WJV  Vol.1 No.4 , November 2011
Dengue Vaccines: Challenge and Confrontation
Abstract: Dengue has been recognized as one of the most important vector-borne human diseases. The disease is induced by dengue virus infection resulting from the bite of an infected Aedes spp. mosquito after imbibing the tainted blood from animals or patients. Dynamic clinical spectrums ranging from asymptomatic, undifferentiated fever, typical dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) have been well documented. Initially, the disease was mainly restricted in tropical and subtropical zones. However, with factors such as ineffective vector control, frequency of human migration, unplanned urbanization, and changing climate temperature, the disease has been spotted at almost every territory of the earth. Dengue has been associated with human disease for more than two centuries. Although classic DF is viewed as a self-limited illness, subjects normally resolve within two weeks and recover without any noticeable complications or sequelae, some of these infected individuals may progress to life-threatening DHF/DSS, characterized with plasma leakage due to an increase in capillary permeability. The significantly increased public health threat and the burden of morbidity and mortality of dengue globally has caught the attention of public officials and prompted an action to find a way to contain and prevent the disease. The lack of specific dengue therapeutics has led to an emphasis on vaccine development, one of the best and effective strategies to reduce and prevent the illness. Making a dengue vaccine has been attempted more than six decades; although some of these products are in clinical trials, vaccine development for the prevention of dengue disease is still at its infancy. So far no dengue vaccine is available for the public. Dengue vaccine development may be hindered by the complexity of the clinical presentations, which implicates that multiple pathogenic mechanisms are involved in dengue disease. Some of these elements will be discussed in the current review. Opening up discussion on these pros and cons and engaging in more research to understand these features would not only improve the understanding of the pathogenesis of the dengue virus infection but also pave a new tactic to develop a safer and effective dengue vaccine.
Cite this paper: nullG. Perng, H. Lei, Y. Lin and K. Chokephaibulkit, "Dengue Vaccines: Challenge and Confrontation," World Journal of Vaccines, Vol. 1 No. 4, 2011, pp. 109-130. doi: 10.4236/wjv.2011.14012.

[1]   D. J. Gubler, “Dengue and Dengue Hemorrhagic Fever,” Clinical Microbiology Reviews, Vol. 11, No. 3, 1998, pp. 480-496.

[2]   B. R. Murphy and S. S. Whitehead, “Immune Response to Dengue Virus and Prospects for a Vaccine,” Annual Review of Immunology, Vol. 29, 2011, pp. 587-619. doi:10.1146/annurev-immunol-031210-101315

[3]   S. J. Thomas and T. P. Endy, “Vaccines for the Prevention of Dengue: Development Update,” Human Vaccines, Vol. 7, No. 6, 2011, pp. 674-684. doi:10.4161/hv.7.6.14985

[4]   D. P. Webster, J. Farrar and S. Rowland-Jones, “Progress towards a Dengue Vaccine,” Lancet Infectious Diseases, Vol. 9, No. 11, 2009, pp. 678-687. doi:10.1016/S1473-3099(09)70254-3

[5]   A. L. Rothman, “Immunity to Dengue Virus: A Tale of Original Antigenic Sin and Tropical Cytokine Storms,” Nature Review Immunology, Vol. 11, No. 8, 2011, pp. 532-543. doi:10.1038/nri30142011

[6]   J. Schmitz, J. Roehrig, A. Barrett and J. Hombach, “Next Generation Dengue Vaccines: A Review of Candidates in Preclinical Development,” Vaccine, Vol. 29, No. 42, 2011, pp. 7276-7284. doi:10.1016/j.vaccine.2011.07.017

[7]   S. Swaminathan, G. Batra and N. Khanna, “Dengue Vaccines: State of the Art,” Expert Opinion on Therapy Patents, Vol. 20, No. 6, 2010, pp. 819-835. doi:10.1517/13543771003767476

[8]   M. G. Gusman, “Dengue Vaccines: New Developments,” Drugs Future, Vol. 36, 2011, pp. 45-62.

[9]   WHO, “Dengue,” World Health Organization, 2004.

[10]   A. A. Hoffmann, B. L. Montgomery, J. Popovici, I. Iturbe-Ormaetxe, P. H. Johnson, F. Muzzi, et al., “Successful Establishment of Wolbachia in Aedes Populations to Suppress Dengue Transmission,” Nature, Vol. 476, No. 7361, 2011, pp. 454-457. doi:10.1038/nature10356

[11]   T. Walker, P. H. Johnson, L. A. Moreira, I. Iturbe-Ormaetxe, F. D. Frentiu, C. J. McMeniman, et al., “The wMel Wolbachia Strain Blocks Dengue and Invades Caged Aedes Aegypti Populations,” Nature, Vol. 476, No. 7361, 2011, pp. 450-453. doi:10.1038/nature10355

[12]   K. B. Anderson, S. Chunsuttiwat, A. Nisalak, M. P. Mammen, D. H. Libraty, A. L. Rothman, et al., “Burden of Symptomatic Dengue Infection in Children at Primary School in Thailand: A Prospective Study,” Lancet, Vol. 369, No. 9571, 2007, pp. 1452-1459. doi:10.1016/S0140-6736(07)60671-0

[13]   D. J. Gubler, “Epidemic Dengue/Dengue Hemorrhagic Fever as a Public Health, Social and Economic Problem in the 21st Century,” Trends in Microbiology, Vol. 10, No. 2, 2002, pp. 100-103.

[14]   J. A. Suaya, D. S. Shepard, J. B. Siqueira, C. T. Martelli, L. C. Lum, L. H. Tan, et al., “Cost of Dengue Cases in Eight Countries in the Americas and Asia: A Prospective Study,” The American Journal of Tropical Medicine and Hygiene, Vol. 80, No. 5, 2009, pp. 846-855.

[15]   WHO, “Dengue Guidelines for Diagnosis, Treatment, Prevention and Control,” Geneva, World Health Organization, 2009.

[16]   WHO, “Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control,” 2nd Edition, World Health Organization, Geneva, 1997.

[17]   J. G. Rigau-Perez, G. G. Clark, D. J. Gubler, P. Reiter, E. J. Sanders and A. V. Vorndam, “Dengue and Dengue Haemorrhagic Fever,” Lancet, Vol. 352, No. 9132, 1998, pp. 971-977.

[18]   J. Barniol, R. Gaczkowski, E. V. Barbato, R. V. da Cunha, D. Salgado, E. Martinez, et al., “Usefulness and Applicability of the Revised Dengue Case Classification by Disease: Multi-Centre Study in 18 Countries,” BMC Infectious Diseases, Vol. 11, 2011, p. 106. doi:10.1186/1471-2334-11-106

[19]   P. S. Basuki, Budiyanto, D. Puspitasari, D. Husada, W. Darmowandowo, Ismoedijanto, et al., “Application of Revised Dengue Classification Criteria as a Severity Marker of Dengue Viral Infection in Indonesia,” Southeast Asian Journal of Tropical Medicine and Public Health, Vol. 41, No. 5, 2010, pp. 1088-1094.

[20]   R. W. Boulton and E. G. Westaway, “Comparisons of Togaviruses: Sindbis Virus (Group A) and Kunjin Virus (Gr- oup B),” Virology, Vol. 49, No. 1, 1972, pp. 283-289.

[21]   G. R. Cleaves and D. T. Dubin, “Methylation Status of Intracellular Dengue Type 2 40 S RNA,” Virology, Vol. 96, No. 1, 1979, pp. 159-165. doi:10.1016/0042-6822(79)90181-8

[22]   G. Wengler and H. J. Gross, “Studies on Virus-Specific Nucleic Acids Synthesized in Vertebrate and Mosquito Cells Infected with Flaviviruses,” Virology, Vol. 89, No. 2, 1978, pp. 423-437. doi:10.1016/0042-6822(78)90185-X

[23]   G. W. Smith and P. J. Wright, “Synthesis of Proteins and Glycoproteins in Dengue Type 2 Virus-Infected Vero and Aedes Albopictus Cells,” Journal of General Virology, Vol. 66, No. 3, 1985, pp. 559-571. doi:10.1099/0022-1317-66-3-559

[24]   S. A. Stohlman, C. L. Wisseman, O. R. Eylar Jr. and D. J. Silverman, “Dengue Virus-Induced Modifications of Host Cell Membranes,” Journal of Virology, Vol. 16, No. 4, 1975, pp. 1017-1026.

[25]   D. J. Gubler and G. Kuno (Eds.), “Dengue and Dengue Hemorrhagic Fever,” CABI, Wallingford, 1997.

[26]   R. Perera and R. J. Kuhn, “Structural Proteomics of Dengue Virus,” Current Opinion in Microbiology, Vol. 11, No. 4, 2008, pp. 369-377. doi:10.1016/j.mib.2008.06.004

[27]   D. W. C. Beasley and A. D. Barrett, “The Infectious Agent,” In: S. B. Halstead, Eds., Dengue, Imperial College Press, London, 2008, pp. 29-73.

[28]   S. Sriurairatna and N. Bhamarapravati, “Replication of Dengue-2 Virus in Aedes Albopictus Mosquitoes. An Electron Microscopic Study,” The American Journal of Tropical Medicine and Hygiene, Vol. 26, No. 6, 1977, pp. 1199-1205.

[29]   S. Sriurairatna, N. Bhamarapravati, A. R. Diwan and S. B. Halstead, “Ultrastructural Studies on Dengue Virus Infection of Human Lymphoblasts,” Infection and Immunity, Vol. 20, No. 1, 1978, pp. 173-179.

[30]   J. R. Paul, J. L. Melnick and A. B. Sabin, “Experimental Attempts to Transmit Phlebotomus and Dengue Fevers to Chimpanzees,” Proceedings of the Society Experimental Biology and Medicine, Vol. 68, No.1, 1948, pp. 193-198. doi:10.3181/00379727-68-16431

[31]   R. J. Kuhn, W. Zhang, M. G. Rossmann, S. V. Pletnev, J. Corver, E. Lenches, et al., “Structure of Dengue Virus: Implications for Flavivirus Organization, Maturation, and Fusion,” Cell, Vol. 1108, No. 5, 2002, pp. 717-725. doi:10.1016/S0092-8674(02)00660-8

[32]   Y. Zhang, J. Corver, P. R. Chipman, W. Zhang, S. V. Pletnev, D. Sedlak, et al., “Structures of Immature Flavivirus Particles,” The EMBO Journal, Vol. 22, No. 11, 2003, pp. 2604-2613. doi:10.1093/emboj/cdg270

[33]   T. M. Stevens and R. W. Schlesinger, “Studies on the Nature of Dengue Viruses. I. Correlation of Particle Density, Infectivity, and RNA Content of Type 2 Virus,” Virology, Vol. 27, No.1, 1965, pp. 103-112. doi:10.1016/0042-6822(65)90147-9

[34]   T. J. Smith, W. E. Brandt, J. L. Swanson, J. M. McCown and E. L. Buescher, “Physical and Biological Properties of Dengue-2 Virus and Associated Antigens,” Journal of Virology, Vol. 5, No.4, 1970, pp. 524-532.

[35]   J. Junjhon, M. Lausumpao, S. Supasa, S. Noisakran, A. Songjaeng, P. Saraithong, et al., “Differential Modulation of prM Cleavage, Extracellular Particle Distribution, and Virus Infectivity by Conserved Residues at Nonfurin Consensus Positions of the Dengue Virus pr-M Junction,” Journal of Virology, Vol. 82, No. 21, 2008, pp. 10776- 10791. doi:10.1128/JVI.01180-08

[36]   F. Masciopinto, C. Giovani, S. Campagnoli, L. Galli- Stampino, P. Colombatto, M. Brunetto, et al., “Association of Hepatitis C Virus Envelope Proteins with Ex- osomes,” European Journal of Immunology, Vol. 34. No. 10, 2004, pp. 2834-2842. doi:10.1002/eji.200434887

[37]   S. B. Halstead, “Dengue,” Lancet, Vol. 370, No. 9599, 2007, pp. 1644-1652. doi:10.1016/S0140-6736(07)61687-0

[38]   E. C. Holmes and S. S. Burch, “The Causes and Consequences of Genetic Variation in Dengue Virus,” Trends in Microbiology, Vol. 8, No. 2, 2000, pp. 74-77. doi:10.1016/S0966-842X(99)01669-8

[39]   T. P. Monath, J. Arroyo, I. Levenbook, Z. X. Zhang, J. Catalan, K. Draper, et al., “Single Mutation in the Flavivirus Envelope Protein Hinge Region Increases Neu- rovirulence for Mice and Monkeys but Decreases Viscerotropism for Monkeys: Relevance to Development and Safety Testing of Live, Attenuated Vaccines,” Journal of Virology, Vol. 76, No. 4, 2002, pp. 1932-1943. doi:10.1128/JVI.76.4.1932-1943.2002

[40]   D. J. Gubler, “Dengue and Dengue Hemorrhagic Fever,” Clinical Microbiology Reviews, Vol. 11, No. 3, 1998, pp. 480-496. doi:10.1016/S0140-6736(97)12483-7

[41]   R. Rico-Hesse, “Dengue Virus Markers of Virulence and Pathogenicity,” Future Virology, Vol. 4, No. 6, 2009, pp. 581-594. doi:10.2217/fvl.09.51

[42]   K. C. Leitmeyer, D. W. Vaughn, D. M. Watts, R. Salas, I. Villalobos, de Chacon, et al., “Dengue Virus Structural Differences That Correlate with Pathogenesis,” Journal of Virology, Vol. 73, No.6, 1999, pp. 4738-4747.

[43]   E. R. Moxon and C. A. Siegrist, “The Next Decade of Vaccines: Societal and Scientific Challenges,” Lancet, Vol. 378, No. 9788, 2011, pp. 348-359. doi:10.1016/S0140-6736(11)60407-8

[44]   M. G. Guzman, S. B. Halstead, H. Artsob, P. Buchy, J. Farrar, D. J. Gubler, et al., “Dengue: A Continuing Glo- bal Threat,” Nature Review Microbiology, Vol. 8, No. 12, 2010, pp. S7016. doi:10.1038/nrmicro2460

[45]   D. W. Vaughn, S. Green, S. Kalayanarooj, B. L. Innis, S. Nimmannitya, S. Suntayakorn, et al., “Dengue in the Early Febrile Phase: Viremia and Antibody Responses,” Journal of Infectious Diseases, Vol. 176, No. 2, 1997, pp. 322-330. doi:10.1086/514048

[46]   J. S. Simmons, J. H. St. John and F. H. K. Reynolds, “Experimental Studies of Dengue,” Philippine Journal of Science, Vol. 44, 1932, pp. 1-251.

[47]   J. F. Siler, M. W. Hall and A. P. Hitchins, “Dengue: Its History, Epidemiology, Mechanism of Transmission, Etiology, Clinical Manifestations, Immunity and Prevention,” Philippine Journal of Science, Vol. 29, 1926, pp. 1-340.

[48]   I. Kurane, U. Kontny, J. Janus and F. A. Ennis, “Dengue-2 Virus Infection of Human Mononuclear Cell Lines and Establishment of Persistent Infections,” Archives of Virology, Vol. 110, No. 1-2, 1990, pp. 91-101. doi:10.1007/BF01310705

[49]   S. Yoksan and N. Bhamarapravati, “Localization of De- ngue Antigens in Tissue Specimens from Fatal Cases of Dengue Hemorrhagic Fever,” In: T. Pang and R. Pathmanathan, Eds., Proceedings of the International Conference on Dengue/Dengue Hemorrhagic Fever, University of Malaya, Kuala Lumpur, 1983, pp. 406-410.

[50]   L. Rosen and M. M. Khin, “Recovery of Virus from the Liver of Children with Fatal Dengue: Reflections on the Pathogenesis of the Disease and Its Possible Analogy with That of Yellow Fever,” Research in Virology, Vol. 140, No. 4, 1989, pp. 351-360. doi:10.1016/S0923-2516(89)80115-3

[51]   A. Nisalak, S. B. Halstead, P. Singharaj, S. Udomsakdi, S. W. Nye and K. Vinijchaikul, “Observations Related to Pathogenesis of Dengue Hemorrhagic Fever. 3. Virologic Studies of Fatal Disease,” The Yale Journal of Biology and Medicine, Vol. 42, No. 5, 1970, pp. 293-310.

[52]   K. Jessie, M. Y. Fong, S. Devi, S. K. Lam and K. T. Wong, “Localization of Dengue Virus in Naturally Infected Human Tissues, by Immunohistochemistry and in Situ hybridization,” Journal of Infectious Diseases, Vol. 189, No. 8, 2004, pp. 1411-1418. doi:10.1086/383043

[53]   S. B. Halstead, E. J. O’Rourke and A. C. Allison, “Dengue Viruses and Mononuclear Phagocytes. II. Identity of Blood and Tissue Leukocytes Supporting in Vitro Infection,” Journal of Experimental Medicine, Vol. 146, No. 1, 1977, pp. 218-229.

[54]   N. Bhamarapravati, “Pathology and Pahtogenesis of DHF. First ICMR Seminar on Dengue and Dengue Heomorrhagic Fever,” Kobe University School of Medicine, Kobe, 1980, pp. 207-216.

[55]   J. Farrar, “Clinical Features of Dengue,” In: S. B. Halstead, Eds., Dengue, Imperial College Press, London, 2008, pp. 171-191.

[56]   H. R. Bierman and E. R. Nelson, “Hematodepressive Virus Diseases of Thailand,” Annals of Internal Medicine, Vol. 62, 1965, pp. 867-884.

[57]   A. Dasaneyavaja and U. Charansri, “First Known Isolation of a Dengue Virus from Other Human Source than Blood. Symposium on Hemorrhagic Fever,” SEATO Me- dical Research Monograph, Bangkok, 1961, p. 61.

[58]   Y. C. Chan, K. A. Lim and B. C. Ho, “Recent Epidemics of Hemorrhagic Fever in Singapore,” Japanese Journal of Medical Science & Biology, Vol. 20, 1967, pp. 81-88.

[59]   S. B. Halstead, “The Alexander D. Langmuir Lecture. The Pathogenesis of Dengue. Molecular Epidemiology in Infectious Disease,” American Journal of Epidemiology, Vol. 114, No. 5, 1981, pp. 632-648.

[60]   S. Green and A. Rothman, “Immunopathological Mechanisms in Dengue and Dengue Hemorrhagic Fever,” Current Opinion in Infectious Diseases, Vol. 19, No. 5, 2006, pp. 429-436. doi:10.1097/01/qco.0000244047.31135.fa

[61]   N. J. Marchette, S. B. Halstead, W. A. Falkler, A. Stenhouse Jr. and D. Nash, “Studies on the Pathogenesis of Dengue Infection in Monkeys. 3. Sequential Distribution of Virus in Primary and Heterologous Infections,” Journal of Infectious Diseases, Vol. 128, No. 1, 1973, pp. 23- 30. doi:10.1093/infdis/128.1.23

[62]   S. B. Halstead, “Epidemiological Studies of Thai Haemorrhagic Fever, 1962-64,” Bulletin of World Health Organization, Vol. 35, No. 1, 1966, pp. 80-81.

[63]   S. B. Halstead, “Pathogenesis of Dengue: Challenges to Molecular Biology,” Science, Vol. 239, No. 4839, 1988, pp. 476-481.

[64]   S. J. Thomas, A. Nisalak, K. B. Anderson, D. H. Libraty, S. Kalayanarooj, D. W. Vaughn, et al., “Dengue Plaque Reduction Neutralization Test (PRNT) in Primary and Secondary dengue Virus Infections: How Alterations in Assay Conditions Impact Performance,” American Journal of Tropical Medicine and Hygiene, Vol. 81, No. 5, 2009, pp. 825-833. doi:10.4259/astmh.2009.08-0625

[65]   T. P. Endy, A. Nisalak, S. Chunsuttitwat, D. W. Vaughn, S. Green, F. A. Ennis, et al., “Relationship of Preexisting Dengue Virus (DV) Neutralizing Antibody Levels to Vir- emia and Severity of Disease in a Prospective Cohort Study of DV Infection in Thailand,” Journal of Infectious Diseases, Vol. 189, No. 6, 2004, pp. 990-1000.

[66]   C. C. Lin, Y. H. Huang, P. Y. Shu, H. S. Wu, Y. S. Lin, T. M. Yeh, et al., “Characteristic of Dengue Disease in Taiwan: 2002-2007,” American Journal of Tropical Medicine and Hygiene, Vol. 82, No. 4, 2010, pp. 731-739. doi:10.4269/astmh.2010.09-0549

[67]   A. Balmaseda, S. N. Hammond, L. Perez, Y. Tellez, S. I. Saborio, J. C. Mercado, et al., “Serotype-Specific Differences in Clinical Manifestations of Dengue,” American Journal of Tropical Medicine Hygiene, Vol. 74, No. 3, 2006, pp. 449-456.

[68]   E. Meltzer and E. Schwartz, “A Travel Medicine View of Dengue and Dengue Hemorrhagic Fever,” Travel Medicine and Infectious Diseases, Vol. 7, No. 5, 2009, pp. 278-283. doi:10.1016/j.tmaid.2009.05.002

[69]   D. H. Libraty, L. P. Acosta, V. Tallo, E. Segubre- Mercado, A. Bautista, J. A. Potts, et al., “A Prospective Nested Case-Control Study of Dengue in Infants: Rethinking and Refining the Antibody-Dependent Enhance- ment Dengue Hemorrhagic Fever Model,” PLoS Medicine, Vol. 6, No. 10, 2009, p. e1000171. doi:10.1371/journal.pmed.1000171

[70]   W. Ruangjirachuporn, S. Boonpucknavig and S. Nimmanitya, “Circulating Immune Complexes in Serum from Patients with Dengue Haemorrhagic Fever,” Clinical and Experimental Immunology, Vol. 36, No. 1, 1979, pp. 46- 53.

[71]   C. F. Lin, H. Y. Lei, C. C. Liu, H. S. Liu, T. M. Yeh, S. T. Wang, et al., “Generation of IgM Anti-Platelet Autoantibody in Dengue Patients,” Journal of Medical Virology, Vol. 63, No. 2, 2001, pp. 143-149. doi:10.1002/1096-9071(20000201)63:2<143::AID-JMV1009>3.0.CO;2-L

[72]   K. Oishi, S. Inoue, M. T. Cinco, E. M. Dimaano, M. T. Alera, J. A. Alfon, et al., “Correlation between Increased Platelet-Associated IgG and Thrombocytopenia in Secondary Dengue Virus Infections,” Journal of Medical Virology, Vol. 71, No. 2, 2003, pp. 259-264. doi:10.1002/jmv.10478

[73]   M. Saito, K. Oishi, S. Inoue, E. M. Dimaano, M. T. Alera, A. M. Robles, et al., “Association of Increased Platelet-Associated Immunoglobulins with Thrombocytopenia and the Severity of Disease in Secondary Dengue Virus Infections,” Clinical and Experimental Immunology, Vol. 138, No. 2, 2004, pp. 299-303. doi:10.1111/j.1365-2249.2004.02626.x

[74]   S. Honda, M. Saito, E. M. Dimaano, P. A. Morales, M. T. Alonzo, L. A. Suarez, et al., “Increased Phagocytosis of Platelets from Patients with Secondary Dengue Virus Infection by Human Macrophages,” American Journal of Tropical Medicine and Hygiene, Vol. 80, No. 5, 2009, pp. 841-845.

[75]   R. W. Faint, “Platelet-Neutrophil Interactions: Their Significance,” Blood Reviews, Vol. 6, No. 2, 1992, pp. 83-91. doi:10.1016/0268-960X(92)90010-N

[76]   J. J. Tsai, Y. H. Jen, J. S. Chang, H. M. Hsiao, S. Noisakran and G. C. Perng, “Frequency Alterations in Key Innate Immune Cell Components in the Peripheral Blood of Dengue Patients Detected by FACS Analysis,” Journal of Innate Immunity, Vol. 3, 2011, pp. 530-540. doi:10.1159/000322904

[77]   WHO, “Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control,” World Health Organization, Geneva, 2009.

[78]   J. B. Cleland, B. Bradley and W. Macdonald, “Further Experiments in the Etiology of Dengue Fever,” Journal of Hygiene (London), Vol. 18, No. 3, 1919, pp. 217-254.

[79]   IMR, “Dengue Fever Studies in Malaysia,” The Institute for Medical Research, Kuala Lumpur, 1986.

[80]   A. B. Sabin and R. W. Schlesinger, “Production of Immunity to Dengue with Virus Modified by Propagation in Mice,” Science, Vol. 101, No. 2634, 1945, pp. 640-642.

[81]   A. B. Sabin, “Research on Dengue during World War II,” American Journal of Tropical Medicine and Hygiene, Vol. 1, 1952, pp. 30-50.

[82]   R. Kimura and S. Hotta, “Studies on Dengue Fever (VI). On the Inoculation of Dengue Virus into Mice (in Japanese),” Nippom Igaku, Vol. 3379, 1944, pp. 629-633.

[83]   S. Hotta, “Experimental Studies on Dengue I Isolation, Identification and Modification of the Virus,” Journal of Infectious Diseases, Vol. 90, No. 1, 1952, pp. 1-9.

[84]   L. E. Yauch and S. Shresta, “Mouse Models of Dengue Virus Infection and Disease,” Antiviral Research, Vol. 80, No. 2, 2008, pp. 87-93. doi:10.1016/j.antiviral.2008.06.010

[85]   M. C. Cassetti, A. Durbin, E. Harris, R. Rico-Hesse, J. Roehrig, A. Rothman, et al., “Report of an NIAID Workshop on Dengue Animal Models,” Vaccine, Vol. 28, No. 26, 2010, pp. 4229-4234. doi:10.1016/j.vaccine.2010.04.045

[86]   K. L. Williams, S. Zompi, P. R. Beatty and E. Harris, “A Mouse Model for Studying Dengue Virus Pathogenesis and Immune Response,” Annals of New York Academic of Science, Vol. 1171, Suppl. 1, 2009, pp. E12-23. doi:10.1111/j.1749-6632.2009.05057.x

[87]   R. M. Zellweger, T. R. Prestwood and S. Shresta, “Enhanced Infection of Liver Sinusoidal Endothelial Cells in a Mouse Model of Antibody-Induced Severe Dengue Dis- ease,” Cell Host and Microbe, Vol. 7, No. 2, 2010, pp. 128-139. doi:10.1016/j.chom.2010.01.004

[88]   S. J. Balsitis, K. L. Williams, R. Lachica, D. Flores, J. L. Kyle, E. Mehlhop, et al., “Lethal Antibody Enhancement of Dengue Disease in Mice Is Prevented by Fc Modification,” PLoS Pathogens, Vol. 6, No. 2, 2010, p. e1000790. doi:10.1371/journal.ppat.1000790

[89]   D. A. Bente and R. Rico-Hesse, “Models of Dengue Virus Infection,” Drug Discovery Today Disease Models, Vol. 3, No. 1, 2006, pp. 97-103. doi:10.1016/j.ddmod.2006.03.014

[90]   J. Mota and R. Rico-Hesse, “Humanized Mice Show Clinical Signs of Dengue Fever According to Infecting Virus Genotype,” Journal of Virology, Vol. 83, No. 17, 2009, pp. 8638-8645. doi:10.1128/JVI.00581-09

[91]   J. Mota and R. Rico-Hesse, “Dengue Virus Tropism in Humanized Mice Recapitulates Human Dengue Fever,” PLoS One, Vol. 6, No. 6, 2011, p. e20762. doi:10.1371/journal.pone.0020762

[92]   J. G. Kuruvilla, R. M. Troyer, S. Devi and R. Akkina, “Dengue Virus Infection and Immune Response in Humanized RAG2(-/-)Gamma(c)(-/-) (RAG-hu) Mice,” Virology, Vol. 369, No. 1, 2007, pp. 143-152. doi:10.1016/j.virol.2007.06.005

[93]   S. B. Halstead, H. Shotwell and J. Casals, “Studies on the Pathogenesis of Dengue Infection in Monkeys. I. Clinical Laboratory Responses to Primary Infection,” Journal of Infectious Diseases, Vol. 128, No. 1, 1973, pp. 7-14. doi:10.1093/infdis/128.1.7

[94]   D. W. Vaughn, S. Green, S. Kalayanarooj, B. L. Innis, S. Nimmannitya, S. Suntayakorn, et al., “Dengue Viremia Titer, Antibody Response Pattern, and Virus Serotype Correlate with Disease Severity,” Journal of Infectious Diseases, Vol. 181, No. 1, 2000, pp. 2-9. doi:10.1086/315215

[95]   N. Onlamoon, S. Noisakran, H. M. Hsiao, A. Duncan, F. Villinger,, A. A. Ansari, et al., “Dengue Virus-Induced Hemorrhage in a Nonhuman Primate Model,” Blood, Vol. 115, No. 9, 2010, pp. 1823-1834. doi:10.1182/blood-2009-09-242990

[96]   G. Blanc and J. Caminopetros, “Contributions to the Study of Vaccination against Dengue,” Bulletin of Academic Medicine, Vol. 102, No. 26, 1929, pp. 40-47.

[97]   J. H. St. John and R. L. Holt, “A Dengue Vaccine Prepared from Macacus Philippinensis,” American Journal of Tropical Medicine and Hygiene, Vol. 11, 1931, pp. 325-336.

[98]   R. L. Holt and J. H. Kintner, “Notes on Dengue,” Philippine Journal of Science, Vol. 46, 1931, pp. 593-599.

[99]   P. M. Ashburn and C. F. Craig, “Experimental Investigations Regarding the Etiology of Dengue,” Journal of Infectious Diseases, Vol. 4, 1907, pp. 440-475.

[100]   S. Hotta, “Some Immunological Properties of Dengue Virus Cultivated in Tissue Culture,” Annals of Tropical Medicine and Parasitology, Vol. 51, No. 3, 1957, pp. 249-255.

[101]   W. R. Dorrance, J. W. Frankel, I. Gordon, P. R. Patterson, R. W. Schlesinger and J. W. Winter, “Clinical and Serologic Response of Man to Immunization with Attenuated Dengue and Yellow Fever Viruses,” Journal of Immunology, Vol. 77, No. 5, 1956, pp. 352-364.

[102]   C. L. Wisserman, B. H. Sweet Jr., E. C. Rosenzweig and O. R. Eylar, “Attenuated Living Type 1 Dengue Vaccines,” American Journal of Tropical Medicine and Hygiene, Vol. 12, 1963, pp. 620-623.

[103]   J. A. Bellanti, A. T. Bourke, E. L. Buescher, F. C. Cadigan, G. A. Cole, Y. El Batawi, et al., “Report of Dengue Vaccine Field Trial in the Caribbean, 1963: A Collaborative Study,” Bulletin of World Health Organization, Vol. 35, No. 1, 1966, p. 93.

[104]   W. M. Hammon, A. Rudnick and G. E. Sather, “Viruses Associated with Epidemic Hemorrhagic Fevers of the Philippines and Thailand,” Science, Vol. 131, 1960, pp. 1102-1103.

[105]   WHO, “Summaries of Papers Presented at the WHO Inter-Regional Seminar on Mosquito-Borne Haemorrhagic Fevers in the South-East Asia and Western Pacific Regions,” Bulletin of World Health Organization, Vol. 35, No. 1, 1966, pp. 37-94.

[106]   D. J. Gubler, “Dengue/Dengue Haemorrhagic Fever: His- tory and Current Status,” Novartis Foundation Symposium, Vol. 277, 2006, pp. 3-16.

[107]   WHO, “Guide for Diagnosis, Treatment and Control of Dengue Hemorrhagic Fever,” World Health Organization, Manila, 1980.

[108]   WHO, “Dengue Vaccine Development: The Role of the WHO South-East Asia Regional Office,” New Delhi, 2010, pp. 1-8.

[109]   A. P. Durbin and S. S. Whitehead, “Dengue Vaccine Candidates in Development,” Current Topics in Microbiology and Immunology, Vol. 338, 2010, pp. 129-143.

[110]   W. H. Bancroft, R. M. Scott, K. H. Eckels, C. H. Hoke, T. E. Simms Jr., K. D. Jesrani, et al., “Dengue Virus Type 2 Vaccine: Reactogenicity and Immunogenicity in Soldiers,” Journal of Infectious Diseases, Vol. 149, No. 6, 1984, pp. 1005-1010. doi:10.1093/infdis/149.6.1005

[111]   K. H. Eckels, R. M. Scott, W. H. Bancroft, J. Brown, D. R. Dubois, P. L. Summers, et al., “Selection of Attenuated Dengue 4 Viruses by Serial Passage in Primary Kidney Cells. V. Human Response to Immunization with a Candidate Vaccine Prepared in Fetal Rhesus Lung Cells,” American Journal of Tropical Medicine and Hygiene, Vol. 33, No. 4, 1984, pp. 684-689.

[112]   N. Bhamarapravati, S. Yoksan, T. Chayaniyayothin, S. Angsubphakorn and A. Bunyaratvej, “Immunization with a Live Attenuated Dengue-2-Virus Candidate Vaccine (16681-PDK 53): Clinical, Immunological and Biological Responses in Adult Volunteers,” Bulletin of World Health Organization, Vol. 35, No. 2, 1987, pp. 189-195.

[113]   N. Bhamarapravati and S. Yoksan, “Study of Bivalent Dengue Vaccine in Volunteers,” Lancet, Vol. 1, No. 8646, p. 1077. doi:10.1016/S0140-6736(89)92471-9

[114]   D. W. Vaughn, C. H. Hoke Jr., S. Yoksan, R. LaChance, B. L. Innis, R. M. Rice, et al., “Testing of a Dengue 2 Live-Attenuated Vaccine (Strain 16681 PDK 53) in Ten American Volunteers,” Vaccine, Vol. 14, No. 4, 1996, pp. 329-336. doi:10.1016/0264-410X(95)00167-Y

[115]   N. Jirakanjanakit, M M. Khin, S. Yoksan and N. Bhamarapravati, “Dynamics of Susceptibility and Transmissibility of the Live, Attenuated, Candidate Vaccines Dengue-1 PDK13, Dengue-3 PGMK30F3, and Dengue-4 PDK48 after Oral Infection in Aedes Aegypti,” American Journal of Tropical Medicine and Hygiene, Vol. 61, No. 4, 1999, pp. 672-676.

[116]   J. Rabablert, T. Dharakul, S. Yoksan and N. Bhamarapravati, “Dengue Virus Specific T Cell Responses to Live Attenuated Monovalent Dengue-2 and Tetravalent Dengue Vaccines,” Asian Pacific Journal of Allergy Immunology, Vol. 18, No. 4, 2000, pp. 227-235.

[117]   A. P. Durbin, B. D. Kirkpatrick, K. K. Pierce, A. C. Schmidt and S. S. Whitehead, “Development and Clinical Evaluation of Multiple Investigational Monovalent DENV Vaccines to Identify Components for Inclusion in a Live Attenuated Tetravalent DENV Vaccine,” Vaccine, Vol. 29, No. 42, 2011, pp. 7242-7250. doi:10.1016/j.vaccine.2011.07.023

[118]   J. R. Danko, C. G. Beckett and K. R. Porter, “Development of Dengue DNA Vaccines,” Vaccine, Vol. 29, No.42, 2011, pp. 7261-7266. doi:10.1016/j.vaccine.2011.07.019

[119]   B. A. Coller, D. E. Clements, A. J. Bett, S. L. Sagar and J. H. Ter Meulen, “The Development of Recombinant Sub- unit Envelope-Based Vaccines to Protect against Dengue Virus Induced Disease,” Vaccine, Vol. 29, No. 42, 2011, pp. 7267-7275. doi:10.1016/j.vaccine.2011.07.021

[120]   J. E. Osorio, C. Y. Huang, R. M. Kinney and D. T. Stinchcomb, “Development of DENVax: A Chimeric Dengue-2 PDK-53-Based Tetravalent Vaccine for Protection against Dengue Fever,” Vaccine, Vol. 29, No. 42, 2011, pp. 7251-7260. doi:10.1016/j.vaccine.2011.07.020

[121]   S. J. Thomas and T. P. Endy, “Critical Issues in Dengue Vaccine Development,” Current Opinion in Infectious Diseases, Vol. 24, No. 5, 2011, pp. 442-450. doi:10.1097/QCO.0b013e32834a1b0b

[122]   L. Rosen, “The Emperor’s New Clothes Revisited, or Re- flections on the Pathogenesis of Dengue Hemorrhagic Fever,” American Journal of Tropical Medicine and Hygiene, Vol. 26, No. 3, 1977, pp. 337-343.

[123]   L. Thomas, O. Verlaeten, A. Cabie, S. Kaidomar, V. Moravie, J. Martial, et al., “Influence of the Dengue Serotype, Previous Dengue Infection, and Plasma Viral Load on Clinical Presentation and Outcome during a Dengue-2 and Dengue-4 Co-Epidemic,” American Journal of Tropical Medicine and Hygiene, Vol. 78, No. 6, 2008, pp. 990- 998.

[124]   N. Sangkawibha, S. Rojanasuphot, S. Ahandrik, S. Viriyapongse, S. Jatanasen, V. Salitul, et al., “Risk Factors in Dengue Shock Syndrome: A Prospective Epidemiologic Study in Rayong, Thailand. I. The 1980 Outbreak,” Am- erican Journal of Epidemiology, Vol. 120, No. 5, 1984, pp. 653-669.

[125]   K. T. Thai, T. Q. Binh, P. T. Giao, H. L. Phuong, Q. Hung, N. Van Nam, et al., “Seroprevalence of Dengue Antibodies, Annual Incidence and Risk Factors among Children in Southern Vietnam,” Tropical Medicine and International Health, Vol. 10, No. 4, 2005, pp. 379-386. doi:10.1111/j.1365-3156.2005.01388.x

[126]   A. N. Theofilopoulos, “Evaluation and Clinical Significance of Circulating Immune Complexes,” Progress in Clinical Immunology, Vol. 4, 1980, pp. 63-106.

[127]   W. K. Wang, H. L. Chen, C. F. Yang, S. C. Hsieh, C. C. Juan, S. M. Chang, et al., “Slower Rates of Clearance of Viral Load and Virus-Containing Immune Complexes in Patients with Dengue Hemorrhagic Fever,” Clinical Infectious Diseases, Vol. 43, No. 8, 2006, pp. 1023-1030. doi:10.1086/507635

[128]   Y. W. Lin, K. J. Wang, H. Y. Lei, Y. S. Lin, T. M. Yeh, H. S. Liu, et al., “Virus Replication and Cytokine Production in Dengue Virus-Infected Human B Lymphocytes,” Journal of Virology, Vol. 76, No. 23, 2002, pp. 12242- 12249. doi:10.1128/FJVI.76.23.12242-12249.2002

[129]   H. Bielefeldt-Ohmann, “Analysis of Antibody-Indepen- dent Binding of Dengue Viruses and Dengue Virus Envelope Protein to Human Myelomonocytic Cells and B Lymphocytes,” Virus Research, Vol. 57, No. 1, 1998, pp. 63-79. doi:10.1016/S0168-1702(98)00087-2

[130]   I. Kurane, D. Hebblewaite, W. E. Brandt and F. A. Ennis, “Lysis of Dengue Virus-Infected Cells by Natural Cell- Mediated Cytotoxicity and Antibody-Dependent Cell- Mediated Cytotoxicity,” Journal of Virology, Vol. 52, No. 1, 1984, pp. 223-230.

[131]   A. N. Theofilopoulos, W. E. Brandt, P. K. Russell and F. T. Dixon, “Replication of Dengue-2 Virus in Cultured Human Lymphoblastoid Cells and Subpopulations of Human Peripheral Leukocytes,” Journal of Immunology, Vol. 117, No. 3, 1976, pp. 953-961.

[132]   T. Takasaki, K. Takada and I. Kurane, “Electron Mic- roscopic Study of Persistent Dengue Virus Infection: Analysis Using a Cell Line Persistently Infected with Dengue-2 Virus,” Intervirology, Vol. 44, No. 1, 2001, pp. 48-54.

[133]   S. Blackley, Z. Kou, H. Chen, M. Quinn, R. C. Rose, J. J. Schlesinger, et al., “Primary Human Splenic Macrophages, but Not T or B Cells, Are the Principal Target Cells for Dengue Virus Infection in Vitro,” Journal of Virology, Vol. 81, No.24, 2007, pp. 13325-13334. doi:10.1128/FJVI.01568-07

[134]   Z. Kou, M. Quinn, H. Chen, W. W. Rodrigo, R. C. Rose, J. J. Schlesinger, et al., “Monocytes, but Not T or B Cells, Are the Principal Target Cells for Dengue Virus (DV) Infection among Human Peripheral Blood Mononuclear Cells,” Journal of Medical Virology, Vol. 80, No. 1, 2008, pp. 134-146. doi:10.1002/jmv.21051

[135]   A. D. King, A. Nisalak, S. Kalayanrooj, K. S. Myint, K. Pattanapanyasat, S. Nimmannitya, et al., “B Cells Are the Principal Circulating Mononuclear Cells Infected by Dengue Virus,” Southeast Asian Journal of Tropical Medicine and Public Health, Vol. 30, No. 4, 1999, pp. 718- 728.

[136]   W. Jampangern, K. Vongthoung, A. Jittmittraphap, S. Worapongpaiboon, K. Limkittikul, A. Chuansumrit, et al., “Characterization of Atypical Lymphocytes and Immuno- phenotypes of Lymphocytes in Patients with Dengue Virus Infection,” Asian Pacific Journal of Allergy Immunology, Vol. 25, No. 1, 2007, pp. 27-36.

[137]   M. O. Baclig, L. T. Gervacio, L. A. Suarez, C. C. Buerano, R. R. Matias, A. Kumatori, et al., “Flow Cytometric Analysis of Dengue Virus-Infected Cells in Peripheral Blood,” Southeast Asian Journal of Tropical Medicine and Public Health, Vol. 41, No. 6, 2010, pp. 1352-1358.

[138]   U. C. Chaturvedi, M. I. Shukla, M. Pahwa and A. Mathur, “Inhibition of B & Helper T Lymphocytes by Dengue Virus-Induced Suppressor Factor,” Indian Journal of Me- dical Research, Vol. 82, 1985, pp. 471-474.

[139]   M. J. Gilbreath, K. Pavanand, R. P. MacDermott, M. Ussery, D. S. Burke, S. Nimmannitya, et al., “Cold-Re- active Immunoglobulin M Antilymphocyte Antibodies Directed against B Cells in Thai Children with Dengue Hemorrhagic Fever,” Journal of Clinical Microbiology, Vol. 17, No. 4, 1983, pp. 672-676.

[140]   I. Kurane, D. Hebblewaite and F. A. Ennis, “Characteri- zation with Monoclonal Antibodies of Human Lympho- cytes Active in Natural Killing and Antibody-Dependent Cell-Mediated Cytotoxicity of Dengue Virus-Infected Cells,” Immunology, Vol. 58, No. 3, 1986, pp. 429-436.

[141]   J. Srinivasappa, J. Saegusa, B. S. Prabhakar, M. K. Gentry, M. J. Buchmeier, Y. J. Wiktor, et al., “Molecular Mimicry: Frequency of Reactivity of Monoclonal Antiviral Antibodies with Normal Tissues,” Journal of Virology, Vol. 57, No. 1, 1986, pp. 397-401.

[142]   M. B. Oldstone, “Molecular Mimicry and Immune-Me- diated Diseases,” FASEB Journal, Vol. 12, No. 13, 1998, pp. 1255-1265.

[143]   N. R. Rose and I. R. Mackay, “Molecular Mimicry: A Critical Look at Exemplary Instances in Human Diseases,” Cellular and Molecular Life Science, Vol. 57, No. 4, 2000, pp. 542-551.

[144]   L. J. Markoff, B. L. Innis, R. Houghten and L. S. Henchal, “Development of Cross-Reactive Antibodies to Plasminogen during the Immune Response to Dengue Virus Infection,” Journal of Infectious Diseases, Vol. 164, No. 2, 1991, pp. 294-301. doi:10.1093/infdis/164.2.294

[145]   Y. S. Lin, T. M. Yeh, C. F. Lin, S. W. Wan, Y. C. Chuang, T. K. Hsu, et al., “Molecular Mimicry between Virus and Host and Its Implications for Dengue Disease Pathogenesis,” Experimental Biology and Medicine (May- wood), Vol. 236, No. 5, 2011, pp. 515-523. doi:10.1258/ebm.2011.010339

[146]   H. J. Cheng, C. F. Lin, H. Y. Lei, H. S. Liu, T. M. Yeh, Y. H. Luo YH, et al., “Proteomic Analysis of Endothelial Cell Autoantigens Recognized by Anti-Dengue Virus Nonstructural Protein 1 Antibodies,” Experimental Biology and Medicine (Maywood), Vol. 234, No. 1, 2009, pp. 63-73. doi:10.3181/0805-RM-147

[147]   C. F. Lin, S. W. Wan, H. J. Cheng, H. Y. Lei and Y. S. Lin, “Autoimmune Pathogenesis in Dengue Virus Infection,” Viral Immunology, Vol. 19, No. 2, 2006, pp. 127- 132. doi:10.1089/vim.2006.19.127

[148]   R. A. Ezekowitz and S. Gordon, “Alterations of Surface Properties by Macrophage Activation: Expression of Receptors for Fc and Mannose-Terminal Glycoproteins and Differentiation Antigens,” Contemporary Topics in Immunobiology, Vol. 13, 1984, pp. 33-56.

[149]   M. Stein, S. Keshav, N. Harris and S. Gordon, “Interleukin 4 Potently Enhances Murine Macrophage Mannose Receptor Activity: A Marker of Alternative Immunologic Macrophage Activation,” Journal of Experimental Medicine, Vol. 176, No. 1, 1992, pp. 287-292.

[150]   S. Goerdt, O. Politz, K. Schledzewski, R. Birk, A. Gratchev, P. Guillot, et al., “Alternative Versus Classical Activation of Macrophages,” Pathobiology, Vol. 67, No. 5-6, 1999, pp. 222-226.

[151]   S. Goerdt and C. E. Orfanos, “Other Functions, Other Genes: Alternative Activation of Antigen-Presenting Cells,” Immunity, Vol. 10, No. 2, 1999, pp. 137-142. doi:10.1016/S1074-7613(00)80014-X

[152]   F. S. Sutterwala, G. J. Noel, R. Clynes and D. M. Mosser, “Selective Suppression of Interleukin-12 Induction after Macrophage Receptor Ligation,” Journal of Experimental Medicine, Vol. 185, No. 11, 1997, pp. 1977-1985.

[153]   F. S. Sutterwala, G. J. Noel, P. Salgame and D. M. Mosser, “Reversal of Proinflammatory Responses by Li- gating the Macrophage Fcgamma Receptor Type I,” Journal of Experimental Medicine, Vol. 188, No. 1, 1998, pp. 217-222.

[154]   C. F. Anderson and D. M. Mosser, “Cutting Edge: Biasing Immune Responses by Directing Antigen to Macrophage Fc Gamma Receptors,” Journal of Immunology, Vol. 168, No. 8, 2002, pp. 3697-3701.

[155]   G. J. Randolph, “Immunology. No Need to Coax Monocytes,” Science, Vol. 332, No. 6035, 2011, pp. 1268-1269. doi:10.1126/science.1208480

[156]   S. J. Jenkins, D. Ruckerl, P. C. Cook, L. H. Jones, F. D. Finkelman, N. van Rooijen, et al., “Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of TH2 Inflammation,” Science, Vol. 332, No. 6035, 2011, pp. 1284-1288. doi:10.1126/science.1204351

[157]   D. M. Mosser, “The Many Faces of Macrophage Activation,” Journal of Leukocyte Biology, Vol. 73, No. 2, 2003, pp. 209-212. doi:10.1189/jlb.0602325

[158]   C. F. Lin, H. Y. Lei, A. L. Shiau, H. S. Liu, T. M. Yeh, S. H. Chen, et al., “Endothelial Cell Apoptosis Induced by Antibodies against Dengue Virus Nonstructural Protein 1 via Production of Nitric Oxide,” Journal of Immunology, Vol. 169, No. 2, 2002, pp. 657-664.

[159]   C. C. Liu, K. J. Huang, Y. S. Lin, T. M. Yeh, H. S. Liu and H. Y. Lei, “Transient CD4/CD8 Ratio Inversion and Aberrant Immune Activation during Dengue Virus Infection,” Journal of Medical Virology, Vol. 68, No. 2, pp. 241-252. doi:10.1002/jmv.10198

[160]   T. H. Nguyen, H. Y. Lei, T. L. Nguyen, Y. S. Lin, K. J. Huang, B. L. Le, et al., “Dengue Hemorrhagic Fever in Infants: A Study of Clinical and Cytokine Profiles,” Journal of Infectious Diseases, Vol. 189, No. 2, 2004, pp. 221-232. doi:10.1086/380762

[161]   H. Y. Lei, T. M. Yeh, H. S. Liu, Y. S. Lin, S. H. Chen and C. C. Liu, “Immunopathogenesis of Dengue Virus Infection,” Journal of Biomedical Science, Vol. 8, No. 5, 2001, pp. 377-388. doi:10.1007/BF02255946

[162]   H. Y. Lei, “Transient Hemophagocytic Activity in Dengue Immunopathogenesis,” Journal of Formosan Medical Association, Vol. 108, No. 8, 2009, pp. 595-598. doi:10.1016/S0929-6646(09)60379-X

[163]   I. J. Su, “Perspectives on the Pathogenesis and Therapy of Hemophagocytic Syndrome,” Journal of Formosan Medical Association, Vol. 107, No. 4, 2008, pp. 277-280. doi:10.1016/S0929-6646(08)60087-X

[164]   M. Leslie, “Cell Biology. Beyond Clotting: The Powers of Platelets,” Science, Vol. 328, No. 5978, 2010, pp. 562- 564. doi:10.1126/science.328.5978.562

[165]   J. W. Semple and J. Freedman, “Platelets and Innate Immunity,” Cellular and Molecular Life Science, Vol. 67, No. 4, 2009, pp. 499-511. doi:10.1007/s00018-009-0205-1

[166]   P. von Hundelshausen and C. Weber, “Platelets as Immune Cells: Bridging Inflammation and Cardiovascular Disease,” Circulation Research, Vol. 100, No. 1, pp. 27- 40. doi:10.1161/01.RES.0000252802.25497.b7

[167]   T. Youssefian, A. Drouin, J. M. Masse, J. Guichard and E. M. Cramer, “Host Defense Role of Platelets: Engulfment of HIV and Staphylococcus Aureus Occurs in a Specific Subcellular Compartment and Is Enhanced by Platelet Activation,” Blood, Vol. 99, No. 11, 2002, pp. 4021-4029. doi:10.1182/blood-2001-12-0191

[168]   A. S. Weyrich and G. A. Zimmerman, “Platelets: Signaling Cells in the Immune Continuum,” Trends in Immunology, Vol. 25, No. 9, 2004, pp. 489-495. doi:10.1016/

[169]   R. Aslam, E. R. Speck, M. Kim, A. R. Crow, K. W. Bang, F. P. Nestel, et al., “Platelet Toll-Like Receptor Expression Modulates Lipopolysaccharide-Induced Thrombocytopenia and Tumor Necrosis Factor-Alpha Production in Vivo,” Blood, Vol. 107, No. 2, 2006, pp. 637-641. doi:10.1182/blood-2005-06-2202

[170]   N. Li, “Platelet-Lymphocyte Cross-Talk,” Journal of Leu- kocyte Biology, Vol. 85, No. 5, 2008, pp. 1069-1078. doi:10.1189/jlb.0907615

[171]   M. Czapiga, A. D. Kirk and J. Lekstrom-Himes, “Platelets Deliver Costimulatory Signals to Antigen-Presenting Cells: A Potential Bridge between Injury and Immune Activation,” Experimental Hematology, Vol. 32, No. 2, 2004, pp. 135-139.

[172]   B. D. Elzey, J. F. Grant, H. W. Sinn, B. Nieswandt, T. J. Waldschmidt and T. L. Ratliff, “Cooperation between Platelet-Derived CD154 and CD4+ T Cells for Enhanced Germinal Center Formation,” Journal of Leukocyte Biology, Vol. 78, No. 1, 2005, pp. 80-84. doi:10.1189/jlb.1104669

[173]   S. Sadallah, C. Eken, P. J. Martin and J. A. Schifferli, “Microparticles (Ectosomes) Shed by Stored Human Platelets Downregulate Macrophages and Modify the Development of Dendritic Cells,” Journal of Immunology, Vol. 186, No. 11, 2011, pp. 6543-6552. doi:10.4049/jimmunol.1002788

[174]   B. D. Elzey, J. Tian, R. J. Jensen, A. K. Swanson, J. R. Lees, S. R. Lentz, et al., “Platelet-Mediated Modulation of Adaptive Immunity. A Communication Link between Innate and Adaptive Immune Compartments,” Immunity, Vol. 19, No. 1, 2003, pp. 9-19. doi:10.1016/S1074-7613(03)00177-8

[175]   J. W. Semple, J. E. Italiano Jr. and J. Freedman, “Platelets and the Immune Continuum,” Nature Reviews Immunology, Vol. 11, No. 4, 2011, pp. 264-274. doi:10.1038/nri2956

[176]   M. I. Furman, D. J. Kereiakes, L.A. Krueger, M. N. Mueller, K. Pieper, T. M. Broderick, et al., “Leukocyte- Platelet Aggregation, Platelet Surface P-Selectin, and Platelet Surface Glycoprotein IIIa after Percutaneous coronary Intervention: Effects of Dalteparin or Unfractionated Heparin in Combination with Abciximab,” American Heart Journal, Vol. 142, No. 5, 2001, pp. 790-798. doi:10.1067/mhj.2001.119128

[177]   M. P. Gawaz, S. K. Mujais, B. Schmidt and H. J. Gurland, “Platelet-Leukocyte Aggregation during Hemodialysis,” Kidney International, Vol. 46, No. 2, 1994, pp. 489-495. doi:10.1038/ki.1994.299

[178]   E. Boilard, P. A. Nigrovic, K. Larabee, G. F. Watts, J. S. Coblyn, M. E. Weinblatt, et al., “Platelets Amplify In- flammation in Arthritis via Collagen-Dependent Micro- particle Production,” Science, Vol. 327, No. 5965, 2010, pp. 580-583. doi:10.1126/science.1181928

[179]   A. Kornberg, N. N. Rao and D. Ault-Riche, “Inorganic Polyphosphate: A Molecule of Many Functions,” Annual Review of Biochemistry, Vol. 68, 1999, pp. 89-125. doi:10.1146/annurev.biochem.68.1.89

[180]   E. Pavlov, R. Aschar-Sobbi, M. Campanella, R. J. Turner, M R. Gomez-Garcia and A. Y. Abramov, “Inorganic Polyphosphate and Energy Metabolism in Mammalian Cells,” Journal of Biological Chemistry, Vol. 285, No. 13, 2010, pp. 9420-9428. doi:10.1074/jbc.M109.013011

[181]   F. A. Ruiz, C. R. Lea, E. Oldfield and R. Docampo, “Human Platelet Dense Granules Contain Polyphosphate and Are Similar to Acidocalcisomes of Bacteria and Unicellular Eukaryotes,” Journal of Biological Chemistry, Vol. 279, No. 43, 2004, pp. 44250-44257. doi:10.1074/jbc.M406261200

[182]   J. Caen and Q. Wu, “Hageman Factor, Platelets and Polyphosphates: Early History and Recent Connection,” Journal of Thrombosis and Haemostasis, Vol. 8, No. 8, 2010, pp. 1670-1674. doi:10.1111/j.1538-7836.2010.03893.x

[183]   L. Hernandez-Ruiz, I. Gonzalez-Garcia, C. Castro, J. A. Brieva and F. A. Ruiz, “Inorganic Polyphosphate and Sp- ecific Induction of Apoptosis in Human Plasma Cells,” Haematologica, Vol. 91, No. 9, 2006, pp. 1180-1186.

[184]   F. Muller, N. J. Mutch, W. A. Schenk, S. A. Smith, L. Esterl, H. M. Spronk, et al., “Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators in Vivo,” Cell, Vol. 139, No. 6, 2009, pp. 1143-1156. doi:10.1016/j.cell.2009.11.001

[185]   S. A. Smith, N. J. Mutch, D. Baskar, P. Rohloff, R. Docampo and J. H. Morrissey, “Polyphosphate Modulates Blood Coagulation and Fibrinolysis,” Proceedings of National Academy of Sciences of the United States of Am- erica, Vol. 103, No. 4, 2006, pp. 903-908. doi:10.1073/pnas.0507195103

[186]   S. Noisakran, K. Chokephaibulkit, P. Songprakhon, N. Onlamoon, H. M. Hsiao, F. Villinger, et al., “A Re- Evaluation of the Mechanisms Leading to Dengue He- morrhagic Fever,” Annals of the New York Academy of Sciences, Vol. 1171, Suppl. 1, 2009, pp. E24-35. doi:10.1111/j.1749-6632.2009.05050.x

[187]   S. Noisakran, R. V. Gibbons, P. Songprakhon, A. Jai- rungsri, C. Ajariyakhajorn, A. Nisalak, et al., “Detection of Dengue Virus in Platelets Isolated from Dengue Patients,” Southeast Asian Journal of Tropical Medicine and Public Health, Vol. 40, No. 2, 2009, pp. 253-262.

[188]   J. Hombach, “Vaccines against Dengue: A Review of Current Candidate Vaccines at Advanced Development Stages,” Revista Panamericana De Salud Publica, Vol. 21, No. 4, 2007, pp. 254-260. doi:10.1590/S1020-49892007000300011

[189]   T. P. Endy, K. B. Anderson, A. Nisalak, I. K. Yoon, S. Green, A. L. Rothman, et al., “Determinants of Inapparent and Symptomatic Dengue Infection in a Prospective Study of Primary School Children in Kamphaeng Phet, Thailand,” PLoS Neglected Tropical Diseases, Vol. 5, No. 3, 2011, p. e975. doi:10.1371/journal.pntd.0000975

[190]   S. S. Whitehead, J. E. Blaney, A. P. Durbin and B. R. Murphy, “Prospects for a Dengue Virus Vaccine,” Nature Reviews Microbiology, Vol. 5, No. 7, 2007, pp. 518-528. doi:10.1038/nrmicro1690

[191]   R. Edelman, “Unique Challenges Faced by the Clinical Evaluation of Dengue Vaccines,” Expert Review of Vaccines, Vol. 10, No. 2, 2011, pp. 133-136. doi:10.1586/erv.10.159

[192]   S. Anantapreecha, A. A-Nuegoonpipat, S. Prakrong, S. Chanama, A. Sa-Ngasang, P. Sawanpanyalert, et al., “Dengue Virus Cross-Reactive Hemagglutination Inhibition Antibody Responses in Patients with Primary Dengue Virus Infection,” Japanese Journal of Infectious Diseases, Vol. 60, No. 5, 2007, pp. 267-270.

[193]   A. P. Durbin, S. S. Whitehead, D. Shaffer, D. Elwood, K. Wanionek, B. Thumar, et al., “A Single Dose of the DENV-1 Candidate Vaccine rDEN1Delta30 Is Strongly Immunogenic and Induces Resistance to a Second Dose in a Randomized Trial,” PLoS Neglected Tropical Dis- eases, Vol. 5, No. 8, 2011, p. e1267. doi:10.1371/journal.pntd.0001267

[194]   M. Beltramello, K. L. Williams, C. P. Simmons, A. Macagno, L. Simonelli, N. T. Quyen, et al., “The Human Immune Response to Dengue Virus Is Dominated by Highly Cross-Reactive Antibodies Endowed with Neutralizing and Enhancing Activity,” Cell Host and Microbe, Vol. 8, No. 3, 2010, pp. 271-283. doi:10.1016/j.chom.2010.08.007

[195]   S. B. Halstead, “Neutralization and Antibody-Dependent Enhancement of Dengue Viruses,” Advances in Virus Research, Vol. 60, 2003, pp. 421-467.

[196]   W. Dejnirattisai, A. Jumnainsong, N. Onsirisakul, P. Fitton, S. Vasanawathana, W. Limpitikul, et al., “Cross- Reacting Antibodies Enhance Dengue Virus Infection in Humans,” Science, Vol. 328, No. 5979, 2010, pp. 745- 748. doi:10.1126/science.1185181

[197]   K. J. Huang, Y. C. Yang, Y. S. Lin, J. H. Huang, H. S. Liu, T. M. Yeh, et al., “The Dual-Specific Binding of Dengue Virus and Target Cells for the Antibody-Depen- dent Enhancement of Dengue Virus Infection,” Journal of Immunology, Vol. 176, No. 5, 2006, pp. 2825-2832.

[198]   E. Chungue, L. Poli, C. Roche, P. Gestas, P. Glaziou and L. J. Markoff, “Correlation between Detection of Plasminogen Cross-Reactive Antibodies and Hemorrhage in Dengue Virus Infection,” Journal of Infectious Diseases, Vol. 170, No. 5, 1994, pp. 1304-1307. doi:10.1093/infdis/170.5.1304

[199]   M. C. Chen, C. F. Lin, H. Y. Lei, S. C. Lin, H. S. Liu, T. M. Yeh, et al., “Deletion of the C-Terminal Region of Dengue Virus Nonstructural Protein 1 (NS1) Abolishes Anti-NS1-Mediated Platelet Dysfunction and Bleeding Tendency,” Journal of Immunology, Vol. 183, No. 3, 2009, pp. 1797-1803. doi:10.4049/jimmunol.0800672

[200]   H. J. Cheng, H. Y. Lei, C. F. Lin, Y. H. Luo, S. W. Wan, H. S. Liu, et al., “Anti-Dengue Virus Nonstructural Protein 1 Antibodies Recognize Protein Disulfide Isomerase on Platelets and Inhibit Platelet Aggregation,” Molecular Immunology, Vol. 47, No. 2-3, 2009, pp. 398-406. doi:10.1016/j.molimm.2009.08.033

[201]   B. Carme, S. Matheus, G. Donutil, O. Raulin, M. Nacher and J. Morvan, “Concurrent Dengue and Malaria in Cayenne Hospital, French Guiana,” Emerging Infectious Dis- eases, Vol. 15, No. 4, 2009, pp. 668-671. doi:10.3201/eid1504.080891

[202]   D. Donati, B. Mok, A. Chene, H. Xu, M. Thangarajh, R. Glas, et al., “Increased B Cell Survival and Preferential Activation of the Memory Compartment by a Malaria Po- lyclonal B Cell Activator,” Journal of Immunology, Vol. 177, No. 5, 2006, pp. 3035-3044.

[203]   R. Mahoney, L. Chocarro, J. Southern, D. P. Francis, J. Vose and H. Margolis, “Dengue Vaccines Regulatory Pa- thways: A Report on Two Meetings with Regulators of Developing Countries,” PLoS Medicine, Vol. 8, No. 2, 2011, p. e1000418. doi:10.1371/journal.pmed.1000418