Review Article | Published:

Adaptive immune responses to primary and secondary dengue virus infections


Dengue is the leading mosquito-borne viral illness infecting humans. Owing to the circulation of multiple serotypes, global expansion of the disease and recent gains in vaccination coverage, pre-existing immunity to dengue virus is abundant in the human population, and secondary dengue infections are common. Here, we contrast the mechanisms initiating and sustaining adaptive immune responses during primary infection with the immune pathways that are pre-existing and reactivated during secondary dengue. We also discuss new developments in our understanding of the contributions of CD4+ T cells, CD8+ T cells and antibodies to immunity and memory recall. Memory recall may lead to protective or pathological outcomes, and understanding of these processes will be key to developing or refining dengue vaccines to be safe and effective.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Bhatt, S. et al. The global distribution and burden of dengue. Nature 496, 504–507 (2013).

  2. 2.

    Lindenbach, B. D. & Rice, C. M. in Fields Virology 4th edn (eds Knipe, D. M. & Howley, P. M.) 991–104 (Lippincott Williams & Wilkins, 2001).

  3. 3.

    Sabin, A. B. Research on dengue during World War II. Am. J. Trop. Med. Hyg. 1, 30–50 (1952).

  4. 4.

    Sangkawibha, N. et al. Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am. J. Epidemiol. 120, 653–669 (1984).

  5. 5.

    Avirutnan, P., Malasit, P., Seliger, B., Bhakdi, S. & Husmann, M. Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis. J. Immunol. 161, 6338–6346 (1998).

  6. 6.

    Jessie, K., Fong, M. Y., Devi, S., Lam, S. K. & Wong, K. T. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J. Infect. Dis. 189, 1411–1418 (2004).

  7. 7.

    Aye, K. S. et al. Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Hum. Pathol. 45, 1221–1233 (2014).

  8. 8.

    de Andino, R. M. et al. The absence of dengue virus in the skin lesions of dengue fever. Int. J. Dermatol. 24, 48–51 (1985).

  9. 9.

    Guzman, M. G., Gubler, D. J., Izquierdo, A., Martinez, E. & Halstead, S. B. Dengue infection. Nat. Rev. Dis. Primers 2, 16055 (2016).

  10. 10.

    Vaughn, D. W. et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J. Infect. Dis. 181, 2–9 (2000).

  11. 11.

    Libraty, D. H. et al. High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J. Infect. Dis. 186, 1165–1168 (2002).

  12. 12.

    Tricou, V., Minh, N. N., Farrar, J., Tran, H. T. & Simmons, C. P. Kinetics of viremia and NS1 antigenemia are shaped by immune status and virus serotype in adults with dengue. PLOS Negl. Trop. Dis. 5, e1309 (2011).

  13. 13.

    Costa, V. V. et al. Subversion of early innate antiviral responses during antibody-dependent enhancement of dengue virus infection induces severe disease in immunocompetent mice. Med. Microbiol. Immunol. 203, 231–250 (2014).

  14. 14.

    Hotta, H. et al. Inoculation of dengue virus into nude mice. J. Gen. Virol. 52, 71–76 (1981).

  15. 15.

    Janssens, A. S. et al. Mast cell distribution in normal adult skin. J. Clin. Pathol. 58, 285–289 (2005).

  16. 16.

    Zaba, L. C., Fuentes-Duculan, J., Steinman, R. M., Krueger, J. G. & Lowes, M. A. Normal human dermis contains distinct populations of CD11c+BDCA–1+ dendritic cells and CD163+FXIIIA+ macrophages. J. Clin. Invest. 117, 2517–2525 (2007).

  17. 17.

    Libraty, D. H., Pichyangkul, S., Ajariyakhajorn, C., Endy, T. P. & Ennis, F. A. Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis. J. Virol. 75, 3501–3508 (2001).

  18. 18.

    Ho, L. J. et al. Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. J. Immunol. 166, 1499–1506 (2001).

  19. 19.

    St John, A. L. et al. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc. Natl Acad. Sci. USA 108, 9190–9195 (2011).

  20. 20.

    McLachlan, J. B. et al. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nat. Immunol. 4, 1199–1205 (2003).

  21. 21.

    Shelburne, C. P. et al. Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host Microbe 6, 331–342 (2009).

  22. 22.

    Taweechaisupapong, S. et al. Langerhans cell density and serological changes following intradermal immunisation of mice with dengue 2 virus. J. Med. Microbiol. 45, 138–145 (1996).

  23. 23.

    Randolph, G. J., Angeli, V. & Swartz, M. A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 5, 617–628 (2005).

  24. 24.

    Marchette, N. J. et al. Studies on the pathogenesis of dengue infection in monkeys. 3. Sequential distribution of virus in primary and heterologous infections. J. Infect. Dis. 128, 23–30 (1973).

  25. 25.

    Kyle, J. L., Beatty, P. R. & Harris, E. Dengue virus infects macrophages and dendritic cells in a mouse model of infection. J. Infect. Dis. 195, 1808–1817 (2007).

  26. 26.

    Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

  27. 27.

    Schmid, M. A. & Harris, E. Monocyte recruitment to the dermis and differentiation to dendritic cells increases the targets for dengue virus replication. PLOS Pathog. 10, e1004541 (2014).

  28. 28.

    Cerny, D. et al. Selective susceptibility of human skin antigen presenting cells to productive dengue virus infection. PLOS Pathog. 10, e1004548 (2014). This study describes cell types and DC subsets infected by DENV in human skin explants.

  29. 29.

    Kwissa, M. et al. Dengue virus infection induces expansion of a CD14+ CD16+ monocyte population that stimulates plasmablast differentiation. Cell Host Microbe 16, 115–127 (2014).

  30. 30.

    St John, A. L., Rathore, A. P., Raghavan, B., Ng, M. L. & Abraham, S. N. Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage. eLife 2, e00481 (2013).

  31. 31.

    Soundravally, R. & Hoti, S. L. Immunopathogenesis of dengue hemorrhagic fever and shock syndrome: role of TAP and HPA gene polymorphism. Hum. Immunol. 68, 973–979 (2007).

  32. 32.

    LaFleur, C. et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum. Immunol. 63, 1039–1044 (2002).

  33. 33.

    Nightingale, Z. D., Patkar, C. & Rothman, A. L. Viral replication and paracrine effects result in distinct, functional responses of dendritic cells following infection with dengue 2 virus. J. Leukoc. Biol. 84, 1028–1038 (2008).

  34. 34.

    Saron, W. A. A. et al. Flavivirus serocomplex cross-reactive immunity is protective by activating heterologous memory CD4 T cells. Sci. Adv. 4, eaar4297 (2018). This study demonstrates functional CD4 + T FH cell responses during secondary homologous dengue or following other flavivirus infections.

  35. 35.

    Gack, M. U. & Diamond, M. S. Innate immune escape by dengue and West Nile viruses. Curr. Opin. Virol. 20, 119–128 (2016).

  36. 36.

    Montoya, M. et al. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 99, 3263–3271 (2002).

  37. 37.

    Wakil, A. E., Wang, Z. E., Ryan, J. C., Fowell, D. J. & Locksley, R. M. Interferon gamma derived from CD4+ T cells is sufficient to mediate T helper cell type 1 development. J. Exp. Med. 188, 1651–1656 (1998).

  38. 38.

    Mathew, A. et al. Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a. J. Clin. Invest. 98, 1684–1691 (1996).

  39. 39.

    Costa, V. V. et al. Dengue virus-infected dendritic cells, but not monocytes, activate natural killer cells through a contact-dependent mechanism involving adhesion molecules. mBio 8, e00741–17 (2017).

  40. 40.

    Gagnon, S. J., Ennis, F. A. & Rothman, A. L. Bystander target cell lysis and cytokine production by dengue virus-specific human CD4+ cytotoxic T-lymphocyte clones. J. Virol. 73, 3623–3629 (1999).

  41. 41.

    Matangkasombut, P. et al. Invariant NKT cell response to dengue virus infection in human. PLOS Negl. Trop. Dis. 8, e2955 (2014).

  42. 42.

    Mongkolsapaya, J. et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat. Med. 9, 921–927 (2003). This paper describes a contribution of T cell original antigenic sin to severe dengue disease.

  43. 43.

    Screaton, G., Mongkolsapaya, J., Yacoub, S. & Roberts, C. New insights into the immunopathology and control of dengue virus infection. Nat. Rev. Immunol. 15, 745–759 (2015).

  44. 44.

    Hatch, S. et al. Intracellular cytokine production by dengue virus-specific T cells correlates with subclinical secondary infection. J. Infect. Dis. 203, 1282–1291 (2011).

  45. 45.

    Gwinn, W., Sun, W., Innis, B. L., Caudill, J. & King, A. D. Serotype-specific T(H)1 responses in recipients of two doses of candidate live-attenuated dengue virus vaccines. Am. J. Trop. Med. Hyg. 69, 39–47 (2003).

  46. 46.

    Rey, F. A., Stiasny, K., Vaney, M. C., Dellarole, M. & Heinz, F. X. The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design. EMBO Rep. 19, 206–224 (2018).

  47. 47.

    Simon-Loriere, E. et al. Increased adaptive immune responses and proper feedback regulation protect against clinical dengue. Sci. Transl Med. 9, eaal5088 (2017). This study highlights that transcriptional signatures of CD4 + T cell activation and enhanced antigen presentation are present during human asymptomatic dengue infection, suggesting adaptive immune control of dengue.

  48. 48.

    Weiskopf, D. et al. HLA-DRB1 alleles are associated with different magnitudes of dengue virus-specific CD4+ T-cell responses. J. Infect. Dis. 214, 1117–1124 (2016).

  49. 49.

    Yauch, L. E. et al. CD4+ T cells are not required for the induction of dengue virus-specific CD8+ T cell or antibody responses but contribute to protection after vaccination. J. Immunol. 185, 5405–5416 (2010).

  50. 50.

    Longhi, M. P. et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J. Exp. Med. 206, 1589–1602 (2009).

  51. 51.

    Le Bon, A. et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat. Immunol. 4, 1009–1015 (2003).

  52. 52.

    Luhn, K. et al. Increased frequencies of CD4+ CD25(high) regulatory T cells in acute dengue infection. J. Exp. Med. 204, 979–985 (2007).

  53. 53.

    Jayaratne, H. E. et al. Regulatory T cells in acute dengue viral infection. Immunology 154, 89–97 (2018).

  54. 54.

    Haltaufderhyde, K. et al. Activation of peripheral T follicular helper cells during acute dengue virus infection. J. Infect. Dis. 218, 1675–1685 (2018).

  55. 55.

    Shulman, Z. et al. T follicular helper cell dynamics in germinal centers. Science 341, 673–677 (2013).

  56. 56.

    Kurane, I., Meager, A. & Ennis, F. A. Dengue virus-specific human T cell clones. Serotype crossreactive proliferation, interferon gamma production, and cytotoxic activity. J. Exp. Med. 170, 763–775 (1989).

  57. 57.

    Weiskopf, D. et al. Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity. Proc. Natl Acad. Sci. USA 112, E4256–E4263 (2015).

  58. 58.

    Tian, Y. et al. Unique phenotypes and clonal expansions of human CD4 effector memory T cells re-expressing CD45RA. Nat. Commun. 8, 1473 (2017). References 57 and 58 suggest a protective role for effector memory CD4 + T cells known as T EMRA cells, which are cytotoxic in nature, during secondary dengue.

  59. 59.

    Friberg, H. et al. Cross-reactivity and expansion of dengue-specific T cells during acute primary and secondary infections in humans. Sci. Rep. 1, 51 (2011).

  60. 60.

    Chandele, A. et al. Characterization of human CD8 T cell responses in dengue virus-infected patients from India. J. Virol. 90, 11259–11278 (2016).

  61. 61.

    Singla, M. et al. Immune response to dengue virus infection in pediatric patients in New Delhi, India—association of viremia, inflammatory mediators and monocytes with disease severity. PLOS Negl. Trop. Dis. 10, e0004497 (2016).

  62. 62.

    Rivino, L. et al. Virus-specific T lymphocytes home to the skin during natural dengue infection. Sci. Transl Med. 7, 278ra235 (2015).

  63. 63.

    Hughes, A. L. Evolutionary change of predicted cytotoxic T cell epitopes of dengue virus. Infect. Genet. Evol. 1, 123–130 (2001).

  64. 64.

    Weiskopf, D. et al. Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells. Proc. Natl Acad. Sci. USA 110, E2046–E2053 (2013). This study suggests a protective role for CD8 + T cells during human dengue disease.

  65. 65.

    Rivino, L. et al. Differential targeting of viral components by CD4+ versus CD8+ T lymphocytes in dengue virus infection. J. Virol. 87, 2693–2706 (2013).

  66. 66.

    Grifoni, A. et al. Global assessment of dengue virus-specific CD4+ T cell responses in dengue-endemic areas. Front. Immunol. 8, 1309 (2017). This multi-cohort study reports immunodominant epitopes of dengue-specific human CD4 + T cells.

  67. 67.

    Balakrishnan, T. et al. Dengue virus activates polyreactive, natural IgG B cells after primary and secondary infection. PLOS ONE 6, e29430 (2011).

  68. 68.

    De Milito, A. et al. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 103, 2180–2186 (2004).

  69. 69.

    Mathew, A. et al. B cell responses during primary and secondary dengue virus infections in humans. J. Infect. Dis. 204, 1514–1522 (2011).

  70. 70.

    Mehlhop, E. et al. Complement protein C1q reduces the stoichiometric threshold for antibody-mediated neutralization of West Nile virus. Cell Host Microbe 6, 381–391 (2009).

  71. 71.

    Dowd, K. A. & Pierson, T. C. Antibody-mediated neutralization of flaviviruses: a reductionist view. Virology 411, 306–315 (2011).

  72. 72.

    Rouvinski, A. et al. Recognition determinants of broadly neutralizing human antibodies against dengue viruses. Nature 520, 109–113 (2015).

  73. 73.

    Fibriansah, G. et al. Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers. Science 349, 88–91 (2015). References 72 and 73 identify broadly neutralizing dengue antibodies targeting the E dimer of DENV.

  74. 74.

    Cockburn, J. J. et al. Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody. Structure 20, 303–314 (2012).

  75. 75.

    Lok, S. M. The interplay of dengue virus morphological diversity and human antibodies. Trends Microbiol. 24, 284–293 (2016).

  76. 76.

    Waggoner, J. J. et al. Homotypic dengue virus reinfections in Nicaraguan children. J. Infect. Dis. 214, 986–993 (2016).

  77. 77.

    Friberg, H. et al. Memory CD8+ T cells from naturally acquired primary dengue virus infection are highly cross-reactive. Immunol. Cell Biol. 89, 122–129 (2011).

  78. 78.

    Mangada, M. M. & Rothman, A. L. Altered cytokine responses of dengue-specific CD4+ T cells to heterologous serotypes. J. Immunol. 175, 2676–2683 (2005).

  79. 79.

    Beaumier, C. M., Mathew, A., Bashyam, H. S. & Rothman, A. L. Cross-reactive memory CD8+ T cells alter the immune response to heterologous secondary dengue virus infections in mice in a sequence-specific manner. J. Infect. Dis. 197, 608–617 (2008).

  80. 80.

    Wrammert, J. et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453, 667–671 (2008).

  81. 81.

    Wrammert, J. et al. Rapid and massive virus-specific plasmablast responses during acute dengue virus infection in humans. J. Virol. 86, 2911–2918 (2012).

  82. 82.

    Priyamvada, L. et al. B cell responses during secondary dengue virus infection are dominated by highly cross-reactive, memory-derived plasmablasts. J. Virol. 90, 5574–5585 (2016).

  83. 83.

    Xu, M. et al. Plasmablasts generated during repeated dengue infection are virus glycoprotein-specific and bind to multiple virus serotypes. J. Immunol. 189, 5877–5885 (2012).

  84. 84.

    Townsley, E. et al. Distinct activation phenotype of a highly conserved novel HLA-B57-restricted epitope during dengue virus infection. Immunology 141, 27–38 (2014).

  85. 85.

    Guzman, M. G. et al. Epidemiologic studies on dengue in Santiago de Cuba, 1997. Am. J. Epidemiol. 152, 793–799; discussion 804 (2000).

  86. 86.

    Chau, T. N. et al. Dengue in Vietnamese infants—results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity. J. Infect. Dis. 198, 516–524 (2008).

  87. 87.

    Katzelnick, L. C. et al. Antibody-dependent enhancement of severe dengue disease in humans. Science 358, 929–932 (2017). This paper supports the concept of ADE of dengue disease in humans.

  88. 88.

    Halstead, S. B. & O’Rourke, E. J. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J. Exp. Med. 146, 201–217 (1977). This paper describes the mechanism of ADE of dengue infection, involving uptake of virus particles, dependent on the Fc region of antibodies.

  89. 89.

    de Alwis, R. et al. Dengue viruses are enhanced by distinct populations of serotype cross-reactive antibodies in human immune sera. PLOS Pathog. 10, e1004386 (2014).

  90. 90.

    Zellweger, R. M., Prestwood, T. R. & Shresta, S. Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 7, 128–139 (2010).

  91. 91.

    Goncalvez, A. P., Engle, R. E., St Claire, M., Purcell, R. H. & Lai, C. J. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc. Natl Acad. Sci. USA 104, 9422–9427 (2007).

  92. 92.

    Syenina, A., Jagaraj, C. J., Aman, S. A., Sridharan, A. & St John, A. L. Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcgamma receptors. eLife 4, e05291 (2015). This study provides evidence that antibody-dependent mast cell activation can contribute to vascular leakage during DENV infection.

  93. 93.

    Rodenhuis-Zybert, I. A. et al. A fusion-loop antibody enhances the infectious properties of immature flavivirus particles. J. Virol. 85, 11800–11808 (2011).

  94. 94.

    Dejnirattisai, W. et al. Cross-reacting antibodies enhance dengue virus infection in humans. Science 328, 745–748 (2010).

  95. 95.

    Pierson, T. C. et al. The stoichiometry of antibody-mediated neutralization and enhancement of West Nile virus infection. Cell Host Microbe 1, 135–145 (2007). This study reports the number of antibodies required to neutralize or exacerbate flavivirus infection.

  96. 96.

    Tsai, T. T. et al. Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes. PLOS Negl. Trop. Dis. 8, e3320 (2014).

  97. 97.

    Kou, Z. et al. Human antibodies against dengue enhance dengue viral infectivity without suppressing type I interferon secretion in primary human monocytes. Virology 410, 240–247 (2011).

  98. 98.

    Garcia-Bates, T. M. et al. Association between magnitude of the virus-specific plasmablast response and disease severity in dengue patients. J. Immunol. 190, 80–87 (2013).

  99. 99.

    Joo, H. et al. Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation. J. Exp. Med. 209, 1335–1348 (2012).

  100. 100.

    Wang, T. T. et al. IgG antibodies to dengue enhanced for FcgammaRIIIA binding determine disease severity. Science 355, 395–398 (2017). This study shows that dengue-specific afucosylated IgG1 antibodies are associated with severe dengue.

  101. 101.

    Israel, E. J. et al. Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology 92, 69–74 (1997).

  102. 102.

    Chau, T. N. et al. Dengue virus infections and maternal antibody decay in a prospective birth cohort study of Vietnamese infants. J. Infect. Dis. 200, 1893–1900 (2009). This paper discusses maternal antibody decay and the associated risk of severe dengue disease in infants.

  103. 103.

    Clapham, H. et al. Epidemiology of infant dengue cases illuminates serotype-specificity in the interaction between immunity and disease, and changes in transmission dynamics. PLOS Negl. Trop. Dis. 9, e0004262 (2015).

  104. 104.

    Libraty, D. H. et al. A prospective nested case-control study of dengue in infants: rethinking and refining the antibody-dependent enhancement dengue hemorrhagic fever model. PLOS Med. 6, e1000171 (2009).

  105. 105.

    Ng, J. K. et al. First experimental in vivo model of enhanced dengue disease severity through maternally acquired heterotypic dengue antibodies. PLOS Pathog. 10, e1004031 (2014).

  106. 106.

    Lee, P. X., Ong, L. C., Libau, E. A. & Alonso, S. Relative contribution of dengue IgG antibodies acquired during gestation or breastfeeding in mediating dengue disease enhancement and protection in type I interferon receptor-deficient mice. PLOS Negl. Trop. Dis. 10, e0004805 (2016).

  107. 107.

    Balsitis, S. J. et al. Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLOS Pathog. 6, e1000790 (2010).

  108. 108.

    Chan, K. R. et al. Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity. Nat. Microbiol. 1, 16164 (2016).

  109. 109.

    Sridhar, S. et al. Effect of dengue serostatus on dengue vaccine safety and efficacy. N. Engl. J. Med. 379, 327–340 (2018). This study compiles data from multiple Dengvaxia clinical trials that showed efficacy against dengue and reports a risk of hospitalization and severe dengue for vaccinated DENV-naive individuals.

  110. 110.

    Halstead, S. B. Dengvaxia sensitizes seronegatives to vaccine enhanced disease regardless of age. Vaccine 35, 6355–6358 (2017).

  111. 111.

    Koraka, P. et al. Elevated levels of total and dengue virus-specific immunoglobulin E in patients with varying disease severity. J. Med. Virol. 70, 91–98 (2003).

  112. 112.

    Kurane, I., Hebblewaite, D., Brandt, W. E. & Ennis, F. A. Lysis of dengue virus-infected cells by natural cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. J. Virol. 52, 223–230 (1984).

  113. 113.

    Culshaw, A. et al. Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8+ T cell response. Nat. Immunol. 18, 1228–1237 (2017). This study reports that bias towards certain TCR–MHC–peptide interactions can lead to increased DENV pathology during secondary infections, indicating possible germline-encoded susceptibility to severe disease.

  114. 114.

    Yauch, L. E. et al. A protective role for dengue virus-specific CD8+ T cells. J. Immunol. 182, 4865–4873 (2009).

  115. 115.

    Zompi, S., Santich, B. H., Beatty, P. R. & Harris, E. Protection from secondary dengue virus infection in a mouse model reveals the role of serotype cross-reactive B and T cells. J. Immunol. 188, 404–416 (2012).

  116. 116.

    Yachi, P. P., Ampudia, J., Zal, T. & Gascoigne, N. R. Altered peptide ligands induce delayed CD8-T cell receptor interaction—a role for CD8 in distinguishing antigen quality. Immunity 25, 203–211 (2006).

  117. 117.

    Imrie, A. et al. Differential functional avidity of dengue virus-specific T cell clones for variant peptides representing heterologous and previously encountered serotypes. J. Virol. 81, 10081–10091 (2007).

  118. 118.

    Dung, N. T. et al. Timing of CD8+ T cell responses in relation to commencement of capillary leakage in children with dengue. J. Immunol. 184, 7281–7287 (2010).

  119. 119.

    Shedlock, D. J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003).

  120. 120.

    Kuno, G., Chang, G. J., Tsuchiya, K. R., Karabatsos, N. & Cropp, C. B. Phylogeny of the genus flavivirus. J. Virol. 72, 73–83 (1998).

  121. 121.

    Calisher, C. H. et al. Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera. J. Gen. Virol. 70, 37–43 (1989).

  122. 122.

    George, J. et al. Prior exposure to zika virus significantly enhances peak dengue-2 viremia in rhesus macaques. Sci. Rep. 7, 10498 (2017).

  123. 123.

    McCracken, M. K. et al. Impact of prior flavivirus immunity on Zika virus infection in rhesus macaques. PLOS Pathog. 13, e1006487 (2017).

  124. 124.

    Guy, B. et al. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses. Vaccine 28, 632–649 (2010).

  125. 125.

    Saez-Llorens, X. et al. Immunogenicity and safety of one versus two doses of tetravalent dengue vaccine in healthy children aged 2–17 years in Asia and Latin America: 18-month interim data from a phase 2, randomised, placebo-controlled study. Lancet Infect. Dis. 18, 162–170 (2018).

  126. 126.

    Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

  127. 127.

    Arts, R. J. W. et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23, 89–100 (2018).

  128. 128.

    Rouvinski, A. et al. Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope. Nat. Commun. 8, 15411 (2017).

  129. 129.

    Arredondo-Garcia, J. L. et al. Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America. Clin. Microbiol. Infect. 24, 755–763 (2018).

  130. 130.

    Lessler, J. et al. Evidence for antigenic seniority in influenza A (H3N2) antibody responses in southern China. PLOS Pathog. 8, e1002802 (2012).

  131. 131.

    Koutsonanos, D. G. et al. Enhanced immune responses by skin vaccination with influenza subunit vaccine in young hosts. Vaccine 33, 4675–4682 (2015).

  132. 132.

    Querec, T. et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J. Exp. Med. 203, 413–424 (2006).

  133. 133.

    Vaughn, D. W. et al. Dengue in the early febrile phase: viremia and antibody responses. J. Infect. Dis. 176, 322–330 (1997).

  134. 134.

    St John, A. L., Abraham, S. N. & Gubler, D. J. Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis. Nat. Rev. Microbiol. 11, 420–426 (2013).

  135. 135.

    Halstead, S. B. Dengue. Lancet 370, 1644–1652 (2007).

  136. 136.

    Rothman, A. L. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat. Rev. Immunol. 11, 532–543 (2011).

Download references


The authors acknowledge funding from the National Medical Research Council of Singapore (NMRC/CBRG/0084/2015), the National Research Foundation of Singapore (NRF2016NRF-CRP001-063) and Duke–National University of Singapore (NUS) Medical School to A.L.S.

Reviewer information

Nature Reviews Immunology thanks S. Halstead, A. Sette, and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

The authors contributed equally to all aspects of the article.

Correspondence to Ashley L. St. John.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


DENV serotypes

All four serotypes of dengue virus (DENV) share similar but distinct antigenic properties. Polyclonal sera raised to one DENV serotype can bind to all four DENV serotypes and may be minimally neutralizing but will efficiently neutralize and provide long-term protection against only the same serotype. DENV serotypes have ~50–60% sequence homology.

Type I interferon

A group of proteins, including IFNα and IFNβ, that are produced and secreted by cells activated by certain stimuli, including infection, for the purpose of host defence. Often, these interferon proteins have antiviral function.

Heterologous DENV infection

A dengue infection with one dengue virus (DENV) serotype following a primary infection by a different DENV serotype. For instance, DENV1 infection followed by DENV2 infection.

Homologous DENV infection

This refers to a secondary dengue virus (DENV) infection with the same serotype that caused the primary infection. For example, DENV1 infection followed by a secondary DENV1 infection.

T effector memory RA cells

(TEMRA cells). Terminally differentiated antigen-specific memory T cells that re-express CD45RA. These cells have been identified in both CD4+ and CD8+ T cell compartments and can have a cytotoxic phenotype.

Original antigenic sin

Reactivation and expansion of an immune memory response that was formed in response to a previous infection upon exposure to a second infection from a pathogen that has similar but distinct antigenic properties to that of the first pathogen. This results in a skewed and potentially suboptimal immune response generated during infection by the second pathogen.


Groups of antigenically related viruses cluster into serocomplexes on the basis of serological assessments. Polyclonal sera against one virus may bind to but will not neutralize viruses of another serocomplex. Important mosquito-borne human flaviviral pathogens that are clustered in different serocomplexes include dengue virus serotype 1 (DENV1) and DENV4 (DENV serocomplex), Japanese encephalitis virus (JEV) and West Nile virus (JEV serocomplex), and Spondweni virus and Zika virus (Spondweni serocomplex).

Reverse Arthus reaction

The immune complex-mediated vasculitis in a type III hypersensitivity reaction that results from the injection of antibodies into the skin following passive infusion of antigen.

Antibody-dependent cellular cytotoxicity

An immune phenomenon where crystallizable fragment (Fc) receptor-bearing cytotoxic immune cells can recognize and lyse antibody-coated, antigen-expressing cells. Antigens that can lead to antibody-dependent cellular cytotoxicity may arise owing to infection.

Antigenic seniority

First described in the context of antibody responses to influenza, this refers to the observation that during repeated infections with related viruses, immune responses are skewed towards the original strain encountered. Similar to original antigenic sin, this concept incorporates the idea that antigenic exposure to similar viruses is influenced by the genetic relationships between them and that certain epitopes of ‘senior strains’ experienced early in life will begin to dominate the immune responses during subsequent exposures to related pathogens.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading

Fig. 1: Time course of acute infection and immune responses during symptomatic dengue virus infection.
Fig. 2: Initiation of anti-dengue virus immunity in the skin and draining lymph nodes.
Fig. 3: Adaptive T cell responses during dengue virus infection.
Fig. 4: Antibody-dependent pathologies during dengue virus infections.
Fig. 5: Theories of T cell contributions to dengue virus protection versus pathology.