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Japanese encephalitis
Japanese encephalitis
Japanese encephalitis
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Japanese encephalitis
Other namesJapanese B encephalitis
The geographic distribution of Japanese encephalitis (dark green)
SpecialtyInfectious disease
SymptomsHeadache, fever, vomiting, confusion, seizures[1]
Usual onset5 to 15 days after infection[1]
CausesJapanese encephalitis virus (spread by mosquitoes)
Diagnostic methodBlood or cerebrospinal fluid testing[2]
PreventionJapanese encephalitis vaccine, avoiding mosquito bites[2]
TreatmentSupportive care[1]
PrognosisPermanent neurological problems occur in up to half of survivors[2]
Frequency68,000[2]
Deaths17,000[2]

Japanese encephalitis (JE) is an infection of the brain caused by the Japanese encephalitis virus (JEV).[3] While most infections result in little or no symptoms, occasional inflammation of the brain occurs.[3] In these cases, symptoms may include headache, vomiting, fever, confusion and seizures.[1] This occurs about 5 to 15 days after infection.[1]

JEV is generally spread by mosquitoes, specifically those of the Culex type.[2] Pigs and wild birds serve as a reservoir for the virus.[2] The disease occurs mostly outside of cities.[2] Diagnosis is based on blood or cerebrospinal fluid testing.[2]

Prevention is generally achieved with the Japanese encephalitis vaccine, which is both safe and effective.[2] Other measures include avoiding mosquito bites.[2] Once infected, there is no specific treatment, with care being supportive.[1] This is generally carried out in a hospital.[1] Permanent problems occur in up to half of people who recover from JE.[2]

The disease primarily occurs in East and Southeast Asia as well as the Western Pacific.[2] About 3 billion people live in areas where the disease occurs.[2] About 68,000 symptomatic cases occur a year, with about 17,000 deaths.[2] Often, cases occur in outbreaks.[2] The disease was first described in Japan in 1871.[2][4]

Signs and symptoms

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The Japanese encephalitis virus (JEV) has an incubation period of 2 to 26 days.[5] The vast majority of infections are asymptomatic.[6] Only 1 in 250 infections develop into encephalitis.[7]

Severe rigors may mark the onset of this disease in humans. Fever, headache, and malaise are other non-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs that develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions, and a raised body temperature between 38–43 °C (100.4–109.4 °F). The mortality rate of the disease is around 25% and is generally higher in children under five, the immuno-suppressed, and the elderly. Transplacental spread has been noted. Neurological disorders develop in 40% of those who survive with lifelong neurological defects such as deafness, emotional lability and hemiparesis occurring in those who had central nervous system involvement.[8]

Japanese encephalitis virus enters the brain through two ways and leads to infection of neurons and encephalitis.

Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis. Microglia are the resident immune cells of the central nervous system (CNS) and have a critical role in host defense against invading microorganisms. Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), which can cause toxic effects in the brain. Additionally, other soluble factors such as neurotoxins, excitatory neurotransmitters, prostaglandin, reactive oxygen, and nitrogen species are secreted by activated microglia.[9]

In a murine model of JE, it was found that in the hippocampus and the striatum, the number of activated microglia was more than anywhere else in the brain, closely followed by that in the thalamus. In the cortex, the number of activated microglia was significantly less when compared to other regions of the mouse brain. An overall induction of differential expression of proinflammatory cytokines and chemokines from different brain regions during a progressive Japanese encephalitis infection was also observed.Shukla M, Garg A, Dhole TN, Chaturvedi R (2023). "Exaggerated levels of some specific TLRs, cytokines and chemokines in Japanese encephalitis infected BV2 and neuro 2A cell lines associated with worst outcome". Virol. J. 20 (1) 16. doi:10.1186/s12985-023-01966-8. PMC 9881527. PMID 36707891.

Although the net effect of the proinflammatory mediators is to kill infectious organisms and infected cells as well as to stimulate the production of molecules that amplify the mounting response to damage, it is also evident that in a non-regenerating organ such as the brain, a dysregulated innate immune response would be deleterious. In JE the tight regulation of microglial activation appears to be disturbed, resulting in an autotoxic loop of microglial activation that possibly leads to bystander neuronal damage.[10] In animals, key signs include infertility and abortion in pigs, neurological disease in horses, and systemic signs including fever, lethargy and anorexia.[11]

Cause

[edit]

It is a disease caused by the mosquito-borne Japanese encephalitis virus (JEV).[12]

Virology

[edit]
Japanese encephalitis virus
Flavivirus structure and genome
Virus classification Edit this classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Kitrinoviricota
Class: Flasuviricetes
Order: Amarillovirales
Family: Flaviviridae
Genus: Orthoflavivirus
Species:
Orthoflavivirus japonicum

JEV is a virus from the family Flaviviridae, part of the Japanese encephalitis serocomplex of nine genetically and antigenically related viruses, some of which are particularly severe in horses, and four of which, including West Nile virus, are known to infect humans.[13] The enveloped virus is closely related to the West Nile virus and the St. Louis encephalitis virus. The positive sense single-stranded RNA genome is packaged in the capsid which is formed by the capsid protein. The outer envelope is formed by envelope protein and is the protective antigen. It aids in the entry of the virus into the cell. The genome also encodes several nonstructural proteins (NS1, NS2a, NS2b, NS3, N4a, NS4b, NS5). NS1 is also produced as a secretory form. NS3 is a putative helicase, and NS5 is the viral polymerase. It has been noted that Japanese encephalitis infects the lumen of the endoplasmic reticulum (ER)[14][15] and rapidly accumulates substantial amounts of viral proteins.

Based on the envelope gene, there are five genotypes (I–V). The Muar strain, isolated from a patient in Malaya in 1952, is the prototype strain of genotype V. Genotype V is the earliest recognized ancestral strain.[16] The first clinical reports date from 1870, but the virus appears to have evolved in the mid-16th century. Complete genomes of 372 strains of this virus have been sequenced as of 2024.[17]

Diagnosis

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Japanese encephalitis is diagnosed by commercially available tests detecting JE virus-specific IgM antibodies in serum and/or cerebrospinal fluid, for example by IgM capture ELISA.[18]

JE virus IgM antibodies are usually detectable 3 to 8 days after onset of illness and persist for 30 to 90 days, but longer persistence has been documented. Therefore, positive IgM antibodies occasionally may reflect a past infection or vaccination. Serum collected within 10 days of illness onset may not have detectable IgM, and the test should be repeated on a convalescent sample. Patients with JE virus IgM antibodies should have confirmatory neutralizing antibody testing.[19] Confirmatory testing in the US is available only at the CDC and a few specialized reference laboratories. In fatal cases, nucleic acid amplification and virus culture of autopsy tissues can be useful. Viral antigens can be shown in tissues by indirect fluorescent antibody staining.[11]

Prevention

[edit]
Japanese encephalitis vaccine "ENCEVAC" in the Japanese language
Main article: Japanese encephalitis vaccine

Infection with Japanese encephalitis confers lifelong immunity. There are currently three vaccines available: SA14-14-2, IXIARO (IC51, also marketed in Australia, New Zealand as JESPECT and India as JEEV[20]) and ChimeriVax-JE (marketed as IMOJEV).[21] All current vaccines are based on the genotype III virus.[citation needed]

A formalin-inactivated mouse-brain-derived vaccine was first produced in Japan in the 1930s and validated for use in Taiwan in the 1960s and Thailand in the 1980s. The widespread use of vaccines and urbanization has led to control of the disease in Japan and Singapore. The high cost of this vaccine, which is grown in live mice, means that poorer countries could not afford to give it as part of a routine immunization program.[12]

The most common adverse effects are redness and pain at the injection site. Uncommonly, an urticarial reaction can develop about four days after injection. Vaccines produced from mouse brain have a risk of autoimmune neurological complications of around 1 per million vaccinations.[22] However where the vaccine is not produced in mouse brains but in vitro using cell culture there are few adverse effects compared to placebo, the main side effects being headache and myalgia.[23]

The neutralizing antibody persists in the circulation for at least two to three years, and perhaps longer.[24][25] The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are recommended every 11 months for people who remain at risk.[26] Some data are available regarding the interchangeability of other JE vaccines and IXIARO.[27]

Treatment

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There is no specific treatment for Japanese encephalitis and treatment is supportive,[28] with assistance given for feeding, breathing or seizure control as required. Raised intracranial pressure may be managed with mannitol.[29] There is no transmission from person to person and therefore patients do not need to be isolated.[citation needed]

A breakthrough in the field of Japanese encephalitis therapeutics is the identification of macrophage receptor involvement in the disease severity. A recent report of an Indian group demonstrates the involvement of monocyte and macrophage receptor CLEC5A in severe inflammatory response in Japanese encephalitis infection of the brain. This transcriptomic study provides a hypothesis of neuroinflammation and a new lead in development of appropriate therapies for Japanese encephalitis.[30][31]

The effectiveness of intravenous immunoglobulin for Japanese encephalitis is unclear due to a paucity of evidence.[32] Intravenous immunoglobulin for Japanese encephalitis appeared to have no benefit.[32]

Epidemiology

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Disability-adjusted life year for Japanese encephalitis per 100,000 inhabitants in 2002
  no data
  less than 1
  1–5
  5–10
  10–15
  15–20
  20–25
  25–30
  30–35
  35–40
  40–45
  45–50
  more than 50

Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, with up to 70,000 cases reported annually.[33] Of those with symptoms case-fatality rates range from 20% to 30%.[34] Rare outbreaks in U.S. territories in the Western Pacific have also occurred.[34] Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas.[34]

Countries that have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, South Korea, Singapore, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia. Japanese encephalitis has been reported in the Torres Strait Islands, and two fatal cases were reported in mainland northern Australia in 1998. There were reported cases in Kachin State, Myanmar in 2013. There were 116 deaths reported in Odisha's Malkangiri district of India in 2016.[citation needed]

In 2022, the notable increase in the distribution of the virus in Australia due to climate change became a concern to health officials as the population has limited immunity to the disease and the presence of large numbers of farmed and feral pigs could act as reservoirs for the virus.[8] In February 2022, Japanese encephalitis was detected and confirmed in piggeries in Victoria, Queensland and New South Wales. On 4 March, cases were detected in South Australia. By October 2022, the outbreak in eastern mainland Australia had caused 42 symptomatic human cases of the disease, resulting in seven deaths. In 2025, further cases and a fatality were recorded in south-eastern Australia.[35][36][37]

Humans, cattle, and horses are dead-end hosts as the disease manifests as fatal encephalitis. Pigs act as amplifying hosts and have a vital role in the epidemiology of the disease. Infection in swine is asymptomatic, except in pregnant sows when abortion and fetal abnormalities are common sequelae. The most important vector is Culex tritaeniorhynchus, which feeds on cattle in preference to humans. The natural hosts of the Japanese encephalitis virus are birds, not humans, and many believe the virus will never be eliminated.[38] In November 2011, the Japanese encephalitis virus was reported in Culex bitaeniorhynchus in South Korea.[39]

Recently, whole genome microarray research of neurons infected with the Japanese encephalitis virus has shown that neurons play an important role in their own defense against Japanese encephalitis infection. Although this challenges the long-held belief that neurons are immunologically quiescent, an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.[40]

A number of drugs have been investigated to either reduce viral replication or provide neuroprotection in cell lines or studies in mice. None are currently advocated in treating human patients.

Evolution

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It is theorized that the virus may have originated from an ancestral virus in the mid-1500s in the Malay Archipelago region and evolved there into five different genotypes that spread across Asia.[47] The mean evolutionary rate has been estimated to be 4.35×10−4 (range: 3.49×10−4 to 5.30×10−4) nucleotide substitutions per site per year.[47]

Outbreak history

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The clinical recognition and recording of Japanese encephalitis (JE) trace back to the 19th century when recurring encephalitis outbreaks were noted during Japan’s summer months. The first clinical case of JE was documented in 1871 in Japan. However, it wasn’t until 1924, during a major outbreak involving over 6,000 cases, that JE’s severity and potential for widespread impact became apparent. Subsequent outbreaks in Japan were recorded in 1927, 1934, and 1935, each contributing to a deeper understanding of the disease and its transmission patterns. The spread of JE extended beyond Japan over the following decades, impacting numerous countries across Asia. On the Korean Peninsula, the first JE cases were reported in 1933, and mainland China documented its initial cases in 1940. The virus reached the Philippines in the early 1950s and continued its westward spread, with Pakistan recording cases in 1983, marking JE’s furthest westward extension. By 1995, JE cases had reached Papua New Guinea and northern Australia (specifically the Torres Strait), representing the virus's southernmost range. According to the World Health Organization (WHO), JE is also endemic to the Western Pacific Islands, but cases are rare, possibly due to an enzootic cycle that does not sustain continuous viral transmission. Epidemics in these islands likely occur only when the virus is introduced from other JE-endemic regions. In the early 2020s, JE had become endemic in the southern parts of Australia with locally contracted human fatalities from the disease being recorded in these areas for the first time.[48][49]

References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Japanese encephalitis

View on Grokipedia
from Grokipedia
Japanese encephalitis is an acute viral infection caused by the Japanese encephalitis virus (JEV), a mosquito-borne flavivirus endemic to , where it circulates primarily among amplifying hosts such as pigs and wading birds before incidental transmission to humans via species mosquitoes. The virus targets the , inducing of the parenchyma in severe cases, though the majority of infections—estimated at over 99%—remain subclinical or present with mild febrile illness indistinguishable from other viral syndromes. Transmission peaks during the rainy season in rural agricultural settings, particularly rice paddies and pig farms, where mosquito breeding and vertebrate host proximity facilitate amplification, with human risk elevated among children under 15 years and those in endemic foci lacking coverage. Globally, JE accounts for approximately 67,900 clinical cases annually, predominantly in and the Western Pacific, with a case-fatality rate of 20–30% among those developing and 20–30% of survivors experiencing lifelong neuropsychiatric sequelae such as , seizures, or Parkinsonism-like symptoms. No specific antiviral therapy exists; management relies on supportive care, underscoring the primacy of prevention through and . Inactivated and live-attenuated JE vaccines, such as SA14-14-2, demonstrate high —over 90% in preventing clinical —when administered in endemic populations or to at-risk travelers, with mass immunization campaigns markedly reducing incidence in regions like and . Despite these advances, sporadic outbreaks persist due to incomplete coverage and emerging spread to non-endemic areas like , highlighting ongoing challenges in and equitable access.

Virology and Etiology

Virus Characteristics and Replication

Japanese encephalitis virus (JEV) is a member of the genus Flavivirus in the family , characterized by a single-stranded, positive-sense approximately 11 kilobases (kb) in length. The contains a single (ORF) encoding a polyprotein of about 3,400 , flanked by 5' and 3' untranslated regions (UTRs) that regulate translation and replication. This polyprotein is post-translationally cleaved by viral and host proteases into three structural proteins— (C), precursor (prM, matured to M), and envelope (E)—and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The mature virion is enveloped, spherical, with a of roughly 50 nm, featuring an icosahedral nucleocapsid core surrounded by a embedded with 180 copies of E and M proteins. The E protein mediates viral attachment and fusion, while NS5 functions as the (RdRp) essential for replication. Replication initiates with JEV attachment to host cell receptors via the E glycoprotein, followed by clathrin-mediated and low-pH-induced fusion in endosomes, releasing the genomic into the . Host ribosomes then translate the positive-sense into the polyprotein, which is co- and post-translationally processed: viral NS2B-NS3 protease cleaves most junctions, while host signalases and handle prM to M maturation. Replication occurs on (ER)-derived membranes, where NS proteins induce vesicle formation for synthesis; NS5, in complex with NS3 , synthesizes a complementary negative-sense intermediate from the 3' UTR, which serves as a template for multiple positive-sense genomic and subgenomic RNAs. Positive-sense RNAs are amplified via RdRp activity, with host factors like Rab4b and DnaJ homologs facilitating trafficking and chaperone functions to support this process. Assembly begins with C protein encapsidating newly synthesized genomic RNA to form nucleocapsids in the cytoplasm, which bud into the ER lumen, acquiring a membrane with prM and E. Immature virions traffic through the Golgi, where furin cleaves prM to enable E-mediated fusion competence and structural rearrangement into mature, infectious particles. Mature virions are released via exocytosis, with replication efficiency modulated by host antiviral responses, such as interferon pathways, though JEV counters these via NS proteins that inhibit signaling. The entire cycle, from entry to release, typically spans 12–24 hours in susceptible cells like neurons or Vero cells, with cytoplasmic replication avoiding nuclear involvement characteristic of other RNA viruses.

Genotypes and Evolutionary Dynamics

The Japanese encephalitis virus (JEV) is classified into five genotypes (GI through GV) based on phylogenetic analysis of the envelope (E) protein gene or complete viral genomes, with all genotypes sharing a single serotype due to high antigenic cross-reactivity. Genotypes differ in geographic distribution, epidemic potential, and subtle variations in virulence; for instance, GI strains have been associated with milder clinical outcomes in some studies compared to GIII, though evidence remains inconsistent across isolates. GI predominates in Southeast Asia and has expanded northward into temperate regions like Korea and Japan since the 1980s, while GII circulates sporadically in Southeast Asia, GIII persists in parts of South Asia and has declined overall, GIV is largely confined to Indonesia but reemerged in Australia in 2022 causing an outbreak in pigs, and GV—first isolated in 1952—reappeared in China in 2009 and remains rare. Evolutionary analyses estimate the most recent common ancestor (MRCA) of JEV emerged approximately 3,255 years ago in , likely the Indonesia-Malaysia region, with subsequent divergence into genotypes radiating outward. Phylogenetic reconstructions indicate GIII as an early diverging lineage, followed by GII, GI, GV, and GIV as the most recent (emerging around 1901, with 95% highest posterior density interval of 1792–1964). The evolves at a rate typical of flaviviruses, approximately 3–5 × 10⁻⁴ substitutions per site per year, under predominantly neutral selection pressures during intra-host replication, though adaptive changes in the E protein may influence vector competence and host . A key dynamic has been the displacement of GIII by GI since the 1970s, particularly sublineage GI-b originating in around the 1950s, attributed to higher fitness in enzootic cycles involving pigs and mosquitoes, possibly enhanced by widespread GIII-targeted reducing competition. Phylogeographic models reveal repeated host shifts between avian reservoirs and pigs, with spatial diffusion from tropical enzootic foci to fronts, driven by anthropogenic factors like pig farming intensification. Reemergences of GIV and GV highlight ongoing diversification, with GIV's Australian incursion in 2022 linked to spillover from Indonesian reservoirs via migratory birds or human-mediated transport, underscoring the virus's potential for range expansion amid climate and trade changes. These patterns emphasize JEV's hallmarks: high rates enabling quasispecies clouds and periodic selective sweeps favoring genotypes with superior transmission efficiency in amplifying hosts.

Ecology and Transmission

Vectors, Reservoirs, and Transmission Cycles

The primary vectors of Japanese encephalitis virus (JEV) are mosquitoes of the genus , with Culex tritaeniorhynchus recognized as the most competent species due to its abundance in agricultural areas like fields and paddies, where it breeds prolifically during seasons. Other Culex species, including Culex vishnui complex (C. vishnui, C. tritaeniorhynchus, and C. pseudovishnui) and C. gelidus, contribute to transmission, particularly in rural and peri-urban environments across . These mosquitoes are anthropophilic and zoophilic, feeding on both humans and amplifying hosts, with peak biting activity at dusk and dawn, aligning with JEV's enzootic dynamics. Ardeid wading birds, such as egrets (Egretta spp.) and (Ardea spp.), serve as the principal hosts, sustaining JEV in sylvatic cycles through persistent, low-level that allows infection without causing high mortality in avian populations. Domestic pigs (Sus scrofa domesticus) function as key amplifying hosts, generating high-titer (often exceeding 10^5–10^7 PFU/mL) for 3–5 days post-, which enhances infection rates and facilitates spillover to habitats near pig farms. Other vertebrates, including wild birds, bats, and occasionally or , may harbor JEV subclinically but play minor roles compared to ardeids and pigs; humans act solely as dead-end hosts, producing insufficient (typically <10^2 PFU/mL) to sustain transmission. JEV transmission occurs via two interconnected cycles: a wild, bird-associated sylvatic cycle where infected mosquitoes maintain the among ardeid birds in wetlands and forests, and a rural, pig-associated domestic cycle where proximity of pigsties to human dwellings amplifies outbreaks, as viremic pigs attract mosquitoes that bridge to incidental human hosts. In the enzootic cycle, mosquitoes acquire JEV by feeding on infected birds or pigs, extrinsically incubate the for 8–12 days (during which it replicates in salivary glands), and transmit it upon subsequent blood meals, with infection rates in vectors ranging from 0.1% to 5% depending on host density and environmental factors. Vertical transmission in mosquitoes is negligible, and direct host-to-host spread is absent, underscoring the arthropod-dependent nature of perpetuation; rare vector-free persistence occurs in porcine tonsils but does not drive epidemics.

Environmental and Anthropogenic Factors Influencing Spread

Temperature, rainfall, and humidity are primary environmental drivers of mosquito vector abundance and Japanese encephalitis (JEV) transmission efficiency. Optimal temperatures for Culex tritaeniorhynchus survival and JEV extrinsic incubation range from 25–30°C, with transmission peaking during warm, wet seasons that facilitate larval breeding in stagnant water. Excessive rainfall, often linked to monsoons or flooding, creates ideal habitats in fields and channels, amplifying vector populations and enzootic cycles among avian reservoirs and porcine amplifiers. Climate change exacerbates these dynamics by altering seasonal patterns and potentially expanding JEV-endemic zones. Rising global temperatures may shorten the virus's extrinsic in mosquitoes and extend vector activity into previously temperate regions, as evidenced by modeling showing increased suitability in areas like parts of and under warmer scenarios. However, empirical indicate that transmission thresholds remain tied to specific and levels, with projections estimating a 10–20% potential northward shift in distribution by 2050 in , contingent on vector adaptation. Anthropogenic activities, particularly agricultural intensification, significantly influence JEV spread by modifying landscapes to favor vector-host interactions. Irrigated cultivation provides persistent breeding sites for floodwater mosquitoes, correlating with higher incidence in paddy-dominated regions of , where field flooding synchronizes with peak vector density. Domestic acts as a key amplifier, as pigs develop high transmissible to feeding mosquitoes; proximity of piggeries to dwellings—often within 1–2 km—increases spillover risk, with studies showing seroprevalence in pigs exceeding 50% in endemic farming areas. Land-use changes, including and , further modulate transmission by altering foraging patterns and host availability. Expansion of peri-urban integrates human, , and vector populations, elevating outbreak potential, as observed in historical shifts where rearing near villages preceded epidemics. While vaccination and mitigate risks, unchecked intensification without spatial separation of from residences sustains enzootic amplification, underscoring causal links between human-modified ecosystems and JEV persistence.

Epidemiology

Global Distribution and Incidence Patterns

Japanese encephalitis virus is endemic in 24 countries across , spanning from the in the north to in the south, and from in the west to the western Pacific islands in the east. Transmission occurs primarily in rural and peri-urban agricultural areas where rice cultivation and coincide, facilitating the virus's enzootic cycle among avian and porcine reservoirs and Culex mosquito vectors. The disease is absent or rare in urban centers and higher-altitude regions above 2,000 meters. Sporadic cases have been reported outside traditional endemic zones, including southern and eastern during 2021–2022, linked to local mosquito amplification following viral introduction. Global incidence is estimated at approximately 67,900 clinical cases per year, though underreporting limits confirmed figures to around 10% of this total, with an overall rate of about 1.8 per 100,000 population in at-risk areas. The majority—86% to 95%—of cases occur in and , where annual reported cases can exceed 1,000 in high-burden years, such as India's 1,548 cases in 2024. Incidence varies widely by country and region, ranging from less than 1 per 100,000 in vaccinated populations to over 10 per 100,000 during outbreaks or in unvaccinated rural children under 15 years old, who account for most symptomatic infections due to lack of prior exposure and immunity. Seasonal patterns align with monsoon and rainy seasons, peaking from May to October in temperate zones like northern India and China, and year-round with bimodal peaks in tropical southern regions such as parts of Indonesia and Thailand. Vaccination programs have driven declines in incidence, exemplified by China's reduction from 0.4171 per 100,000 in 2004 to 0.0298 per 100,000 in 2019, and similar trends in Japan and South Korea post-widespread immunization. However, persistent hotspots remain in areas with low vaccine coverage, such as parts of India, Nepal, and Bangladesh, where environmental factors like flooding exacerbate vector density and transmission risk. Recent data through 2025 indicate ongoing sporadic cases in Taiwan (six confirmed as of July) and Australia, underscoring evolving patterns amid climate variability and human encroachment on wetland habitats. Japanese encephalitis (JE) was first documented in in 1871, with the virus isolated in 1935 from the brain tissue of a fatal case. Epidemics were observed seasonally in starting in 1924, linked to mosquito transmission during summer months. In , national surveillance began in 1946, recording hundreds to thousands of cases annually before 1983, with widespread occurrence tied to pig farming and rice cultivation. Major historical outbreaks included those in (1947–1948) and Saipan (1990) in the Western Pacific, though these areas are no longer considered endemic. In , significant events occurred, such as a 2016 adult-predominant outbreak in West Bengal's northern region, highlighting shifts in age distribution amid partial vaccination coverage. Outbreaks have persisted in despite vaccination programs, with global estimates of approximately 100,000 clinical cases annually, though underreporting remains common due to surveillance limitations. Incidence has declined in vaccinated regions like (forecasted at 7 cases per year for 2023–2025) and parts of (from 0.4171 to 0.0298 per 100,000 between 2004 and 2019). However, unvaccinated rural areas in South and continue to report seasonal peaks from July to November, driven by Culex mosquito vectors and amplifying hosts like pigs. From 2023 to 2025, outbreaks intensified in several endemic zones. In , cases rose to 105 in 2023 and 86 in 2024, with 63 confirmed cases and 17 deaths from June to September 2024 alone; by August 2025, 11 infections and 2 deaths affected 9 districts, signaling gaps in routine immunization. reported 224 confirmed cases across 11 states by August 12, 2025, with broader tallies exceeding 468 cases and 56 fatalities by late August, concentrated in underserved regions. Australia's 2022 emergence persisted, with detections in humans, pigs, and mosquitoes across Victoria, , and in 2024–2025, including 2 confirmed human cases in Victoria during the 2024–25 season; cumulative cases since 2021 reached 45 by early 2023, with 7 deaths. Sporadic imported cases included two severe infections in travelers returning from 2023–2024, and South Korea's first 2025 case. These trends reflect stable endemic transmission in , vaccine-preventable surges in low-coverage areas, and southward expansion risks from and vector dynamics, though no evidence supports dramatic global upticks beyond localized reporting improvements.

Pathogenesis and Clinical Manifestations

Mechanisms of Infection and Immune Response

Japanese encephalitis virus (JEV), a member of the family, initiates infection in humans via the bite of an infected mosquito, leading to in skin and lymphoid tissues followed by dissemination through the bloodstream as develops. The virus attaches to host cell receptors such as glucose-regulated protein 78 (GRP78), which facilitates entry primarily through ; in neuronal cells, this occurs via caveolin-1-mediated, clathrin-independent pathways regulated by cytoskeleton dynamics, whereas fibroblasts employ clathrin-dependent mechanisms. Once internalized, JEV uncoats its positive-sense single-stranded genome, which is translated into a polyprotein cleaved into structural (, prM/M, ) and non-structural proteins essential for replication in the , exploiting host membranes to form replication complexes. Neuroinvasion occurs as JEV crosses the blood-brain barrier (BBB), with evidence indicating that initial (CNS) infection and precede overt BBB disruption, allowing viral entry via transcellular , direct endothelial cell infection, or paracellular leakage induced by viral proteins. Non-structural protein 1 (NS1) and its extended form NS1' contribute to BBB permeability by promoting (MIF)-mediated and altering proteins through JEV-induced changes in endothelial cells. Ezrin, a cytoskeletal protein, is critical for JEV entry into human brain microvascular endothelial cells, underscoring the role of host cellular machinery in facilitating this process. Within the CNS, JEV preferentially targets neurons, where replication triggers direct cytopathic effects alongside host-mediated damage. The host to JEV involves both innate and adaptive components, but dysregulated exacerbates beyond direct viral . Innate immunity activates and , which produce pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β) and , initiating reactive and recruiting peripheral immune cells; however, JEV antagonizes signaling via non-structural proteins like NS2B-NS3 to dampen early antiviral responses, prolonging viral persistence. Adaptive responses include neutralizing antibodies targeting the protein, which limit but show limited efficacy against established CNS , and + T cells that clear infected neurons yet can contribute to through excessive in cross-reactive scenarios, as observed in JEV-primed responses to related flaviviruses. Overall, the balance tips toward harmful , with glial cells shaping the local immune landscape and infected promoting neuronal , leading to , tissue damage, and high fatality rates in symptomatic cases.

Signs, Symptoms, and Disease Progression

The majority of Japanese encephalitis virus (JEV) infections are or manifest as mild, nonspecific febrile illness, with severe neurological disease occurring in approximately 1 in 250 to 1 in 1,000 cases. The typically lasts 5 to 15 days, during which the virus replicates in peripheral tissues before potentially crossing the blood-brain barrier. Symptomatic cases often begin with a prodromal phase of 1 to 2 days characterized by high fever (often exceeding 38°C), chills, headache, nausea, vomiting, myalgia, and sometimes diarrhea or upper respiratory symptoms; in children, gastrointestinal complaints may predominate. This phase transitions rapidly into the acute encephalitic stage in severe cases, marked by neurological signs including altered mental status, agitation, confusion, disorientation, neck stiffness, tremors, and focal or generalized seizures. Adults frequently report prominent headache and meningismus, while children may exhibit irritability or lethargy earlier. Additional features can include psychosis, flexor or extensor posturing, respiratory irregularities, and spastic paralysis if brainstem or spinal cord involvement occurs. Disease progression in encephalitic cases accelerates over 2 to 4 days, potentially culminating in , ventilatory failure, or death, with case fatality rates of 20% to 30% in hospitalized patients; survivors often enter a recovery phase lasting weeks to months, though up to 50% experience persistent neurological deficits such as , motor weakness, or psychiatric disorders. Factors influencing severity include viral genotype, host age (worse outcomes in extremes of age), and immune status, with adults sometimes showing higher rates of complications like pulmonary issues compared to children. relies on clinical suspicion during endemic seasons, as symptoms overlap with other encephalitides.

Complications and Long-Term Outcomes

Severe Japanese encephalitis cases frequently involve acute complications such as generalized seizures, , , and , which drive a case-fatality rate of 20–30% among symptomatic patients. These outcomes stem from widespread neuronal damage and cytokine-mediated in the , with higher mortality observed in adults and the elderly, where rates can reach 36–45% during hospitalization or follow-up. Among survivors, 30–50% develop permanent neurological, cognitive, or psychiatric sequelae, including epilepsy, parkinsonism, cognitive impairment, and movement disorders such as dystonia or tremor. Specific deficits often encompass hearing loss, vision impairment, speech apraxia, and behavioral disturbances, with pediatric survivors particularly prone to developmental delays and psychiatric issues, affecting up to 45–63% in cohort studies. Long-term disability imposes substantial healthcare burdens, with many requiring ongoing care for motor impairments or recurrent seizures; one-year post-discharge data indicate only 46% of patients achieve full recovery, while others face persistent sequelae necessitating rehabilitation. Outcomes vary by age, viral genotype, and access to intensive care, but neuronal loss in the , , and cortex underlies the irreversible nature of these effects in a significant proportion of cases.

Diagnosis

Laboratory Methods and Diagnostic Criteria

Laboratory diagnosis of Japanese encephalitis (JE) primarily relies on serological detection of virus-specific immunoglobulin M (IgM) antibodies in cerebrospinal fluid (CSF) or serum using the IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA), which is the standard method recommended by the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO). JEV-specific IgM typically becomes detectable 3 to 8 days after illness onset and persists for 30 to 90 days, though longer durations have been observed; CSF testing is preferred for higher specificity due to reduced cross-reactivity with other flaviviruses compared to serum. Cross-reactivity in serum MAC-ELISA with dengue or other flaviviruses necessitates confirmatory plaque reduction neutralization testing (PRNT) for definitive identification. Molecular methods, such as (RT-PCR) for JEV RNA detection in CSF, blood, or tissue, offer early diagnosis during the viremic phase but are less sensitive than and not routinely used outside reference laboratories due to technical requirements and variable performance. Virus isolation remains the gold standard for confirmation, involving of clinical specimens into cell cultures (e.g., Vero or C6/36 cells), suckling mice, or inoculation, but it is rarely performed owing to biosafety level 3 containment needs, low yield from human samples, and prolonged turnaround time of days to weeks. Diagnostic criteria for laboratory-confirmed JE, as outlined in surveillance protocols, include detection of JEV RNA by RT-PCR in any specimen, successful isolation from clinical material, presence of JEV-specific IgM in CSF, or JEV-specific IgM in serum absent evidence of recent flavivirus infection (confirmed via PRNT or clinical-epidemiological exclusion). These criteria require integration with clinical features (e.g., acute with fever) and epidemiological risk (e.g., exposure in endemic areas), as no single test achieves 100% sensitivity or specificity; for instance, MAC-ELISA sensitivity exceeds 90% in CSF but drops in serum without confirmation. Challenges include delayed presentation reducing IgM detection and co-circulating pathogens mimicking JE, underscoring the need for multiplex assays in endemic regions.

Differential Diagnosis and Challenges

The differential diagnosis of Japanese encephalitis (JE) encompasses other causes of acute or meningoencephalitis, including infections by , varicella-zoster virus, enteroviruses, and arboviruses such as , , and St. Louis encephalitis virus, as these present with overlapping features like fever, altered mental status, seizures, and focal neurological deficits. Bacterial etiologies like meningococcal or pneumococcal meningitis must also be excluded, particularly in patients with meningismus or rapid progression, while non-infectious mimics such as (e.g., anti-NMDA receptor) or metabolic encephalopathies require consideration in atypical cases. A thorough epidemiological history, including recent travel to endemic regions in or exposure to mosquito bites during rice cultivation seasons, is essential to prioritize JE over non-endemic pathogens. Key diagnostic challenges stem from the nonspecific prodromal symptoms—fever, headache, and gastrointestinal upset—that mimic ubiquitous tropical illnesses like dengue or , delaying suspicion of JE until neurological involvement emerges, often after 5–15 days of illness. Serological testing via IgM capture on (CSF) or serum remains the cornerstone for confirmation, yet antigenic with other flaviviruses (e.g., dengue, West Nile) can yield false positives, necessitating paired acute-convalescent samples or plaque reduction neutralization tests for specificity. In rural endemic areas, where most cases occur, limited access to , RT-PCR for viral RNA, or specialized labs exacerbates underdiagnosis, with studies revealing JE in up to 20–30% of unexplained pediatric deaths despite negative premortem tests. is transient and low-titer, rendering direct detection unreliable outside the early phase, while CSF pleocytosis (lymphocytic predominance) is supportive but nondiagnostic. These hurdles contribute to reliance on clinical judgment, empirical supportive care, and syndromic surveillance in resource-constrained settings, potentially inflating misattribution to treatable alternatives like bacterial .

Treatment

Supportive Care Protocols

Supportive care forms the cornerstone of management for Japanese encephalitis (JE), as no specific antiviral therapy exists to target the flavivirus directly. Hospitalization is typically required for patients exhibiting severe symptoms, enabling close monitoring for neurological deterioration, respiratory compromise, or secondary infections. Initial stabilization involves intravenous (IV) administration to maintain hydration and balance, alongside antipyretics such as acetaminophen to control fever and analgesics for relief in cases of meningeal irritation. Seizure management is critical, given their prevalence in up to 50% of severe JE cases; anticonvulsants like or benzodiazepines are administered promptly to prevent and associated brain injury. For patients developing raised due to , measures such as infusion, , or corticosteroids may be employed, though evidence for the latter remains limited and controversial in . Respiratory support, including , is indicated for those with compromised airway protection or acute , which occurs in approximately 20-30% of hospitalized patients. Nutritional support via nasogastric feeding is often necessary for comatose individuals to prevent and support recovery. Early initiation of these protocols correlates with improved outcomes, reducing mortality from historical highs of 30-50% to around 20-30% in adequately resourced settings, though long-term sequelae persist in 30-50% of survivors. Multidisciplinary involvement, including neurologists, intensivists, and infectious disease specialists, optimizes care by addressing complications like autonomic dysfunction or secondary bacterial infections through targeted antibiotics when indicated. In resource-limited endemic areas, challenges such as delayed presentation underscore the need for rapid and basic supportive interventions to mitigate progression.

Experimental and Antiviral Approaches

No licensed antiviral therapy exists for Japanese encephalitis virus (JEV) , with limited to supportive care. Experimental approaches primarily involve , natural compounds, and novel inhibitors targeting , entry, or host factors, though most remain in preclinical stages without proven efficacy in humans. Ribavirin, a guanosine analog with broad-spectrum antiviral activity, has been evaluated in clinical settings for JE. A (NCT00216268) tested intravenous in Vietnamese patients with severe JE, finding no significant reduction in mortality or neurological sequelae compared to , despite inhibition of JEV. Combination therapy with , interferon-α2b, and immunoglobulin showed tolerability in a small South Korean case series of seven patients, with five achieving favorable outcomes, but lacked a control group and broader validation. Interferon-α2a alone, assessed in a double-blind , did not improve or sequelae rates. Promising preclinical candidates include repurposed FDA-approved drugs identified via high-throughput screening. Minocycline, a tetracycline antibiotic, reduced JEV replication and neuroinflammation in mouse models by modulating microglial activation and cytokine release, prompting calls for human trials. Methotrimeprazine, a phenothiazine antipsychotic, exhibited dual antiviral and anti-inflammatory effects in vitro and in mice by inhibiting JEV entry via clathrin-mediated endocytosis, with potential neuroprotective benefits. Screening of approved drugs also highlighted cytoplasmic calcium dysregulation as a target, with inhibitors like thapsigargin showing efficacy against JEV in cell cultures. Natural products and derivatives have demonstrated antiviral potential in laboratory models. inhibited JEV production in human cells in a dose- and time-dependent manner, linked to reduced and . , a , attenuated viral entry and replication while exerting immunomodulatory effects , with IC50 values indicating moderate potency. Indirubin, from plant sources, suppressed JEV propagation in cells by targeting non-structural proteins, suggesting lead optimization for new agents. Curcumin-loaded targeted the JEV envelope protein, reducing in mice. Other candidates like diallyl trisulfide from and belladonna extracts showed replication inhibition in cell lines, though human translation remains untested. Host-targeted therapies offer alternative experimental avenues. PARP1 inhibitors protected mice from lethal JEV challenge by preserving neuronal integrity and limiting inflammation, without direct virucidal activity. protein overexpression conferred resistance in cell and animal models by interfering with viral attachment. Intravenous immunoglobulin was trialed (NCT01856205) in Nepalese children with JE, aiming to neutralize virus via antibodies, but results indicated limited impact on severe outcomes. These approaches underscore the focus on mitigating alongside viral control, yet clinical trials are scarce due to JE's sporadic nature and ethical challenges in endemic areas.

Prevention

Vector Control and Environmental Management

Vector control for Japanese encephalitis (JE) primarily targets Culex mosquitoes, especially Culex tritaeniorhynchus, the principal vector responsible for transmitting the Japanese encephalitis virus (JEV) from amplifying hosts like pigs and wading birds to humans. These mosquitoes preferentially breed in sunlit, shallow, vegetated waters such as flooded rice paddies, irrigation ditches, and borrow pits, with peak larval densities occurring 1–2 weeks after flooding. Effective control disrupts this breeding cycle and reduces adult mosquito populations, thereby interrupting zoonotic transmission, as JEV maintains an enzootic cycle in rural agricultural settings where rice farming and pig rearing coincide. Environmental management forms the foundation of sustainable vector control by altering habitats to minimize breeding sites. In rice-growing regions, alternate wetting and drying (AWD) irrigation—flooding fields intermittently rather than maintaining continuous water—reduces C. tritaeniorhynchus larval habitats by up to 90% during critical periods, as larvae require stable flooding for development. Additional measures include draining or filling unused ditches, wells, and ponds; covering water storage containers; and clearing vegetation around farms to eliminate shaded resting sites for adults. In pig-rearing areas, where pigs amplify JEV viremia (reaching titers sufficient for mosquito infection within 2–5 days post-exposure), siting piggeries at least 1–2 km from human dwellings and installing fine-mesh screens on pens limit mosquito access to hosts, reducing spillover risk. These non-chemical approaches are cost-effective in endemic zones, with studies in Asia showing decreased JE incidence following widespread adoption in integrated agricultural systems. Chemical interventions complement environmental strategies, particularly during outbreaks or high-risk seasons (June–October in temperate ). Larvicides such as (Bti) or are applied to rice fields and ditches, targeting immature stages with minimal ecological disruption, as C. tritaeniorhynchus larvae are highly susceptible. Adulticiding via ultra-low volume (ULV) space spraying of pyrethroids like covers peridomestic areas, though efficacy wanes against resistant populations, necessitating rotation of insecticides. In and parts of , integrated mosquito management at piggeries incorporates weekly larviciding of confirmed breeding sites alongside environmental cleanup, achieving over 80% reduction in vector density during JEV incursions as of 2022. Emerging biological methods, such as Wolbachia-infected mosquito releases, show promise for suppressing populations by inducing cytoplasmic incompatibility, potentially reducing JEV transmission in rice agroecosystems; field trials in endemic areas reported 70–90% vector suppression without environmental harm. Surveillance, including ovitraps and light traps for C. tritaeniorhynchus monitoring, informs targeted interventions, with pig serosurveillance providing early warnings of amplification. Overall, combining these tactics in an integrated vector (IVM) framework—prioritizing environmental modification over reliance on chemicals—has historically lowered JEV incidence in controlled settings, though challenges persist in resource-limited regions with expanding irrigated agriculture.

Personal Protective Measures

Personal protective measures form the primary strategy for preventing Japanese encephalitis transmission by reducing exposure to bites from Culex species mosquitoes, the principal vectors, which are most active from to dawn. These nocturnal vectors thrive in rural, agricultural settings near rice fields and farms, where amplification occurs via vertebrate hosts like pigs and wading birds. Application of EPA-registered insect repellents to exposed skin is recommended, with effective active ingredients including at concentrations of 20–50% for adults (lower for children), picaridin (20%), IR3535 (20%), oil of lemon (30%), para-menthane-diol (apply as directed), or 2-undecanone (up to 7.75%). Repellents should be reapplied every 4–8 hours depending on the product, environmental conditions, and activity level, avoiding application under clothing or on wounds, and not using on infants under 2 months. Wearing protective clothing—long-sleeved shirts, long pants tucked into socks, closed footwear, and wide-brimmed hats—creates a mechanical barrier, particularly effective when combined with treatment (0.5% concentration) on clothing, gear, and bed nets, which repels and kills mosquitoes upon contact without requiring skin application. -treated items retain efficacy through multiple washes, lasting up to 70 when following manufacturer guidelines. Sleeping in air-conditioned or well-screened rooms excludes mosquitoes; in their absence, insecticide-treated bed nets (ITNs) with pyrethroids provide essential protection, especially in endemic rural areas where Culex breeding is prevalent. Indoor use of mosquito coils or vaporizers emitting spatial repellents like allethrin can supplement barriers by reducing ambient mosquito density. Limiting outdoor activities, particularly in rural or peri-urban areas during peak biting hours (evening through morning), minimizes risk, as human cases peak in rainy seasons when vector populations surge. These measures, rigorously applied, prevent the vast majority of infections in travelers and residents, though adherence challenges persist in high-transmission zones due to behavioral and infrastructural factors.

Vaccination Programs and Efficacy Data

The live-attenuated SA14-14-2 vaccine constitutes the cornerstone of mass immunization campaigns against in endemic Asian countries, typically administered as a single subcutaneous dose to children aged 8 months and older. Introduced in in 1988 by the Chengdu of Biological Products, this vaccine has been deployed in over 100 million doses nationwide, correlating with marked declines in JE incidence from peaks exceeding 20,000 cases annually in the 1970s to fewer than 3,000 by the . Similar programs in , initiated in high-burden districts like since 2006, have targeted children under 15 years through catch-up campaigns and routine schedules, achieving coverage rates above 80% in prioritized areas. Efficacy evaluations of SA14-14-2 demonstrate high protective effectiveness; a case-control study in Uttar Pradesh involving 122 confirmed JE cases reported 99.5% (95% CI: 84.1-100%) effectiveness six months after a single dose, based on matched controls from immunization records. Observational data from multiple case-control studies across endemic sites indicate approximately 95% effectiveness persisting up to five years post-vaccination, though protection wanes to around 71% by six years in some cohorts, prompting considerations for boosters in sustained high-risk settings. The World Health Organization's 2015 position paper affirms a single-dose efficacy of 99.3% (95% CI: 94.9-100%) in preventing clinical JE, derived from integrated trial and surveillance data, supporting its role in routine immunization where annual incidence exceeds 1 per 100,000. Population-level impacts from these programs are evident in 13 endemic countries and regions, including , , , and , where JE has reduced confirmed cases by 50-90% post-introduction, with the greatest declines in areas achieving early high coverage before 2010. In Province, , 13 years of surveillance post- showed a shift in age distribution from children to adults alongside an overall incidence drop, attributable to herd effects from pediatric immunization. WHO advocates integrating SA14-14-2 into national schedules in moderate- to high-transmission zones, emphasizing cost-effectiveness at under $1 per dose in bulk procurement. For non-endemic populations, such as travelers to JE-risk areas, the CDC recommends inactivated Vero cell-derived like IXIARO (IC51), administered in a two-dose series spaced 28 days apart, with an accelerated 7-day interval permissible for urgent travel; however, the risk remains very low for most short-term travelers to Asia, particularly those in urban or coastal tourist areas like Krabi in Thailand, with routine vaccination not recommended unless extended rural exposure (e.g., ≥1 month) during transmission season. Estimated incidence among non-endemic travelers is less than 1 case per million, prioritizing mosquito bite prevention over vaccination for typical itineraries. rates for JE virus neutralizing antibodies reach 98% by day 56 post-series, non-inferior to comparator inactivated , though direct clinical efficacy data are absent, relying instead on immunogenicity as a surrogate marker correlated with protection in prior formulations. Long-term persistence data indicate sustained antibodies in over 80% of recipients at five years, with boosters advised for prolonged exposure risks.

History and Vaccine Development

Discovery and Early Research

The first documented outbreak of encephalitis suggestive of Japanese encephalitis occurred in in 1871, with epidemics recurring periodically thereafter, particularly during summer and autumn seasons. These early cases were characterized by acute febrile illness leading to neurological symptoms, high mortality rates approaching 30-50% in severe epidemics, and sequelae in survivors, though the viral etiology remained unidentified. A major outbreak in 1924 affected over 6,000 individuals in , highlighting the disease's epidemic potential in rice-growing regions where human proximity to mosquito vectors and animal reservoirs intensified transmission. The causative agent, Japanese encephalitis virus (JEV), a flavivirus, was first isolated in 1935 from the brain tissue of a patient who succumbed to the disease in . This isolation, achieved through intracerebral inoculation of animal models such as mice and monkeys, confirmed the neurotropic nature of the pathogen and enabled serological differentiation from other encephalitides like those caused by or enteroviruses. Early experimental transmissions in the late demonstrated mosquito-borne spread, specifically implicating Culex tritaeniorhynchus as a primary vector, with pigs identified as key amplifying hosts due to their sustaining mosquito infection cycles. These findings established the enzootic cycle involving birds, pigs, and , underscoring environmental factors like irrigated in disease emergence. Subsequent research in the 1940s and 1950s focused on virological characterization, revealing JEV's single-stranded genome and antigenic relatedness to other flaviviruses such as . Neutralization tests and complement-fixation assays developed during this period facilitated diagnosis and epidemiological surveillance, though challenges persisted due to the virus's genetic variability across genotypes. By the mid-20th century, studies in endemic areas confirmed the virus's expansion beyond to , correlating outbreaks with post-World War II population movements and agricultural intensification. These foundational efforts laid the groundwork for and development, despite initial limitations in laboratory techniques and the absence of molecular tools until later decades.

Evolution of Vaccination Strategies

The initial vaccination strategies for Japanese encephalitis (JE) relied on formalin-inactivated vaccines derived from , developed in the 1930s and licensed in in using the Nakayama strain. These vaccines, administered in multiple doses with periodic boosters, demonstrated protective efficacy of 80-90% in clinical trials and contributed to sharp declines in JE incidence in and through widespread childhood programs starting in the . However, production limitations, high costs, and rare adverse events—such as hypersensitivity reactions and (ADEM) linked to contaminants from mouse neural tissue—prompted gradual phase-outs, with Japan's manufacturer discontinuing the Nakayama-based formulation by the early 2000s. In parallel, pioneered live-attenuated vaccines in the 1980s, licensing the SA14-14-2 strain in 1988 after serial passaging of the wild-type SA14 isolate in primary kidney and Vero cells. This single-dose regimen for children aged 8 months to 10 years achieved 95-97.5% efficacy in field studies and enabled scalable national campaigns, administering over 110 million doses annually by the 2000s and reducing JE cases province-by-province. The strategy emphasized mass vaccination in endemic rural areas, prioritizing cost-effectiveness (under $1 per dose) and long-term immunity without frequent boosters, contrasting with the multi-dose requirements of inactivated vaccines. WHO prequalification of SA14-14-2 in 2013 facilitated Gavi-supported introductions in low-income countries like , , and , shifting global strategies toward routine pediatric integrated with campaigns. By the 2000s, safety concerns with mouse-brain vaccines accelerated transitions to cell-culture platforms, exemplified by Japan's 2009 approval of the inactivated Beijing-1 strain vaccine (JEBIK V) grown in Vero cells and the U.S. licensure of IXIARO (vero cell-derived, SA14-14-2 ) in 2009 for adults, extended to children in 2013. These two-dose regimens (days 0 and 28) offered improved safety profiles, avoiding neural tissue contaminants while inducing neutralizing antibodies comparable to predecessors, though requiring boosters after 1-2 years for ongoing risk. India's JEEV (vero cell-inactivated) gained WHO prequalification in 2013, supporting targeted campaigns in high-burden states like . Emerging chimeric vaccines, such as JE-CV ( 17D backbone with JE prM/E genes), licensed in in 2010 and later globally, further evolved strategies by providing single-dose protection suitable for travelers and rapid-response scenarios. Overall, evolution has progressed from resource-intensive, multi-dose inactivated products suited to affluent settings toward affordable, single-dose live-attenuated options for endemic control, complemented by safer inactivated alternatives for non-endemic use. This shift, informed by data and surveillance, has prioritized genotypic strain coverage (primarily GIII-based vaccines effective against dominant GI strains via cross-protection) and integration into national programs, though challenges persist in low-coverage regions due to logistical barriers.

Major Milestones and Genotypic Shifts

The Japanese encephalitis virus (JEV) was first isolated in 1935 by Japanese researchers from the brain of a patient who died of , marking the initial identification of the pathogen as a distinct flavivirus. Early development commenced in the 1940s with formalin-inactivated vaccines derived from infected mouse brains, which demonstrated immunogenicity but raised safety concerns due to potential allergic reactions from neural antigens. A significant advancement occurred in the with the creation of the SA14-14-2 live-attenuated in , based on serial passage of a genotype III (GIII) strain, which proved highly effective in reducing incidence following mass campaigns starting in 1990. In 2006, the Vero cell-derived inactivated IC51 (Ixiaro) received WHO prequalification, expanding safer options for travelers and endemic populations, while Japan's routine immunization program, initiated in the 1960s with mouse-brain vaccines and upgraded to cell-culture versions by 2009, contributed to near-elimination of cases domestically. Genotypic classification of JEV into five lineages (I–V) emerged from phylogenetic analyses in the , revealing influencing and cross-protection. Genotype III predominated globally from the 1930s through the late , associated with most historical epidemics, but genotype I (GI) began displacing it in during the 1970s–, becoming dominant after 2000 due to higher evolutionary rates, better adaptation to avian reservoirs like Ardeola bacchus, and possibly enhanced transmission efficiency. This shift, documented in from , , and , correlated with changing outbreak patterns, including sustained transmission in areas previously dominated by GIII. Recent re-emergences include genotype IV (GIV) in (2017) and genotype V (GV) in (2009, 2021), the latter—the oldest lineage originating around 3000 years ago—potentially evading immunity from GIII-based vaccines due to antigenic divergence, though cross-protection data remain limited. These shifts underscore the need for genotype , as GI's has prompted evaluations confirming adequate of existing vaccines against it, despite their GIII origins.

Controversies and Critiques

Vaccine Safety Profiles and Adverse Events

Inactivated Vero cell-derived Japanese encephalitis (JE) vaccines, such as Ixiaro (JE-VC), have been evaluated in clinical trials involving thousands of participants, showing primarily mild solicited adverse events including injection-site pain (up to 20%), (10-15%), and (5-10%), with serious adverse events occurring at rates not exceeding those of control vaccines (risk ratio 0.7 for events within 6-7 months post-dose). Post-marketing surveillance among U.S. military personnel confirmed low rates of or urticaria (less than 1% within one month), with no clustering of neurological events beyond background rates. Unsolicited adverse events were reported in 11-67% of cases, often coinciding with co-administered vaccines, but causality attribution to JE-VC alone remains limited by factors in observational data. Mouse brain-derived inactivated vaccines, like JE-VAX (discontinued in 2009 in the U.S. due to concerns), exhibited higher reactogenicity, with reactions including generalized urticaria (0.2%), facial swelling (0.1%), and affecting up to 1-104 per 10,000 doses, attributed to mouse neural proteins and stabilizers. These events typically manifested 1-17 days post-vaccination, prompting recommendations for observation periods and in those with prior allergies. Allergic mucocutaneous reactions comprised 73 of 101 reported events in from 1983-1995, highlighting batch variability and underreporting risks in early surveillance systems. Live-attenuated SA14-14-2 , widely used in with over 100 million doses administered, demonstrates an excellent short- and long-term safety profile, with adverse events limited to fever (1-5%) and (under 1%) in randomized trials and campaigns, comparable to background rates in unvaccinated controls. Post-marketing studies in 12,000+ children reported vasovagal syncope (25%) and minor rashes (21%), but no excess serious events like or , even when co-administered with measles-rubella . Contraindications include acute infections or , though virulence reversion risks appear negligible based on genotypic stability assessments. Rare neurological adverse events, including (ADEM), have been temporally associated with JE vaccination, predominantly with mouse brain-derived or early Nakayama strains, as in seven Japanese pediatric cases from 1968-1988 exhibiting myelitis-like symptoms post-vaccination. Isolated reports link ADEM to Vero cell-derived vaccines, but incidence remains below 1 per million doses, with uncertain causality due to potential post-infectious mimicry or coincidence, as JE virus itself triggers similar immune-mediated demyelination. Historical clusters, such as in prompting 2005 policy shifts away from routine mouse-brain vaccination, underscore vigilance for autoimmune triggers, though modern inactivated and attenuated formulations show no elevated signals in large-scale . Overall, while JE vaccines prevent far more severe outcomes than they cause, underreporting and diagnostic overlap with natural infection complicate absolute risk attribution, necessitating ongoing surveillance.

Debates on Public Health Implementation and Hesitancy

implementation of Japanese encephalitis (JE) vaccination programs has faced debates over balancing against rare s, with hesitancy often stemming from safety concerns such as reports of post- encephalitis or reactions. In , a 2014 cluster of suspected encephalitis cases following vaccination raised alarms, though subsequent investigations deemed them unrelated to the vaccine, highlighting how unverified reports can amplify distrust despite the vaccine's overall favorable safety profile. Parental hesitancy rates have reached 84.3% in some endemic settings, driven by fears of neurological complications, particularly in children with pre-existing conditions, and exacerbated by on cross-reactivity with . Implementation challenges include inadequate , which underestimates the annual global burden at around 67,900 symptomatic cases versus only 4,402 reported in 2018, complicating cost-effectiveness analyses and policy decisions for introduction in low-resource endemic areas. While national programs in countries like and have boosted coverage to 82% and 95% respectively by 2021, leading to over 90% incidence reductions in early adopters like and , gaps persist due to supply constraints from single manufacturers and variable real-world efficacy against emerging genotypes like V. Debates center on targeted versus universal strategies, with evidence favoring mass campaigns in high-burden rural areas but critiquing insufficient boosters for sustained seroprotection (80-92%). For travelers, acceptance remains low at 0.2-28.5%, attributed to high costs (e.g., $540 for two doses in ) and perceived minimal risk, prompting calls for risk-benefit tools showing vaccination reduces symptomatic and mortality by ~80% in at-risk groups. Cultural and religious factors have necessitated tailored engagement, as in where collaboration with leaders reduced hesitancy, underscoring debates on integrating community trust-building into frameworks amid broader vaccine skepticism influenced by global events. Empirical data affirm that expanded programs have averted over 300,000 cases globally from 2000-2015, yet critics argue for enhanced to address like urticaria (affecting <1% in studies) and maintain against rising vector-borne threats.

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