Review Article | Published:

The immune response against flaviviruses

Nature Immunologyvolume 19pages11891198 (2018) | Download Citation

Abstract

Arthropod-borne flaviviruses are important human pathogens that cause a diverse range of clinical conditions, including severe hemorrhagic syndromes, neurological complications and congenital malformations. Consequently, there is an urgent need to develop safe and effective vaccines, a process requiring better understanding of the immunological mechanisms involved during infection. Decades of research suggest a paradoxical role of the immune response against flaviviruses: although the immune response is crucial for the control, clearance and prevention of infection, poor clinical outcomes are commonly associated with virus-specific immunity and immunopathogenesis. This relationship is further complicated by the high homology among viruses and the implication of cross-reactive immune responses in protection and pathogenesis. This Review examines the dual role of the adaptive immune response against flaviviruses, particularly emphasizing the most recent findings regarding cross-reactive T cell and antibody responses, and the effects that these concepts have on vaccine-development endeavors.

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References

  1. 1.

    Family - Flaviviridae. in Virus Taxonomy (eds. King, A.M.Q. et al.) 1003–1020 (Elsevier, San Diego, 2012).

  2. 2.

    Culshaw, A., Mongkolsapaya, J. & Screaton, G. The immunology of Zika virus. F1000Res. 7, 203 (2018).

  3. 3.

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

  4. 4.

    Lindenbach, B.D., Heinz-Jurgen, T. & Rice, C.M. Flaviviridae: the viruses and their replication. in Fields’ Virology 5th edn. (eds. Fields, B.N., Knipe, D.M. & Howley, P.M.) (Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, 2007).

  5. 5.

    Modis, Y. Relating structure to evolution in class II viral membrane fusion proteins. Curr. Opin. Virol. 5, 34–41 (2014).

  6. 6.

    Sirohi, D. et al. The 3.8 Å resolution cryo-EM structure of Zika virus. Science 352, 467–470 (2016).

  7. 7.

    Perera, R. & Kuhn, R. J. Structural proteomics of dengue virus. Curr. Opin. Microbiol. 11, 369–377 (2008).

  8. 8.

    Yu, I. M. et al. Structure of the immature dengue virus at low pH primes proteolytic maturation. Science 319, 1834–1837 (2008).

  9. 9.

    Plevka, P. et al. Maturation of flaviviruses starts from one or more icosahedrally independent nucleation centres. EMBO Rep. 12, 602–606 (2011).

  10. 10.

    Cherrier, M. V. et al. Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibody. EMBO J. 28, 3269–3276 (2009).

  11. 11.

    Dejnirattisai, W. et al. Cross-reacting antibodies enhance dengue virus infection in humans. Science 328, 745–748 (2010). This paper shows that antibodies to prM are strong inducers of ADE and have poor neutralizing activity.

  12. 12.

    Dejnirattisai, W. et al. A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat. Immunol. 16, 170–177 (2015). This paper describes human mAbs against the quaternary EDE epitopes and their ability to potently neutralize all four DENV serotypes.

  13. 13.

    Kuhn, R. J., Dowd, K. A., Beth Post, C. & Pierson, T. C. Shake, rattle, and roll: Impact of the dynamics of flavivirus particles on their interactions with the host. Virology 479-480, 508–517 (2015).

  14. 14.

    Zhang, X. et al. Dengue structure differs at the temperatures of its human and mosquito hosts. Proc. Natl. Acad. Sci. USA 110, 6795–6799 (2013).

  15. 15.

    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). This review describes in detail the structural properties of the flavivirus particle, their interaction with the humoral response and the mechanisms involved in antibody-mediated neutralization.

  16. 16.

    Duangchinda, T. et al. Immunodominant T-cell responses to dengue virus NS3 are associated with DHF. Proc. Natl. Acad. Sci. USA 107, 16922–16927 (2010).

  17. 17.

    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).

  18. 18.

    Weiskopf, D. et al. The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes. J. Virol. 89, 120–128 (2015).

  19. 19.

    Grifoni, A. et al. Global assessment of dengue virus-specific CD4+ T cell responses in dengue-endemic areas. Front. Immunol. 8, 1309 (2017).

  20. 20.

    Turtle, L. et al. Human T cell responses to Japanese encephalitis virus in health and disease. J. Exp. Med. 213, 1331–1352 (2016).

  21. 21.

    James, E. A. et al. Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins. J. Virol. 87, 12794–12804 (2013).

  22. 22.

    Akondy, R. S. et al. The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J. Immunol. 183, 7919–7930 (2009).

  23. 23.

    Grifoni, A. et al. Prior Dengue virus exposure shapes T cell immunity to Zika virus in humans. J. Virol. https://doi.org/10.1128/JVI.01469-17 (2017).

  24. 24.

    Ricciardi, M. J. et al. Ontogeny of the B- and T-cell response in a primary Zika virus infection of a dengue-naïve individual during the 2016 outbreak in Miami, FL. PLoS Negl. Trop. Dis. 11, e0006000 (2017).

  25. 25.

    Reynolds, C. J. et al. T cell immunity to Zika virus targets immunodominant epitopes that show cross-reactivity with other Flaviviruses. Sci. Rep. 8, 672 (2018).

  26. 26.

    Elong Ngono, A. et al. Mapping and role of the CD8+ T cell response during primary Zika virus infection in mice. Cell Host Microbe 21, 35–46 (2017).

  27. 27.

    Shrestha, B., Samuel, M. A. & Diamond, M. S. CD8+ T cells require perforin to clear West Nile virus from infected neurons. J. Virol. 80, 119–129 (2006).

  28. 28.

    Shrestha, B., Pinto, A. K., Green, S., Bosch, I. & Diamond, M. S. CD8+ T cells use TRAIL to restrict West Nile virus pathogenesis by controlling infection in neurons. J. Virol. 86, 8937–8948 (2012).

  29. 29.

    Jain, N. et al. CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function. PLoS Negl. Trop. Dis. 11, e0005329 (2017).

  30. 30.

    Huang, H. et al. CD8+ T cell immune response in immunocompetent mice during Zika virus infection. J. Virol. 91, e00900–17 (2017).

  31. 31.

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

  32. 32.

    Bassi, M. R. et al. CD8+ T cells complement antibodies in protecting against yellow fever virus. J. Immunol. 194, 1141–1153 (2015).

  33. 33.

    Nazerai, L. et al. A new in vivo model to study protective immunity to Zika virus infection in mice with intact type I interferon signaling. Front. Immunol. 9, 593 (2018).

  34. 34.

    Wang, Y., Lobigs, M., Lee, E. & Müllbacher, A. CD8+ T cells mediate recovery and immunopathology in West Nile virus encephalitis. J. Virol. 77, 13323–13334 (2003).

  35. 35.

    Jurado, K. A. et al. Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice. Nat. Microbiol. 3, 141–147 (2018). This paper provides evidence that CD8 + T cell–derived immunopathology might be involved in the development of neural complications in ZIKV-infected mice with impaired innate resistance.

  36. 36.

    Phares, T. W. et al. CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J. Virol. 86, 2416–2427 (2012).

  37. 37.

    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).

  38. 38.

    Brien, J. D., Uhrlaub, J. L. & Nikolich-Zugich, J. West Nile virus-specific CD4 T cells exhibit direct antiviral cytokine secretion and cytotoxicity and are sufficient for antiviral protection. J. Immunol. 181, 8568–8575 (2008).

  39. 39.

    Biswas, S. M., Ayachit, V. M., Sapkal, G. N., Mahamuni, S. A. & Gore, M. M. Japanese encephalitis virus produces a CD4+ Th2 response and associated immunoprotection in an adoptive-transfer murine model. J. Gen. Virol. 90, 818–826 (2009).

  40. 40.

    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 shows that the breadth and magnitude of the anti-DENV CD8 + T cell response in humans are associated with specific HLA alleles and a protective role for this cell population against DENV.

  41. 41.

    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).

  42. 42.

    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).

  43. 43.

    Kohler, S. et al. The early cellular signatures of protective immunity induced by live viral vaccination. Eur. J. Immunol. 42, 2363–2373 (2012).

  44. 44.

    Cimini, E. et al. Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells. Sci. Rep. 7, 6313 (2017).

  45. 45.

    Quaresma, J. A. et al. Hepatocyte lesions and cellular immune response in yellow fever infection. Trans. R. Soc. Trop. Med. Hyg. 101, 161–168 (2007).

  46. 46.

    Mongkolsapaya, J. et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat. Med. 9, 921–927 (2003). This study shows original antigenic sin in dengue infection, in which many DENV-specific T cell responses during secondary dengue had low affinity for the infecting serotype but higher affinity to other serotypes, probably the previously infecting serotype.

  47. 47.

    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).

  48. 48.

    Webster, R. G. Disquisitions of original antigenic sin. I. Evidence in man. J. Exp. Med. 124, 331–345 (1966).

  49. 49.

    Mangada, M. M. et al. Dengue-specific T cell responses in peripheral blood mononuclear cells obtained prior to secondary dengue virus infections in Thai schoolchildren. J. Infect. Dis. 185, 1697–1703 (2002).

  50. 50.

    Talarico, L. B. et al. The role of heterotypic DENV-specific CD8+T lymphocytes in an immunocompetent mouse model of secondary dengue virus infection. EBioMedicine 20, 202–216 (2017). This study shows that cross-reactive T cell responses generated from the first infection contribute to the development of hemorrhagic disease in mice secondarily infected with the other serotype.

  51. 51.

    Elong Ngono, A. et al. Protective role of cross-reactive CD8 T cells against dengue virus infection. EBioMedicine 13, 284–293 (2016).

  52. 52.

    Zellweger, R. M. et al. CD8+ T cells can mediate short-term protection against heterotypic dengue virus reinfection in mice. J. Virol. 89, 6494–6505 (2015). This paper addresses the contribution of cross-reactive anti-DENV T cell responses and shows that this type of immunity is required to protect against infection with a heterotypic DENV serotype but not against homotypic reinfection.

  53. 53.

    Wen, J. et al. Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+ T cells. Nat. Microbiol. 2, 17036 (2017). The results presented in this paper not only identify DENV and ZIKV cross-reactive epitopes but also show that the T cell response against ZIKV is altered in DENV-immune and naïve mice.

  54. 54.

    Li, J. et al. Cross-protection induced by Japanese encephalitis vaccines against different genotypes of Dengue viruses in mice. Sci. Rep. 6, 19953 (2016).

  55. 55.

    Stettler, K. et al. Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection. Science 353, 823–826 (2016). This paper provides in vivo evidence of serological interaction between DENV and ZIKV, demonstrating that antibodies to ZIKV can enhance DENV infection in mice.

  56. 56.

    Zhao, H. et al. Structural basis of Zika virus-specific antibody protection. Cell 166, 1016–1027 (2016).

  57. 57.

    Beltramello, M. et al. The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. Cell Host Microbe 8, 271–283 (2010). Through analysis of samples from DENV-infected patients, this study shows that the human antibody response is dominated by cross-reactive antibodies to EDI/DII and prM.

  58. 58.

    Throsby, M. et al. Isolation and characterization of human monoclonal antibodies from individuals infected with West Nile Virus. J. Virol. 80, 6982–6992 (2006).

  59. 59.

    Wahala, W. M., Kraus, A. A., Haymore, L. B., Accavitti-Loper, M. A. & de Silva, A. M. Dengue virus neutralization by human immune sera: role of envelope protein domain III-reactive antibody. Virology 392, 103–113 (2009).

  60. 60.

    Robbiani, D. F. et al. Recurrent potent human neutralizing antibodies to Zika virus in Brazil and Mexico. Cell 169, 597–609.e511 (2017).

  61. 61.

    Yu, L. et al. Delineating antibody recognition against Zika virus during natural infection. JCI Insight 2, e93042 (2017).

  62. 62.

    Dejnirattisai, W. et al. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat. Immunol. 17, 1102–1108 (2016).

  63. 63.

    Nelson, S. et al. Maturation of West Nile virus modulates sensitivity to antibody-mediated neutralization. PLoS Pathog. 4, e1000060 (2008).

  64. 64.

    Fibriansah, G. & Lok, S. M. The development of therapeutic antibodies against dengue virus. Antiviral Res. 128, 7–19 (2016).

  65. 65.

    Teoh, E. P. et al. The structural basis for serotype-specific neutralization of dengue virus by a human antibody. Sci. Transl. Med. 4, 139ra83 (2012).

  66. 66.

    de Alwis, R. et al. In-depth analysis of the antibody response of individuals exposed to primary dengue virus infection. PLoS Negl. Trop. Dis. 5, e1188 (2011).

  67. 67.

    Fibriansah, G. et al. A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. Nat. Commun. 6, 6341 (2015).

  68. 68.

    Fibriansah, G. et al. A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. EMBO Mol. Med. 6, 358–371 (2014).

  69. 69.

    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).

  70. 70.

    Qiu, X. et al. Structural basis for neutralization of Japanese encephalitis virus by two potent therapeutic antibodies. Nat. Microbiol. 3, 287–294 (2018).

  71. 71.

    Hasan, S. S. et al. A human antibody against Zika virus crosslinks the E protein to prevent infection. Nat. Commun. 8, 14722 (2017).

  72. 72.

    Kaufmann, B. et al. Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354. Proc. Natl. Acad. Sci. USA 107, 18950–18955 (2010).

  73. 73.

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

  74. 74.

    Abbink, P. et al. Therapeutic and protective efficacy of a dengue antibody against Zika infection in rhesus monkeys. Nat. Med. 24, 721–723 (2018).

  75. 75.

    Barba-Spaeth, G. et al. Structural basis of potent Zika–dengue virus antibody cross-neutralization. Nature 536, 48–53 (2016).

  76. 76.

    Smith, S. A. et al. Persistence of circulating memory B cell clones with potential for dengue virus disease enhancement for decades following infection. J. Virol. 86, 2665–2675 (2012).

  77. 77.

    Junjhon, J. 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. J. Virol. 82, 10776–10791 (2008).

  78. 78.

    Watterson, D., Modhiran, N. & Young, P. R. The many faces of the flavivirus NS1 protein offer a multitude of options for inhibitor design. Antiviral Res. 130, 7–18 (2016).

  79. 79.

    Modhiran, N. et al. Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci. Transl. Med. 7, 304ra142 (2015).

  80. 80.

    Puerta-Guardo, H., Glasner, D. R. & Harris, E. Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability. PLoS Pathog. 12, e1005738 (2016).

  81. 81.

    Schlesinger, J. J., Brandriss, M. W. & Walsh, E. E. Protection against 17D yellow fever encephalitis in mice by passive transfer of monoclonal antibodies to the nonstructural glycoprotein gp48 and by active immunization with gp48. J. Immunol. 135, 2805–2809 (1985).

  82. 82.

    Henchal, E. A., Henchal, L. S. & Schlesinger, J. J. Synergistic interactions of anti-NS1 monoclonal antibodies protect passively immunized mice from lethal challenge with dengue 2 virus. J. Gen. Virol. 69, 2101–2107 (1988).

  83. 83.

    Chung, K. M. et al. Antibodies against West Nile Virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptor-dependent and -independent mechanisms. J. Virol. 80, 1340–1351 (2006).

  84. 84.

    Beatty, P. R. et al. Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci. Transl. Med. 7, 304ra141 (2015). This paper, together with refs. 79,80 , shows that DENV NS1 is involved in the development of vascular leakage in mice.

  85. 85.

    Chuang, Y. C., Lin, J., Lin, Y. S., Wang, S. & Yeh, T. M. Dengue virus nonstructural protein 1-induced antibodies cross-react with human plasminogen and enhance its activation. J. Immunol. 196, 1218–1226 (2016).

  86. 86.

    Chuang, Y. C., Lin, Y. S., Liu, H. S. & Yeh, T. M. Molecular mimicry between dengue virus and coagulation factors induces antibodies to inhibit thrombin activity and enhance fibrinolysis. J. Virol. 88, 13759–13768 (2014).

  87. 87.

    Halstead, S. B., Chow, J. S. & Marchette, N. J. Immunological enhancement of dengue virus replication. Nat. New Biol. 243, 24–26 (1973).

  88. 88.

    Halstead, S. B. & O’Rourke, E. J. Antibody-enhanced dengue virus infection in primate leukocytes. Nature 265, 739–741 (1977).

  89. 89.

    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).

  90. 90.

    Kliks, S. C., Nimmanitya, S., Nisalak, A. & Burke, D. S. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am. J. Trop. Med. Hyg. 38, 411–419 (1988).

  91. 91.

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

  92. 92.

    Hadinegoro, S. R. et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N. Engl. J. Med. 373, 1195–1206 (2015).

  93. 93.

    Halstead, S. B. & Russell, P. K. Protective and immunological behavior of chimeric yellow fever dengue vaccine. Vaccine 34, 1643–1647 (2016).

  94. 94.

    SAGE Working Group on Dengue Vaccines and WHO Secretariat. Background paper on dengue vaccines: revision to the background paper from 17 March 2016. SAGE Meeting of April 2018 http://www.who.int/immunization/sage/meetings/2018/april/2_DengueBackgrPaper_SAGE_Apr2018.pdf?ua=1 (2018)

  95. 95.

    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).

  96. 96.

    Haslwanter, D., Blaas, D., Heinz, F. X. & Stiasny, K. A novel mechanism of antibody-mediated enhancement of flavivirus infection. PLoS Pathog. 13, e1006643 (2017). This work describes a new modality of ADE in which enhancement of viral entry is derived from an antibody-mediated increase in the exposure of the fusion loop and is independent of other cell-surface proteins.

  97. 97.

    Zellweger, R. M., Eddy, W. E., Tang, W. W., Miller, R. & Shresta, S. CD8+ T cells prevent antigen-induced antibody-dependent enhancement of dengue disease in mice. J. Immunol. 193, 4117–4124 (2014).

  98. 98.

    Fagbami, A. H., Halstead, S. B., Marchette, N. J. & Larsen, K. Cross-infection enhancement among African flaviviruses by immune mouse ascitic fluids. Cytobios 49, 49–55 (1987).

  99. 99.

    Halstead, S. B., Porterfield, J. S. & O’Rourke, E. J. Enhancement of dengue virus infection in monocytes by flavivirus antisera. Am. J. Trop. Med. Hyg. 29, 638–642 (1980).

  100. 100.

    Priyamvada, L. et al. Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus. Proc. Natl. Acad. Sci. USA 113, 7852–7857 (2016).

  101. 101.

    Bardina, S. V. et al. Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. Science 356, 175–180 (2017).

  102. 102.

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

  103. 103.

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

  104. 104.

    Halai, U. A. et al. Maternal Zika virus disease severity, virus load, prior dengue antibodies, and their relationship to birth outcomes. Clin. Infect. Dis. 65, 877–883 (2017).

  105. 105.

    Anderson, K. B. et al. Preexisting Japanese encephalitis virus neutralizing antibodies and increased symptomatic dengue illness in a school-based cohort in Thailand. PLoS Negl. Trop. Dis. 5, e1311 (2011).

  106. 106.

    Saito, Y. et al. Japanese encephalitis vaccine-facilitated dengue virus infection-enhancement antibody in adults. BMC Infect. Dis. 16, 578 (2016).

  107. 107.

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

  108. 108.

    Scherwitzl, I., Mongkolsapaja, J. & Screaton, G. Recent advances in human flavivirus vaccines. Curr. Opin. Virol. 23, 95–101 (2017).

  109. 109.

    Kirkpatrick, B. D. et al. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci. Transl. Med. 8, 330ra36 (2016).

  110. 110.

    Guy, B. et al. From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine. Vaccine 29, 7229–7241 (2011).

  111. 111.

    Sabchareon, A. et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 380, 1559–1567 (2012).

  112. 112.

    Capeding, M. R. et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 384, 1358–1365 (2014).

  113. 113.

    Villar, L. et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N. Engl. J. Med. 372, 113–123 (2015).

  114. 114.

    Sridhar, S. et al. Effect of dengue serostatus on dengue vaccine safety and efficacy. N. Engl. J. Med. 379, 327–340 (2018). This study on cumulative safety and efficacy confirms the higher risk of severe dengue among seronegative Dengvaxia recipients than among seronegative vaccine controls.

  115. 115.

    Lima, N. S., Rolland, M., Modjarrad, K. & Trautmann, L. T cell immunity and Zika virus vaccine development. Trends Immunol. 38, 594–605 (2017).

  116. 116.

    Guy, B. & Jackson, N. Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Nat. Rev. Microbiol. 14, 45–54 (2016).

  117. 117.

    Ishikawa, T., Yamanaka, A. & Konishi, E. A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available. Vaccine 32, 1326–1337 (2014).

  118. 118.

    Brault, A. C. et al. A Zika vaccine targeting NS1 protein protects immunocompetent adult mice in a lethal challenge model. Sci. Rep. 7, 14769 (2017).

  119. 119.

    Ishikawa, T. et al. Enhancing the utility of a prM/E-expressing chimeric vaccine for Japanese encephalitisby addition of the JEV NS1 gene.Vaccine 29, 7444–7455 (2011).

  120. 120.

    Chen, M. C. et al. Deletion of the C-terminal region of dengue virus nonstructural protein 1 (NS1) abolishes anti-NS1-mediated platelet dysfunction and bleeding tendency. J. Immunol. 183, 1797–1803 (2009).

  121. 121.

    Zheng, A., Umashankar, M. & Kielian, M. In vitro and in vivo studies identify important features of dengue virus pr-E protein interactions. PLoS Pathog. 6, e1001157 (2010).

  122. 122.

    Crill, W. D. et al. Sculpting humoral immunity through dengue vaccination to enhance protective immunity. Front. Immunol. 3, 334 (2012).

  123. 123.

    Richner, J. M. et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114–1125.e1110 (2017).

  124. 124.

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

  125. 125.

    Slon Campos, J. L. et al. Temperature-dependent folding allows stable dimerization of secretory and virus-associated E proteins of Dengue and Zika viruses in mammalian cells. Sci. Rep. 7, 966 (2017).

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Acknowledgements

This work was supported by the Wellcome Trust, UK, and the Newton-Medical Research Council, UK. G.R.S. is supported as a Wellcome Trust Senior Investigator.

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Affiliations

  1. Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    • Jose Luis Slon Campos
    •  & Juthathip Mongkolsapaya
  2. Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Siriraj Hospital, Faculty of Medicine, Mahidol University, Bangkok, Thailand

    • Juthathip Mongkolsapaya
  3. Division of Medical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK

    • Gavin R. Screaton

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Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Gavin R. Screaton.

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DOI

https://doi.org/10.1038/s41590-018-0210-3