Japanese encephalitis — the prospects for new treatments

Key Points

  • Japanese encephalitis is a severe disease caused by Japanese encephalitis virus, genus Flavivirus, family Flaviviridae, which is endemic to most of rural Asia and for which no specific treatment exists.

  • Japanese encephalitis causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition.

  • Pathogenesis studies indicate that inhibition of viral replication, viral spread and the host response are needed in combination for optimal therapy.

  • Animal models and in vitro experiments highlight a number of compounds that are potentially suitable for treatment of Japanese encephalitis in humans that could be tested without delay.

  • The minimum clinically significant treatment effect has probably been underestimated, and previous clinical trials of Japanese encephalitis have been too small; larger, pragmatic trials are needed.

Abstract

Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.

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Figure 1: JEV structure.
Figure 2: Features of Japanese encephalitis.
Figure 3: Clinical outcome of Japanese encephalitis.
Figure 4: Origin and genotype spread of JEV in Southeast Asia.
Figure 5: Overview of the pathogenesis of Japanese encephalitis.
Figure 6: CD4+ T cell responses in patients recovered from Japanese encephalitis.

References

  1. 1

    Campbell, G. L. et al. Estimated global incidence of Japanese encephalitis: a systematic review. Bull. World Health Organ. 89, 766–774 (2011).

  2. 2

    Mathers, C. D., Ezzati, M. & Lopez, A. D. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl. Trop. Dis. 1, e114 (2007).

  3. 3

    World Health Organisation. The World Health Report 2004: Changing History (WHO, Geneva, 2004).

  4. 4

    Lindenbach, B. D. & Rice, C. M. Molecular biology of flaviviruses. Adv. Virus Res. 59, 23–61 (2003).

  5. 5

    Sumiyoshi, H. et al. Complete nucleotide sequence of the Japanese encephalitis virus genome RNA. Virology 161, 497–510 (1987).

  6. 6

    Buescher, E. L. & Scherer, W. F. Ecologic studies of Japanese encephalitis virus in Japan. IX. Epidemiologic correlations and conclusions. Am. J. Trop. Med. Hyg. 8, 719–722 (1959).

  7. 7

    Konno, J., Endo, K., Agatsuma, H. & Ishida, N. Cyclic outbreaks of Japanese encephalitis among pigs and humans. Am. J. Epidemiol. 84, 292–300 (1966).

  8. 8

    Lord, J. S., Gurley, E. S. & Pulliam, J. R. Rethinking Japanese encephalitis virus transmission: a framework for implicating host and vector species. PLoS Negl. Trop. Dis. 9, e0004074 (2015).

  9. 9

    Simon-Loriere, E. et al. Autochthonous Japanese encephalitis with yellow fever coinfection in Africa. N. Engl. J. Med. 376, 1483–1485 (2017).

  10. 10

    Ricklin, M. E. et al. Vector-free transmission and persistence of Japanese encephalitis virus in pigs. Nat. Commun. 7, 10832 (2016).

  11. 11

    Hanna, J. N. et al. An outbreak of Japanese encephalitis in the Torres Strait, Australia, 1995. Med. J. Aust. 165, 256–260 (1996).

  12. 12

    Halstead, S. B. & Jacobson, J. Japanese encephalitis. Adv. Virus Res. 61, 103–138 (2003).

  13. 13

    Lincoln, A. F. & Sivertson, S. E. Acute phase of Japanese B encephalitis; two hundred and one cases in American soldiers, Korea, 1950. J. Am. Med. Assoc. 150, 268–273 (1952).

  14. 14

    Hills, S. L., Griggs, A. C. & Fischer, M. Japanese encephalitis in travelers from non-endemic countries, 1973–2008. Am. J. Trop. Med. Hyg. 82, 930–936 (2010).

  15. 15

    Xu, Y. et al. Viral etiology of acute childhood encephalitis in Beijing diagnosed by analysis of single samples. Pediatr. Infect. Dis. J. 15, 1018–1024 (1996).

  16. 16

    Kumari, R. et al. First indigenous transmission of Japanese encephalitis in urban areas of National Capital Territory of Delhi, India. Trop. Med. Int. Health 18, 743–749 (2013).

  17. 17

    Miles, J. A. Epidemiology of the arthropod-borne encephalitides. Bull. World Health Organ. 22, 339–371 (1960).

  18. 18

    Grossman, R. A., Edelman, R. & Gould, D. J. Study of Japanese encephalitis virus in Chiangmia Valley, Thailand. VI. Summary and conclusions. Am. J. Epidemiol. 100, 69–76 (1974).

  19. 19

    Kari, K. et al. A hospital-based surveillance for Japanese encephalitis in Bali. Indonesia. BMC Med. 4, 8 (2006).

  20. 20

    Southam, C. M. Serological studies of encephalitis in Japan. II. Inapparent infections by Japanese B encephalitis virus. J. Infect. Dis. 99, 163–169 (1956).

  21. 21

    Grossman, R. A., Edelman, R., Willhight, M., Pantuwatana, S. & Udomsakdi, S. Study of Japanese encephalitis virus in Chiangmai Valley, Thailand. 3. Human seroepidemiology and inapparent infections. Am. J. Epidemiol. 98, 133–149 (1973).

  22. 22

    Scherer, W. F. et al. Immunologic studies of Japanese encephalitis virus in Japan. II. Antibody responses following inapparent human infection. J. Immunol. 83, 594–604 (1959).

  23. 23

    Kono, R. & Kim, K. H. Comparative epidemiological features of Japanese encephalitis in the Republic of Korea, China (Taiwan) and Japan. Bull. World Health Organ. 40, 263–277 (1969).

  24. 24

    Arai, S. et al. Japanese encephalitis: surveillance and elimination effort in Japan from 1982 to 2004. Jpn J. Infect. Dis. 61, 333–338 (2008).

  25. 25

    Watt, G. & Jongsakul, K. Acute undifferentiated fever caused by infection with Japanese encephalitis virus. Am. J. Trop. Med. Hyg. 68, 704–706 (2003).

  26. 26

    Misra, U. K. & Kalita, J. Movement disorders in Japanese encephalitis. J. Neurol. 244, 299–303 (1997).

  27. 27

    Solomon, T. et al. Poliomyelitis-like illness due to Japanese encephalitis virus. Lancet 351, 1094–1097 (1998).

  28. 28

    Solomon, T. et al. Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis. Brain 125, 1084–1093 (2002).

  29. 29

    Kumar, R., Tripathi, P., Singh, S. & Bannerji, G. Clinical features in children hospitalized during the 2005 epidemic of Japanese encephalitis in Uttar Pradesh, India. Clin. Infect. Dis. 43, 123–131 (2006).

  30. 30

    Sarkari, N. B. et al. Japanese encephalitis (JE). Part I: clinical profile of 1,282 adult acute cases of four epidemics. J. Neurol. 259, 47–57 (2012).

  31. 31

    Ravi, V. et al. Association of Japanese encephalitis virus infection with Guillain-Barre syndrome in endemic areas of south India. Acta Neurol. Scand. 90, 67–72 (1994).

  32. 32

    Xiang, J. Y., Zhang, Y. H., Tan, Z. R., Huang, J. & Zhao, Y. W. Guillain-Barre syndrome associated with Japanese encephalitis virus infection in China. Viral Immunol. 27, 418–420 (2014).

  33. 33

    Sejvar, J. J. et al. Acute flaccid paralysis and West Nile virus infection. Emerg. Infect. Dis. 9, 788–793 (2003).

  34. 34

    Miyake, M. The pathology of Japanese encephalitis. A Review. Bull. World Health Organ. 30, 153–160 (1964).

  35. 35

    Carod-Artal, F. J., Wichmann, O., Farrar, J. & Gascon, J. Neurological complications of dengue virus infection. Lancet Neurol. 12, 906–919 (2013).

  36. 36

    Ahmed, S., Libman, R., Wesson, K., Ahmed, F. & Einberg, K. Guillain-Barre syndrome: an unusual presentation of West Nile virus infection. Neurology 55, 144–146 (2000).

  37. 37

    Verma, R., Praharaj, H. N., Patil, T. B. & Giri, P. Acute transverse myelitis following Japanese encephalitis viral infection: an uncommon complication of a common disease. BMJ Case Rep. https://doi.org/10.1136/bcr-2012-007094 (2012).

  38. 38

    Chen, W. L., Liao, M. F., Chiang, H. L. & Lin, S. K. A possible case of acute disseminated encephalomyelitis after Japanese encephalitis. Acta Neurol. Taiwan. 22, 169–173 (2013).

  39. 39

    Ma, J., Zhang, T. & Jiang, L. Japanese encephalitis can trigger antiNmethyl-Daspartate receptor encephalitis. J. Neurol. 264, 1127–1131 (2017).

  40. 40

    Das, S. & Basu, A. Japanese encephalitis virus infects neural progenitor cells and decreases their proliferation. J. Neurochem. 106, 1624–1636 (2008).

  41. 41

    Chaturvedi, U. C. et al. Transplacental infection with Japanese encephalitis virus. J. Infect. Dis. 141, 712–715 (1980).

  42. 42

    Patgiri, S. J. et al. An appraisal of clinicopathological parameters in Japanese encephalitis and changing epidemiological trends in upper Assam, India. Indian J. Pathol. Microbiol. 57, 400–406 (2014).

  43. 43

    Hsu, S. T. et al. The effect of vaccination with a live attenuated strain of Japanese encephalitis virus on stillbirths in swine in Taiwan. Bull. World Health Organ. 46, 465–471 (1972).

  44. 44

    Rayamajhi, A. et al. Clinical and prognostic features among children with acute encephalitis syndrome in Nepal; a retrospective study. BMC Infect. Dis. 11, 294 (2011).

  45. 45

    Rayamajhi, A. et al. A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal. PLoS ONE 10, e0122608 (2015).

  46. 46

    Burke, D. S., Nisalak, A., Ussery, M. A., Laorakpongse, T. & Chantavibul, S. Kinetics of IgM and IgG responses to Japanese encephalitis virus in human serum and cerebrospinal fluid. J. Infect. Dis. 151, 1093–1099 (1985).

  47. 47

    Leake, C. J., Burke, D. S., Nisalak, A. & Hoke, C. H. Isolation of Japanese encephalitis virus from clinical specimens using a continuous mosquito cell line. Am. J. Trop. Med. Hyg. 35, 1045–1050 (1986).

  48. 48

    Sarkar, A., Datta, S., Pathak, B. K., Mukhopadhyay, S. K. & Chatterjee, S. Japanese encephalitis associated acute encephalitis syndrome cases in West Bengal, India: a sero-molecular evaluation in relation to clinico-pathological spectrum. J. Med. Virol. 87, 1258–1267 (2015).

  49. 49

    Sapkal, G. N., Wairagkar, N. S., Ayachit, V. M., Bondre, V. P. & Gore, M. M. Detection and isolation of Japanese encephalitis virus from blood clots collected during the acute phase of infection. Am. J. Trop. Med. Hyg. 77, 1139–1145 (2007).

  50. 50

    Zhao, H. et al. Japanese encephalitis virus RNA not detected in urine. Clin. Infect. Dis. 57, 157–158 (2013).

  51. 51

    Kalita, J., Misra, U. K., Mani, V. E. & Bhoi, S. K. Can we differentiate between herpes simplex encephalitis and Japanese encephalitis? J. Neurol. Sci. 366, 110–115 (2016).

  52. 52

    Dung, N. M. et al. An evaluation of the usefulness of neuroimaging for the diagnosis of Japanese encephalitis. J. Neurol. 256, 2052–2060 (2009).

  53. 53

    Hoke, C. H. et al. Protection against Japanese encephalitis by inactivated vaccines. N. Engl. J. Med. 319, 608–614 (1988).

  54. 54

    San Luis, A., Hayes, C. G., O'Rourke, T. & Manaloto, C. R. The neurologic features of Japanese encephalitis in the Philippines. Phil. J. Microbiol. Infect. Dis. 35, 67 (1990).

  55. 55

    Kumar, R. et al. Japanese encephalitis—an important cause of acute childhood encephalopathy in Lucknow, India. Postgrad. Med. J. 64, 18–22 (1988).

  56. 56

    Hoke, C. H. Jr. et al. Effect of high-dose dexamethasone on the outcome of acute encephalitis due to Japanese encephalitis virus. J. Infect. Dis. 165, 631–637 (1992).

  57. 57

    Libraty, D. H. et al. Clinical and immunological risk factors for severe disease in Japanese encephalitis. Trans. R. Soc. Trop. Med. Hyg. 96, 173–178 (2002).

  58. 58

    Kalita, J., Misra, U. K., Pandey, S. & Dhole, T. N. A comparison of clinical and radiological findings in adults and children with Japanese encephalitis. Arch. Neurol. 60, 1760–1764 (2003).

  59. 59

    Solomon, T. et al. Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial. Lancet 361, 821–826 (2003).

  60. 60

    Tiroumourougane, S. V., Raghava, P., Srinivasana, S. & Badrinath . Management parameters affecting the outcome of Japanese encephalitis. J. Trop. Pediatr. 49, 153–156 (2003).

  61. 61

    Gurav, Y. K. et al. A large outbreak of Japanese encephalitis predominantly among adults in northern region of West Bengal, India. J. Med. Virol. 88, 2004–2011 (2016).

  62. 62

    Kumar, R. et al. Randomized, controlled trial of oral ribavirin for Japanese encephalitis in children in Uttar Pradesh, India. Clin. Infect. Dis. 48, 400–406 (2009).

  63. 63

    Ma, J. & Jiang, L. Outcome of children with Japanese encephalitis and predictors of outcome in southwestern China. Trans. R. Soc. Trop. Med. Hyg. 107, 660–665 (2013).

  64. 64

    Maha, M. S. et al. Outcome and extent of disability following Japanese encephalitis in Indonesian children. Int. J. Infect. Dis. 13, e389–393 (2009).

  65. 65

    Olsen, S. J. et al. Japanese encephalitis virus remains an important cause of encephalitis in Thailand. Int. J. Infect. Dis. 14, e888–892 (2010).

  66. 66

    Ooi, M. H. et al. The epidemiology, clinical features, and long-term prognosis of Japanese encephalitis in central sarawak, malaysia, 1997–2005. Clin. Infect. Dis. 47, 458–468 (2008).

  67. 67

    Partridge, J., Ghimire, P., Sedai, T., Bista, M. B. & Banerjee, M. Endemic Japanese encephalitis in the Kathmandu valley, Nepal. Am. J. Trop. Med. Hyg. 77, 1146–1149 (2007).

  68. 68

    Yin, Z. et al. Japanese encephalitis disease burden and clinical features of Japanese encephalitis in four cities in the People's Republic of China. Am. J. Trop. Med. Hyg. 83, 766–773 (2010).

  69. 69

    Barzaga, N. G. A review of Japanese encephalitis cases in the Philippines (1972–1985). Southeast Asian J. Trop. Med. Publ. Health 20, 587–592 (1989).

  70. 70

    Ravi, V., Vanajakshi, S., Gowda, A. & Chandramuki, A. Laboratory diagnosis of Japanese encephalitis using monoclonal antibodies and correlation of findings with the outcome. J. Med. Virol. 29, 221–223 (1989).

  71. 71

    Kumar, R. et al. Clinical features and prognostic indicators of Japanese encephalitis in children in Lucknow (India). Indian J. Med. Res. 91, 321–327 (1990).

  72. 72

    Rathi, A. K. et al. JE virus encephalitis: 1988 epidemic at Gorakhpur. Indian Pediatr. 30, 325–333 (1993).

  73. 73

    Desai, A. et al. Co-existence of cerebral cysticercosis with Japanese encephalitis: a prognostic modulator. Epidemiol. Infect. 118, 165–171 (1997).

  74. 74

    Mayo, I. Japanese encephalitis at the Cotabato Regional Hospital. Phil. J. Pediatr. 47, 190–194 (1998).

  75. 75

    Baruah, H. C., Biswas, D., Patgiri, D. & Mahanta, J. Clinical outcome and neurological sequelae in serologically confirmed cases of Japanese encephalitis patients in Assam, India. Indian Pediatr. 39, 1143–1148 (2002).

  76. 76

    Potula, R., Badrinath, S. & Srinivasan, S. Japanese encephalitis in and around Pondicherry, South India: a clinical appraisal and prognostic indicators for the outcome. J. Trop. Pediatr. 49, 48–53 (2003).

  77. 77

    Rayamajhi, A., Singh, R., Prasad, R., Khanal, B. & Singhi, S. Clinico-laboratory profile and outcome of Japanese encephalitis in Nepali children. Ann. Trop. Paediatr. 26, 293–301 (2006).

  78. 78

    Wierzba, T. F. et al. Laboratory-based Japanese encephalitis surveillance in Nepal and the implications for a national immunization strategy. Am. J. Trop. Med. Hyg. 78, 1002–1006 (2008).

  79. 79

    Ompusunggu, S. et al. Confirmation of Japanese encephalitis as an endemic human disease through sentinel surveillance in Indonesia. Am. J. Trop. Med. Hyg. 79, 963–970 (2008).

  80. 80

    Touch, S. et al. Epidemiology and burden of disease from Japanese encephalitis in Cambodia: results from two years of sentinel surveillance. Trop. Med. Int. Health 14, 1365–1373 (2009).

  81. 81

    Yen, N. T. et al. Surveillance for Japanese encephalitis in Vietnam, 1998–2007. Am. J. Trop. Med. Hyg. 83, 816–819 (2010).

  82. 82

    Hossain, M. J. et al. Hospital-based surveillance for Japanese encephalitis at four sites in Bangladesh, 2003–2005. Am. J. Trop. Med. Hyg. 82, 344–349 (2010).

  83. 83

    Borah, J., Dutta, P., Khan, S. A. & Mahanta, J. A comparison of clinical features of Japanese encephalitis virus infection in the adult and pediatric age group with Acute Encephalitis Syndrome. J. Clin. Virol. 52, 45–49 (2011).

  84. 84

    Kakoti, G., Dutta, P., Ram Das, B., Borah, J. & Mahanta, J. Clinical profile and outcome of Japanese encephalitis in children admitted with acute encephalitis syndrome. Biomed. Res. Int. 2013, 152656 (2013).

  85. 85

    Tan le, V. et al. Viral aetiology of central nervous system infections in adults admitted to a tertiary referral hospital in southern Vietnam over 12 years. PLoS Negl. Trop. Dis. 8, e3127 (2014).

  86. 86

    Ravi, V. et al. Persistence of Japanese encephalitis virus in the human nervous system. J. Med. Virol. 40, 326–329 (1993).

  87. 87

    Sharma, S. et al. Japanese encephalitis virus latency in peripheral blood lymphocytes and recurrence of infection in children. Clin. Exp. Immunol. 85, 85–89 (1991).

  88. 88

    Mathur, A., Arora, K. L., Rawat, S. & Chaturvedi, U. C. Persistence, latency and reactivation of Japanese encephalitis virus infection in mice. J. Gen. Virol. 67, 381–385 (1986).

  89. 89

    Murray, K. et al. Persistent infection with West Nile virus years after initial infection. J. Infect. Dis. 201, 2–4 (2010).

  90. 90

    Chen, L. K. et al. Persistence of Japanese encephalitis virus is associated with abnormal expression of the nonstructural protein NS1 in host cells. Virology 217, 220–229 (1996).

  91. 91

    Thongtan, T. et al. Highly permissive infection of microglial cells by Japanese encephalitis virus: a possible role as a viral reservoir. Microbes Infect. 12, 37–45 (2010).

  92. 92

    Yang, K. D. et al. A model to study neurotropism and persistency of Japanese encephalitis virus infection in human neuroblastoma cells and leukocytes. J. Gen. Virol. 85, 635–642 (2004).

  93. 93

    Solomon, T. et al. Origin and evolution of Japanese encephalitis virus in southeast Asia. J. Virol. 77, 3091–3098 (2003).

  94. 94

    Schuh, A. J., Ward, M. J., Brown, A. J. & Barrett, A. D. Phylogeography of Japanese encephalitis virus: genotype is associated with climate. PLoS Negl. Trop. Dis. 7, e2411 (2013).

  95. 95

    Pan, X. L. et al. Emergence of genotype I of Japanese encephalitis virus as the dominant genotype in Asia. J. Virol. 85, 9847–9853 (2011).

  96. 96

    Han, N. et al. Comparison of genotypes I and III in Japanese encephalitis virus reveals distinct differences in their genetic and host diversity. J. Virol. 88, 11469–11479 (2014).

  97. 97

    Schuh, A. J., Ward, M. J., Leigh Brown, A. J. & Barrett, A. D. Dynamics of the emergence and establishment of a newly dominant genotype of Japanese encephalitis virus throughout Asia. J. Virol. 88, 4522–4532 (2014).

  98. 98

    Williams, D. T., Wang, L. F., Daniels, P. W. & Mackenzie, J. S. Molecular characterization of the first Australian isolate of Japanese encephalitis virus, the FU strain. J. Gen. Virol. 81, 2471–2480 (2000).

  99. 99

    Hanna, J. N. et al. Japanese encephalitis in north Queensland, Australia, 1998. Med. J. Aust. 170, 533–536 (1999).

  100. 100

    Van Den Hurk, A. F. et al. Short report: the first isolation of Japanese encephalitis virus from mosquitoes collected from mainland Australia. Am. J. Trop. Med. Hyg. 75, 21–25 (2006).

  101. 101

    van den Hurk, A. F., Ritchie, S. A. & Mackenzie, J. S. Ecology and geographical expansion of Japanese encephalitis virus. Annu. Rev. Entomol. 54, 17–35 (2009).

  102. 102

    Nett, R. J., Campbell, G. L. & Reisen, W. K. Potential for the emergence of Japanese encephalitis virus in California. Vector Borne Zoonot. Dis. 9, 511–517 (2009).

  103. 103

    Platonov, A. et al. Does the Japanese encephalitis virus (JEV) represent a threat for human health in Europe? Detection of JEV RNA sequences in birds collected in Italy. Eurosurveillance 17, 20241 (2012).

  104. 104

    Ravanini, P. et al. Japanese encephalitis virus RNA detected in Culex pipiens mosquitoes in Italy. Eurosurveillance 17, 20221 (2012).

  105. 105

    Gaibani, P. et al. Retrospective screening of serum and cerebrospinal fluid samples from patients with acute meningo-encephalitis does not reveal past Japanese encephalitis virus infection, Emilia Romagna, Italy, 2011. Eurosurveillance 17, 20257 (2012).

  106. 106

    Hegde, N. R. & Gore, M. M. Japanese encephalitis vaccines: Immunogenicity, protective efficacy, effectiveness, and impact on the burden of disease. Hum. Vaccin. Immunother. 13, 1–18 (2017).

  107. 107

    Ni, H. & Barrett, A. D. Molecular differences between wild-type Japanese encephalitis virus strains of high and low mouse neuroinvasiveness. J. Gen. Virol. 77, 1449–1455 (1996).

  108. 108

    Sohn, Y. M. et al. Primary and booster immune responses to SA14-14-2 Japanese encephalitis vaccine in Korean infants. Vaccine 17, 2259–2264 (1999).

  109. 109

    Gatchalian, S. et al. Comparison of the immunogenicity and safety of measles vaccine administered alone or with live, attenuated Japanese encephalitis SA 14142 vaccine in Philippine infants. Vaccine 26, 2234–2241 (2008).

  110. 110

    Wijesinghe, P. R. et al. Safety and immunogenicity of live-attenuated Japanese encephalitis SA 14142 vaccine co-administered with measles vaccine in 9-month-old infants in Sri Lanka. Vaccine 32, 4751–4757 (2014).

  111. 111

    Zaman, K. et al. Lot-to-lot consistency of live attenuated SA 14-14-2 Japanese encephalitis vaccine manufactured in a good manufacturing practice facility and non-inferiority with respect to an earlier product. Vaccine 32, 6061–6066 (2014).

  112. 112

    Erra, E. O. et al. Cross-protection elicited by primary and booster vaccinations against Japanese encephalitis: a two-year follow-up study. Vaccine 32, 119–123 (2013).

  113. 113

    Erra, E. O. et al. Cross-protective capacity of Japanese encephalitis (JE) vaccines against circulating heterologous JE virus genotypes. Clin. Infect. Dis. 56, 267–270 (2013).

  114. 114

    Singh, A. et al. A Japanese Encephalitis vaccine from India induces durable and cross-protective immunity against temporally and spatially wide-ranging global field strains. J. Infect. Dis. 212, 715–725 (2015).

  115. 115

    Zhang, J. S. et al. Isolation and genetic characteristics of human genotype 1 Japanese encephalitis virus, China, 2009. PLoS ONE 6, e16418 (2011).

  116. 116

    Li, M. H. et al. Genotype v Japanese encephalitis virus is emerging. PLoS Negl. Trop. Dis. 5, e1231 (2011).

  117. 117

    Cao, L. et al. Low protective efficacy of the current Japanese encephalitis vaccine against the emerging genotype 5 Japanese encephalitis virus. PLoS Negl. Trop. Dis. 10, e0004686 (2016).

  118. 118

    Yang, S. E., Pan, M. J., Tseng, H. F. & Liau, M. Y. The efficacy of mouse-brain inactivated Nakayama strain Japanese encephalitis vaccine — results from 30 years experience in Taiwan. Vaccine 24, 2669–2673 (2006).

  119. 119

    Wang, H., Li, Y., Liang, X. & Liang, G. Japanese encephalitis in mainland china. Jpn J. Infect. Dis. 62, 331–336 (2009).

  120. 120

    Kumar, R., Tripathi, P. & Rizvi, A. Effectiveness of one dose of SA 14-14-2 vaccine against Japanese encephalitis. N. Engl. J. Med. 360, 1465–1466 (2009).

  121. 121

    Vashishtha, V. M. et al. Indian Academy of Pediatrics (IAP) recommended immunization schedule for children aged 0 through 18 years, India, 2013 and updates on immunization. Indian Pediatr. 50, 1095–1108 (2013).

  122. 122

    Turtle, L. et al. Cellular immune responses to live attenuated Japanese encephalitis (JE) vaccine SA14-14-2 in adults in a JE/Dengue co-endemic area. PLoS Negl. Trop. Dis. 11, e0005263 (2017).

  123. 123

    Shyu, W. R., Wang, Y. C., Chin, C. & Chen, W. J. Assessment of neutralizing antibodies elicited by a vaccine (Nakayama) strain of Japanese encephalitis virus in Taiwan. Epidemiol. Infect. 119, 79–83 (1997).

  124. 124

    Larena, M., Prow, N. A., Hall, R. A., Petrovsky, N. & Lobigs, M. JE-ADVAX vaccine protection against Japanese encephalitis virus mediated by memory B cells in the absence of CD8(+) T cells and pre-exposure neutralizing antibody. J. Virol. 87, 4395–4402 (2013).

  125. 125

    Huang, C. H. & Wong, C. Relation of the peripheral multiplication of Japanese B encephalitis virus to the pathogenesis of the infection in mice. Acta Virol. 7, 322–330 (1963).

  126. 126

    Mathur, A. et al. Immunopathological study of spleen during Japanese encephalitis virus infection in mice. Br. J. Exp. Pathol. 69, 423–432 (1988).

  127. 127

    Aleyas, A. G. et al. Functional modulation of dendritic cells and macrophages by Japanese encephalitis virus through MyD88 adaptor molecule-dependent and -independent pathways. J. Immunol. 183, 2462–2474 (2009).

  128. 128

    Cao, S. et al. Japanese encephalitis Virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells. Virol. J. 8, 39 (2011).

  129. 129

    Li, Y. et al. Infection of mouse bone marrow-derived dendritic cells by live attenuated Japanese encephalitis virus induces cells maturation and triggers T cells activation. Vaccine 29, 855–862 (2011).

  130. 130

    Gupta, N. et al. Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD-L1 on dendritic cells. Eur. J. Immunol. 44, 1363–1374 (2014).

  131. 131

    Wu, S. J. et al. Human skin Langerhans cells are targets of dengue virus infection. Nat. Med. 6, 816–820 (2000).

  132. 132

    Myint, K. S. et al. Production of lethal infection that resembles fatal human disease by intranasal inoculation of macaques with Japanese encephalitis virus. Am. J. Trop. Med. Hyg. 60, 338–342 (1999).

  133. 133

    Rudolph, K. E., Lessler, J., Moloney, R. M., Kmush, B. & Cummings, D. A. Incubation periods of mosquito-borne viral infections: a systematic review. Am. J. Trop. Med. Hyg. 90, 882–891 (2014).

  134. 134

    Kimura-Kuroda, J. & Yasui, K. Protection of mice against Japanese encephalitis virus by passive administration with monoclonal antibodies. J. Immunol. 141, 3606–3610 (1988).

  135. 135

    Larena, M., Regner, M., Lee, E. & Lobigs, M. Pivotal role of antibody and subsidiary contribution of CD8+ T cells to recovery from infection in a murine model of Japanese encephalitis. J. Virol. 85, 5446–5455 (2011).

  136. 136

    Konishi, E. et al. The anamnestic neutralizing antibody response is critical for protection of mice from challenge following vaccination with a plasmid encoding the Japanese encephalitis virus premembrane and envelope genes. J. Virol. 73, 5527–5534 (1999).

  137. 137

    German, A. C. et al. A preliminary neuropathological study of Japanese encephalitis in humans and a mouse model. Trans. R. Soc. Trop. Med. Hyg. 100, 1135–1145 (2006).

  138. 138

    Johnson, R. T. et al. Japanese encephalitis: immunocytochemical studies of viral antigen and inflammatory cells in fatal cases. Ann. Neurol. 18, 567–573 (1985).

  139. 139

    Desai, A., Shankar, S. K., Ravi, V., Chandramuki, A. & Gourie-Devi, M. Japanese encephalitis virus antigen in the human brain and its topographic distribution. Acta Neuropathol. 89, 368–373 (1995).

  140. 140

    Mishra, M. K., Dutta, K., Saheb, S. K. & Basu, A. Understanding the molecular mechanism of blood-brain barrier damage in an experimental model of Japanese encephalitis: correlation with minocycline administration as a therapeutic agent. Neurochem. Int. 55, 717–723 (2009).

  141. 141

    Mathur, A., Khanna, N. & Chaturvedi, U. C. Breakdown of blood-brain barrier by virus-induced cytokine during Japanese encephalitis virus infection. Int. J. Exp. Pathol. 73, 603–611 (1992).

  142. 142

    Li, F. et al. Viral infection of the central nervous system and neuroinflammation precede blood-brain barrier disruption during Japanese encephalitis virus infection. J. Virol. 89, 5602–5614 (2015).

  143. 143

    Myint, K. S. et al. Neuropathogenesis of Japanese encephalitis in a primate model. PLoS Negl. Trop. Dis. 8, e2980 (2014).

  144. 144

    Iwasaki, Y., Sako, K., Tsunoda, I. & Ohara, Y. Phenotypes of mononuclear cell infiltrates in human central nervous system. Acta Neuropathol. 85, 653–657 (1993).

  145. 145

    Johnson, R. T., Intralawan, P. & Puapanwatton, S. Japanese encephalitis: identification of inflammatory cells in cerebrospinal fluid. Ann. Neurol. 20, 691–695 (1986).

  146. 146

    Iwasaki, Y., Zhao, J. X., Yamamoto, T. & Konno, H. Immunohistochemical demonstration of viral antigens in Japanese encephalitis. Acta Neuropathol. 70, 79–81 (1986).

  147. 147

    Han, Y. W. et al. Distinct dictation of Japanese encephalitis virus-induced neuroinflammation and lethality via triggering TLR3 and TLR4 signal pathways. PLoS Pathog. 10, e1004319 (2014).

  148. 148

    Kim, S. B. et al. Amelioration of Japanese encephalitis by blockage of 4-1BB signaling is coupled to divergent enhancement of type I/II IFN responses and Ly-6C(hi) monocyte differentiation. J. Neuroinflamm. 12, 216 (2015).

  149. 149

    Kim, J. H. et al. CCL2, but not its receptor, is essential to restrict immune privileged central nervous system-invasion of Japanese encephalitis virus via regulating accumulation of CD11b(+) Ly-6C(hi) monocytes. Immunology 149, 186–203 (2016).

  150. 150

    Ravi, V. et al. Correlation of tumor necrosis factor levels in the serum and cerebrospinal fluid with clinical outcome in Japanese encephalitis patients. J. Med. Virol. 51, 132–136 (1997).

  151. 151

    Winter, P. M. et al. Proinflammatory cytokines and chemokines in humans with Japanese encephalitis. J. Infect. Dis. 190, 1618–1626 (2004).

  152. 152

    Ye, J. et al. Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. J. Infect. Dis. 210, 875–889 (2014).

  153. 153

    Larena, M., Regner, M. & Lobigs, M. Cytolytic effector pathways and IFN-gamma help protect against Japanese encephalitis. Eur. J. Immunol. 43, 1789–1798 (2013).

  154. 154

    Murali-Krishna, K., Ravi, V. & Manjunath, R. Protection of adult but not newborn mice against lethal intracerebral challenge with Japanese encephalitis virus by adoptively transferred virus-specific cytotoxic T lymphocytes: requirement for L3T4+ T cells. J. Gen. Virol. 77, 705–714 (1996).

  155. 155

    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).

  156. 156

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

  157. 157

    Maitland, K. et al. Mortality after fluid bolus in African children with severe infection. N. Engl. J. Med. 364, 2483–2495 (2011).

  158. 158

    Heyman, B. Regulation of antibody responses via antibodies, complement, and Fc receptors. Annu. Rev. Immunol. 18, 709–737 (2000).

  159. 159

    Kumar, R. et al. Role of oral Minocycline in acute encephalitis syndrome in India — a randomized controlled trial. BMC Infect. Dis. 16, 67 (2016).

  160. 160

    Singh, A. et al. Minocycline trial in japanese encephalitis: a double blind, randomized placebo study. Int. J. Pediatr. Res. 3, 371–377 (2016).

  161. 161

    Ishikawa, T. & Konishi, E. Potential chemotherapeutic targets for Japanese encephalitis: current status of antiviral drug development and future challenges. Expert Opin. Ther. Targets 19, 1379–1395 (2015).

  162. 162

    Mastrangelo, E. et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J. Antimicrob. Chemother. 67, 1884–1894 (2012).

  163. 163

    Swarup, V., Ghosh, J., Mishra, M. K. & Basu, A. Novel strategy for treatment of Japanese encephalitis using arctigenin, a plant lignan. J. Antimicrob. Chemother. 61, 679–688 (2008).

  164. 164

    Fang, J. et al. Identification of three antiviral inhibitors against Japanese encephalitis virus from library of pharmacologically active compounds 1280. PLoS ONE 8, e78425 (2013).

  165. 165

    Shi, Z. et al. Nitazoxanide inhibits the replication of Japanese encephalitis virus in cultured cells and in a mouse model. Virol. J. 11, 10 (2014).

  166. 166

    Swarup, V., Ghosh, J., Ghosh, S., Saxena, A. & Basu, A. Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis. Antimicrob. Agents Chemother. 51, 3367–3370 (2007).

  167. 167

    Mishra, M. K. & Basu, A. Minocycline neuroprotects, reduces microglial activation, inhibits caspase 3 induction, and viral replication following Japanese encephalitis. J. Neurochem. 105, 1582–1595 (2008).

  168. 168

    Sehgal, N., Kumawat, K. L., Basu, A. & Ravindranath, V. Fenofibrate reduces mortality and precludes neurological deficits in survivors in murine model of Japanese encephalitis viral infection. PLoS ONE 7, e35427 (2012).

  169. 169

    Di Perri, G. et al. Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. J. Infect. Dis. 171, 1317–1322 (1995).

  170. 170

    Salgado, D., Zabaleta, T. E., Hatch, S., Vega, M. R. & Rodriguez, J. Use of pentoxifylline in treatment of children with dengue hemorrhagic fever. Pediatr. Infect. Dis. J. 31, 771–773 (2012).

  171. 171

    Sebastian, L., Desai, A., Madhusudana, S. N. & Ravi, V. Pentoxifylline inhibits replication of Japanese encephalitis virus: a comparative study with ribavirin. Int. J. Antimicrob. Agents 33, 168–173 (2009).

  172. 172

    Shirey, K. A. et al. The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497, 498–502 (2013).

  173. 173

    Getts, D. R. et al. Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages. J. Neuroinflamm. 9, 246 (2012).

  174. 174

    Ye, J. et al. Quantitative phosphoproteomic analysis identifies the critical role of JNK1 in neuroinflammation induced by Japanese encephalitis virus. Sci. Signal. 9, ra98 (2016).

  175. 175

    Lewthwaite, P. et al. Disability after encephalitis: development and validation of a new outcome score. Bull. World Health Organ. 88, 584–592 (2010).

  176. 176

    Wang, X. et al. Near-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability. Nat. Commun. 8, 14 (2017).

  177. 177

    Luca, V. C., AbiMansour, J., Nelson, C. A. & Fremont, D. H. Crystal structure of the Japanese encephalitis virus envelope protein. J. Virol. 86, 2337–2346 (2012).

  178. 178

    Centers for Disease Control and Prevention. Geographic distribution of japanese encephalitis virus. CDC https://www.cdc.gov/japaneseencephalitis/maps/ (2015).

  179. 179

    Turtle, L., Griffiths, M. J. & Solomon, T. Encephalitis caused by flaviviruses. QJM 105, 219–223 (2012).

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Acknowledgements

L.T. is a Wellcome clinical career development fellow supported by grant number 205228/Z/16/Z. T.S. is a UK National Institute for Health Research (NIHR) senior investigator and member of the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. This work was conducted independently of influence from the NIHR. T.S. and L.T. are also supported by the European Union's Horizon 2020 Research and Innovation programme under grant agreement 734584 and the Zika Pan Latin American Network (ZikaPLAN).

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Both authors contributed substantially to the discussion of content for the article, wrote the article and reviewed and edited the article before submission. L.T. researched data for the article.

Correspondence to Lance Turtle.

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Turtle, L., Solomon, T. Japanese encephalitis — the prospects for new treatments. Nat Rev Neurol 14, 298–313 (2018) doi:10.1038/nrneurol.2018.30

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