DEN Phase II Walter Reed Army Institute of Research (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Live attenuated dengue vaccine Pre-clinical GlaxoSmithKline (United Kingdom) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Purified inactivated tetravalent vaccine Pre-clinical GlaxoSmithKline (United Kingdom) Type Disease Product/Research Program Current Phase Vaccine Dengue fever T-DEN Phase II Sanofi Pasteur (France) Type Disease Product/Research Program Current Phase Vaccine Dengue fever ChimeriVax™ Tetravalent Dengue Vaccine Phase III Centers for Disease Control and Prevention (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever DENVax Phase I InViragen, Inc. (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever DENVax Phase I National Institute of Allergy and Infectious Diseases (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever Onconase® (Ranpirnase), Natural P31, and Recombinant Amphinase 2 Pre-clinical National Institute of Allergy and Infectious Diseases (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever TetraVax-DV Phase I Johns Hopkins Bloomberg School of Public Health (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever TetraVax-DV Phase I Merck & Co., Inc. (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever DEN1-80E Phase I Novartis Institute for Tropical Diseases (Singapore) Type Disease Product/Research Program Current Phase Drug Dengue fever Novartis dengue drug discovery program Discovery Siga Technologies, Inc. (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever Siga dengue drug discovery program Discovery Autoimmune Technologies LLC (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever ASB010 Pre-clinical AVI BioPharma (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever Neugene dengue antisense compound Pre-clinical AVI BioPharma (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever AVI 6006 Pre-clinical Canopus BioPharma (Ireland) Type Disease Product/Research Program Current Phase Drug Dengue fever CB5300 Pre-clinical NanoViricides, Inc. (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever NanoViricides dengue drug discovery program Discovery NanoViricides, Inc. (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever DengueCide Pre-clinical Phynova (United Kingdom) Type Disease Product/Research Program Current Phase Drug Dengue fever PYN-18 Pre-clinical Tamir Biotechnology (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever Onconase® (Ranpirnase), Natural P31, and Recombinant Amphinase 2 Pre-clinical Environmental Health Institute (Singapore) Type Disease Product/Research Program Current Phase Diagnostic Dengue fever ACA-ELISA Pre-clinical Altravax (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever AltraDENV Pre-clinical Biotron (Australia) Type Disease Product/Research Program Current Phase Drug Dengue fever Virion Dengue Discovery St. Kitts Biomedical Research Foundation (St. Kitts and Nevis) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Live attenuated dengue vaccine Pre-clinical Arbovax (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Live attenuated dengue vaccine Pre-clinical Inovio Pharmaceuticals, Inc. (United States) Type Disease Product/Research Program Current Phase Vaccine Dengue fever Quadravalent dengue vaccine Pre-clinical Emory Institute for Drug Discovery (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever Anti-viral discovery program Discovery Zirus (United States) Type Disease Product/Research Program Current Phase Drug Dengue fever Anti-viral discovery program Discovery