RARE DISEASE
Japanese encephalitis
Japanese encephalitis
Japanese encephalitis
Drug discovery
3
drugs
With orphan designations
Overview
Japanese encephalitis (JE) is a mosquito-borne flavivirus endemic to Asia and the Western Pacific, transmitted primarily by Culex mosquitoes in rural agricultural regions. It causes acute encephalitis with a 20–30% mortality rate and permanent neurologic sequelae in 30–50% of survivors [1][5][16]. Diagnosis relies on IgM antibody detection in CSF or serum [1][6]. Prevention centers on vaccination (e.g., SA 14-14-2) and vector control [1][16].
Population
Categories: rare infectious diseases, rare neurological diseases
Research Papers
1,712 drug discovery papers about Japanese encephalitis, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,712 drug discovery papers about Japanese encephalitis, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-09-29 | MAVS maintains mitochondrial import competence and also limits RNA virus replication independently of interferon signaling.
Intrinsic, cell-autonomous antiviral defenses can restrict infection without involving paracrine interferon (IFN) programs. Previous studies have demonstrated the importance of intact mitochondrial homeostasis in antiviral immunity. Mitochondrial antiviral signaling (MAVS) protein is a critical adaptor molecule in the RLR pathway that regulates IFN production in response to RNA viral infections. Here, we identify a potent intrinsic antiviral immunity that is orchestrated through stable mitochondria. We further identify MAVS as a regulator of mitochondrial import machinery whose activity is required for an IFN-independent antiviral state. Loss of MAVS leads to severe mitochondrial fragmentation, depolarization, and mitophagy, accompanied by diminished mitochondrial bioenergetics and protein import. Mechanistically, MAVS maintains mitochondrial integrity by maintaining the expression and assembly of the translocase of the outer membrane complex and sustaining the abundance of its core components. Restoration of MAVS expression reverses these defects and reinstates a robust antiviral state. Remarkably, this mitochondrial-driven immunity efficiently restricts SARS-CoV-2 replication even under IFN-deficient conditions and operates alongside the IFN pathways during infection by RNA viruses, such as the Japanese encephalitis virus. Our findings reveal a mitochondrial maintenance function of MAVS that operates in parallel to, and independently of, canonical interferon signaling during RNA virus infection. These findings highlight mitochondrial integrity as a common determinant behind a broad, collective antiviral immunity that involves both intrinsic and IFN-dependent mechanisms.IMPORTANCEHow do mitochondria contribute to the intrinsic cellular antiviral defense even when the primary immune arsenal is silenced? This work reveals that MAVS, long known for triggering interferon, acts as a vital bridge that stabilizes mitochondria to impart a potent intrinsic antiviral state against RNA viruses. We show that MAVS serves as a structural guardian of the organelle, a function it orchestrates by stabilizing the translocase of the outer membrane complex, the essential gateway for mitochondrial protein import. When MAVS is lost or targeted by viruses like SARS-CoV-2 and Japanese encephalitis virus (JEV), this gateway collapses, leading to organelle failure that viruses exploit. Crucially, we demonstrate that MAVS can restrict viral replication entirely independently of traditional interferon signaling. This discovery shifts our understanding of MAVS from a simple signal transducer to a multidimensional protector. By safeguarding the cell's "powerhouse," MAVS provides a fundamental layer of intrinsic immunity that remains active even when other immune responses are evaded.
2026-09-23 | SAMSN1 restricts Japanese encephalitis virus replication by recruiting TRIM21 to degrade viral proteins and activate the interferon pathway.
Japanese encephalitis virus (JEV), a zoonotic mosquito-transmitted flavivirus, induces human encephalitis and swine reproductive diseases. No antiviral drugs or treatments exist for flavivirus infections, which cause severe symptoms. Even though some host proteins can suppress flavivirus proliferation, the virus can inhibit this antiviral effect. This study identified a host protein SAMSN1 (SAM domain, SH3 domain, and nuclear localization signal 1; also referred to as HACS1, SLY2, and NASH1) having antiviral activity during JEV replication. SAMSN1 was upregulated during JEV infection. The expression of SAMSN1 inhibits JEV replication by binding and degrading JEV-encoded nonstructural proteins (NS1, NS5) through the proteasome and the SAMSN1-TRIM21-p62 autophagy protein degradation pathways. SAMSN1 induced expression of type I interferon through the RIG-I/MyD88-TBK1-IRF3 axis in the JEV infection process. Current findings reveal a novel role of SAMSN1 in inhibiting JEV replication and proliferation, through viral protein degradation and interferon pathway upregulation.
2026-09-16 | Travel vaccination in senior travelers: current evidence, challenges, and prevention.
The substantial number of older adults undertaking international travel has increased the relevance of pre-travel prevention in this population. However, vaccination strategies in this group require consideration of immune aging, baseline status, medication use, and travel-related exposure. This narrative review summarizes the current evidence on vaccination in senior travelers, with particular attention to the vaccines most relevant to this population, the differences in the strength of evidence across vaccines, and the clinical factors that should guide pre-travel decision-making. Routine vaccines, including influenza, COVID-19, pneumococcal, respiratory syncytial virus, herpes zoster, and tetanus-diphtheria vaccines, constitute an essential part of pre-travel assessment, whereas travel-specific vaccines, such as hepatitis A, hepatitis B, typhoid, rabies, Japanese encephalitis, tick-borne encephalitis, and cholera, should be considered according to the destination, itinerary, expected exposure, and time before departure. Yellow fever vaccination represents a particular clinical challenge because advancing age is associated with a greater risk of serious vaccine-associated adverse events, making individualized risk‒benefit assessment essential. Recently introduced dengue and chikungunya vaccines should also be considered on an individualized basis, taking into account exposure risk, potential benefits, comorbidities, and the current limitations of the available evidence. The review also highlights the importance of integrating vaccination with non-vaccine preventive strategies, including food and water precautions, vector avoidance, and hygiene measures. Although the evidence base has expanded, important uncertainties remain, particularly because age-specific data are limited and frail older adults remain underrepresented in clinical studies. Overall, pre-travel care for senior travelers should be comprehensive, exposure-based, and individualized according to the clinical profile and travel characteristics of each traveler.
2026-08-13 | NLRC5 restricts Japanese encephalitis virus replication and neuroinflammation by interacting with the viral NS3 protein in an IFN-γ-dependent manner.
NLRC5 is a known activator of MHC class I genes and a regulator of type I interferon activity. Although its expression increases in brains infected with Japanese encephalitis virus (JEV), its specific contribution to JEV pathogenesis and neuroinflammation remains unclear. We utilised in vitro cell cultures, in silico modelling, and in vivo mouse knockdown models of NLRC5 to investigate its impact on JEV replication, antiviral immune responses, central nervous system (CNS) inflammation, and overall disease progression. JEV infection upregulated NLRC5 expression in the brain, microglia, and non-neuronal cells, but not in neuronal cells. However, NLRC5 expression could be induced in neuroblastoma cells via IFN-γ treatment. Experimental modulation demonstrated that the typical antiviral restriction of JEV replication by IFN-γ is lost in NLRC5-deficient cells. Evaluation of stable cell lines expressing different NLRC5 variants showed that cytoplasmic retention and NLRC5 leucine-rich repeats (LRRs) are essential for viral restriction. Mechanistically, in silico modelling, co-immunoprecipitation, and immunofluorescence confirmed that NLRC5 binds directly to the viral NS3 protein in an LRR-dependent manner. In mouse models, in vivo knockdown of NLRC5 in the brain significantly accelerated clinical disease progression, heightened mortality, and triggered uncontrolled viral replication, indicated by elevated viral titers and NS3/NS1 expression. This viral surge induced severe neuroinflammation, as evidenced by significantly elevated levels of ASC and cleaved caspase-3 in NLRC5-deficient brains. These findings demonstrate that NLRC5 functions as a cell-type-specific antiviral regulator during JEV infection. It suppresses viral replication by directly binding to and degrading the viral NS3 protein. Loss of NLRC5 impairs IFN-γ-mediated antiviral restriction, leading to enhanced viral replication, severe neuroinflammation, and accelerated disease progression in vivo.
2026-06-22 | Integrative modelling of innate immune response dynamics during virus infection.
Positive-sense RNA viruses that constitute a large class of human pathogens employ various strategies to suppress and evade host immune defenses. Understanding the dynamic interaction between the viral life cycle and immune signaling is crucial to designing effective antiviral strategies. Although significant progress has been made, quantitative models that can accurately capture the intricate interactions and the intertwined dynamics during viral infection of cells remain missing. In this study, we develop a comprehensive mathematical model that integrates the intracellular viral life cycle with key cellular innate immune pathways, including RIG-I-mediated detection and JAK-STAT signaling. The model provides mechanistic insights into long-standing observations, capturing both virus-specific dynamics and innate immune response, and the key components driving their coupled dynamics. For example, a comparison of viruses shows how the Japanese Encephalitis virus undergoes a dramatic reduction in viral load in cells, due to its rapid replication that robustly activates the RIG-I pathway, in contrast to the poor immune control of Hepatitis C virus. More importantly, our model demonstrates how virus-host interactions exhibit a sharp transition boundary behavior, where minor differences in immune strength or viral suppression capacity can determine whether infections resolve or persist. We propose that ISG mRNA translation and viral replication predominantly dictate these bimodal infection outcomes. Additionally, the model not only recapitulates IFN desensitization but also identifies the molecular players involved. We demonstrate how our model's ability to capture IFN dynamics allows us to predict optimal timing and dosing strategies for interferon-based prophylactic therapies. Together, our approach reveals fundamental features that govern the delicate balance between the establishment of infection and immune control in RNA virus infections.
vaccines
2026-09-13 | Immunogenicity of a Vero cell-adapted Japanese encephalitis attenuated virus strain SA14-14-2 VC6.
To develop a Vero cell-adapted Japanese encephalitis (JE) SA14-14-2 strain for the production of JE SA14-14-2 live attenuated vaccine (LAV) using Vero cells as the substrate, the SA14-14-2 PHKC strain was adapted to Vero cells and subjected to plaque purification followed by clone selection. A highly attenuated strain, SA14-14-2 VC6, was isolated, whose phenotypic and genotypic characteristics were highly consistent with those of its parental strain SA14-14-2 PHKC. Immunogenicity assays demonstrated that the VC6 strain exhibited comparable immunogenicity to the parental SA14-14-2 strain. Under the experimental conditions used in this study, the VC6 strain induced stronger neutralizing antibody (NAb) responses, protection against intraperitoneal (i.p.) or intracerebral (i.c.) challenge with wild-type JE virus (JEV), viremia inhibition, and cellular immune responses than the chimeric JE-CV vaccine. Collectively, these findings indicate that the SA14-14-2 VC6 retains the immunogenic properties of the parental SA14-14-2 strain after adaptation to Vero cells and warrants further preclinical evaluation before its potential use in Vero cell-based JE vaccine development.
2026-08-05 | Japanese Encephalitis in Bangladesh: A Decade of Hospital-Based Sentinel Surveillance, 2007-2016
Japanese encephalitis (JE) is a mosquito-borne flavivirus disease amplified by pigs and transmitted by Culex mosquitoes breeding in irrigated rice paddies -- a One Health disease at the intersection of livestock husbandry, agriculture, and human health. This study compiles a decade of hospital-based sentinel surveillance data for Bangladesh into a single reproducible summary. No public API or dashboard exists for this disease, and no second published source was found to cross-validate the data against -- disclosed explicitly, unlike the companion HPAI, rabies, and Nipah virus analyses in this series. Key findings: (1) of 6,525 tested acute meningitis-encephalitis syndrome patients at four sentinel hospitals (Rangpur, Rajshahi, Chittagong, Khulna), 548 (8%) were confirmed JE cases, 2007-2016; (2) cases spanned 36 of 64 districts (56%), concentrated in the northwest; (3) 193 cases (35%) were aged 15 years or younger; (4) cases were sharply seasonal -- 436 (80%) had onset July-November, peaking in October, consistent with monsoon-driven Culex mosquito breeding in rice paddies; (5) approximately 50% of pigs in the Rajshahi catchment were JEV-seropositive by age 3, direct evidence of the amplifying-host cycle; (6) the apparent case rise after 2010 coincides with the Rangpur site joining surveillance that year, likely reflecting expanded capacity rather than purely rising incidence. Data source: transcribed with full citation from Paul et al. (2020, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.07.026). All analysis code and data are available at: https://github.com/khalilurrrahmanridoykhan/bangladesh-je-2007-2016
2026-07-07 | Japanese encephalitis in Nepal: closing the adult immunity gap.
Japanese encephalitis (JE) in Nepal is undergoing an epidemiological shift from a predominantly pediatric, Terai-centered disease to a geographically broader threat affecting susceptible adults. Despite successful childhood vaccination, the 2025 resurgence, with 175 confirmed cases and 34 deaths, exposed a major immunity gap among older cohorts, particularly adults over 40 years. Expanding transmission into hill districts and higher-altitude areas, likely influenced by climate variability, land-use change, and vector ecology, further challenges existing control strategies. Because JE overlaps clinically and radiologically with other endemic encephalitides, rapid laboratory confirmation is essential. Nepal's emerging adult vaccination policy should be integrated with climate-informed surveillance, One Health data systems, vector control, and survivor rehabilitation before future monsoon-driven outbreaks.
2026-07-04 | Japanese Encephalitis With a Characteristic Neuropathological Distribution Following Early MRI-Based Diagnosis: An Autopsy Case.
Japanese encephalitis (JE) is a mosquito-borne viral infection of the central nervous system for which no specific antiviral treatment is available. We report the case of a 79-year-old man residing in Kumamoto Prefecture, southwestern Japan, with JE who presented with fever, impaired consciousness, and respiratory failure, and subsequently died of multiple organ failure despite early supportive care. Magnetic resonance imaging (MRI) revealed characteristic bilateral thalamic lesions, leading to an early clinical suspicion of JE before serological confirmation. Neuropathological findings, particularly, the involvement of the thalamus, substantia nigra, hippocampus, and anterior horn of the spinal cord, were consistent with previously reported cases of JE, while also demonstrating a broader distribution of lesions than suggested by antemortem MRI. As most cases of JE occur in unvaccinated individuals, vaccination should be considered in middle-aged and older adults, particularly, those with low antibody titers against the JE virus.
2026-06-26 | Nucleotide variations in 3' untranslated region contribute to the enhanced virulence and replication efficiency of reemerging Japanese encephalitis virus genotype V.
Japanese encephalitis virus, a major causative agent of viral encephalitis in Asia, is classified into five genotypes. Genotype V (GV) has reemerged after more than 50 years of apparent absence, following identification of the sole GV isolate - the Muar strain - in 1952. Newly reemerged GV strains are genetically distinct from the ancestral Muar strain. In this study, we compared virulence and replication efficiency between the newly reemerged XZ0934 strain and the ancestral Muar strain. Viral titers in cultured cells, as well as viremia and mortality in mice infected with the XZ0934 strain, were significantly higher than those observed with the Muar strain, indicating enhanced virulence and replication efficiency of the XZ0934 strain. Multiple nucleotide variations in the 3' untranslated region (3'UTR) were identified between the XZ0934 and Muar strains; such variations contributed to the increased virulence and replication efficiency of the XZ0934 strain. These nucleotide variations resulted in substantial differences in the stem - loop (SL) I, SLII, and 3'SL structures of the 3'UTR and led to differential production of subgenomic flaviviral RNA (sfRNA). The variations also were responsible for differential inhibition of type I interferon production in vitro and in vivo between the two strains. These effects collectively contributed to the enhanced virulence and replication efficiency of the XZ0934 strain relative to the Muar strain. Our findings provide insight into the role of genetic variation in determining virulence and replication efficiency between newly reemerged and ancestral GV strains, as well as the molecular basis underlying GV virus reemergence.
small molecules
2026-09-28 | Targeting the catalytic ATP-binding site of Japanese Encephalitis Virus RNA-dependent RNA polymerase using integrated structure-based drug discovery.
Despite current advances, Japanese Encephalitis Virus (JEV) still poses a considerable risk because effective antiviral drugs are lacking. The RdRp protein is the main component of viral genome replication and therefore a primary target for antiviral drug development. In this study, we applied a drug discovery protocol with multiple parameters to identify RdRp inhibitors. Using a pharmacophore model, ligand-based screening of the ADMET-like Screening Compound Library, which had more than 448,000 molecules, was carried out, and 102,496 hits were generated. The three-level docking cascade, namely HTVS, SP, and XP, together with an initial MM-GBSA calculation, was used to identify F6548-1309, F0877-0123, and F1683-2814 as candidate inhibitors due to their good binding affinities. Further optimization was done through density functional theory (DFT), and the reactivity and electronic stability of the candidates were studied. Five independent Molecular dynamics (MD) simulations with random velocities were carried out to ensure accuracy and reproducibility. The MD simulations revealed that the candidates were dynamically stable. Furthermore, the PCA and FEL showed the candidates' conformational stability. This indicates that the selected compounds have stronger binding affinity to RdRp than the reference compound CHEMBL464432.
2026-09-04 | PTBP1 at the host-virus interface: mechanistic roles in viral RNA translation, replication, and immune modulation.
Viruses require the involvement of host RNA binding proteins for completion of important steps of their life cycle. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein found ubiquitously which performs important regulatory functions like alternative splicing, RNA stability, RNA localization, and translation by virtue of its four RRMs and shuttling between nucleus and cytoplasm. There is increasing evidence showing that many viruses make use of such regulatory roles of PTBP1 to facilitate their gene expression and replication. This review describes the existing mechanistic knowledge about the PTBP1 functions during viral infection, paying attention to the role of PTBP1 in viral RNA translation, viral RNA genome replication, and regulation of host antiviral response. Special attention is paid to the regulation by PTBP1 of IRES-dependent translation of enteroviruses and hepatitis C virus, as well as to the PTBP1 contribution to RNA stabilization, long-distance RNA interactions, and genome cyclization of flaviviruses such as dengue virus and Japanese encephalitis virus. Recent data on the PTBP1 function in coronavirus RNA metabolism are discussed as well. Furthermore, the role of PTBP1 in being both proviral and antiviral is reviewed in terms of innate immunity signalling pathways, stress granule biology, and virus-host interaction. Finally, we will explore the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein.
2026-08-27 | AMPK-Orchestrated Metabolic Reprogramming in Some Flavivirus Infections: Mechanisms and Therapeutic Opportunities.
5'-Adenosine monophosphate-activated protein kinase (AMPK) is the principal cellular energy sensor that coordinates metabolic adaptation by balancing anabolic and catabolic pathways in response to energic stress. Beyond its canonical role in maintaining energy homeostasis, AMPK has emerged as a central regulator of host-pathogen interactions by integrating lipid metabolism, autophagy, mitochondrial dynamics, oxidative stress, and innate immune signaling. Flaviviruses, including dengue virus, Zika virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus, extensively remodel host metabolism to establish productive infection. As a master regulator of cellular metabolism, AMPK can either restrict or facilitate flavivirus replication in a context-dependent manner by regulating lipid droplet biogenesis, fatty acid synthesis and beta-oxidation, autophagy, mitochondrial homeostasis, and interferon-mediated antiviral responses. Conversely, flaviviruses actively manipulate AMPK signaling and its downstream metabolic networks to promote endoplasmic reticulum remodeling, replication organelle biogenesis, energy production, and immune evasion. In this review, we summarize recent advances in understanding the multifaceted roles of AMPK during flavivirus infection, with an emphasis on its regulation of metabolic reprogramming, organelle remodeling, and antiviral immunity. We further discuss the therapeutic potential of pharmacologically targeting AMPK and its downstream pathways as a host-directed strategy for broad-spectrum antiviral intervention against flaviviruses.
2026-08-20 | CYLD restricts Japanese encephalitis virus pathogenic progression via blocking viral replication and virus-triggered GSDMD-dependent pyroptosis in neural cells.
Japanese encephalitis virus (JEV), a typical mosquito-borne neurotropic pathogen, triggers neuronal cell death and robust inflammatory responses within the central nervous system, posing severe threats to public health and animal husbandry worldwide. The host protein cylindromatosis (CYLD) acts as a vital deubiquitinating enzyme and negatively modulates a spectrum of inflammatory signaling cascades via its deubiquitinase activity; nevertheless, its functional role and underlying mechanism during JEV infection remain poorly defined. The present study was designed to explore the regulatory effects and molecular mechanism of CYLD in JEV replication as well as virus-elicited neuronal pyroptosis. Our results revealed that JEV infection markedly downregulated endogenous CYLD expression in a time-dependent fashion. Functional validation experiments demonstrated that CYLD overexpression remarkably restrained JEV replication, while CYLD knockdown exerted the opposite pro-viral effect, and such regulatory functions were independent of the interferon signaling pathway. Additionally, ectopic CYLD expression effectively mitigated JEV-triggered neuronal pyroptosis, whereas CYLD deficiency significantly exacerbated this pyroptotic process. Notably, the inhibitory effects of CYLD on viral replication and neuronal pyroptosis were completely abrogated by the application of deubiquitinase activity-deficient mutants and truncated CYLD constructs, confirming that the biological functions of CYLD are strictly dependent on its deubiquitinase active domain. Consistently, in vivo mouse infection models further validated the critical involvement of CYLD in JEV pathogenicity. Mechanistically, combined in vivo and in vitro assays illustrated that CYLD alleviates JEV-induced neuronal pyroptosis through targeted inhibition of the JNK/p38 MAPK signaling pathway and subsequent suppression of downstream NLRP3 inflammasome activation. Collectively, this study for the first time identifies CYLD as a pivotal negative regulator of neuronal pyroptosis upon JEV infection. CYLD exerts prominent neuroprotective effects and restricts JEV replication via suppressing NLRP3 inflammasome-dependent pyroptosis, which sheds new light on the molecular pathogenesis of Japanese encephalitis and provides a promising novel therapeutic target for the prevention and clinical treatment of JEV encephalitis.
2026-08-13 | Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.
oligonucleotides
2026-09-30 | Human Infection with Japanese Encephalitis Virus Genotype V, China, 2025.
Japanese encephalitis virus genotype V (JEV GV) has caused multiple cases of viral encephalitis in South Korea. We report a human case of JEV GV in China, confirmed by serology, sequencing, and quantitative reverse transcription PCR. We confirm JEV GV infection in China, highlighting the persistent threat of this virus.
2026-09-30 | Viral RNA-Targeting Locked Nucleic Acid Gapmers: Design and In Vitro Evaluation.
Recurrent viral outbreaks, such as coronavirus disease 2019 (COVID-19), seasonal influenza, and flavivirus infections, highlight the urgent need for rapid-response therapies against viral diseases. These outbreaks are mainly caused by viruses with RNA genomes. Accordingly, antisense oligonucleotides (ASOs), which bind target RNA in a sequence-specific manner to modulate its functions, represent a promising modality for developing antiviral agents. Recent studies, particularly those on RNase H-recruiting ASOs incorporating the nucleic acid analogue locked nucleic acid (LNA), known as LNA gapmers, have demonstrated effective antiviral activity via targeted viral RNA degradation. Since the approval of fomivirsen, the first ASO drug targeting cytomegalovirus RNA, in 1998, the development of LNA gapmers has positioned viral RNA degradation as a promising approach for clinical application. Here, using Japanese encephalitis virus (JEV), a flavivirus of major public health concern, as a model system, we describe a step-by-step protocol for the design and in vitro evaluation of the antiviral efficacy and cytotoxicity of JEV RNA-targeting LNA gapmers. The approaches presented here provide a basis for the design and screening of antiviral LNA gapmers and can be applied to other viruses.
2026-09-06 | A rational multi-target RNA interference approach for effective suppression of Japanese encephalitis virus replication
Japanese encephalitis virus (JEV), a major cause of viral encephalitis in the Asia–Pacific region, remains a significant public health concern due to suboptimal vaccine coverage and the lack of approved antiviral therapies. RNA interference (RNAi) provides a sequence-specific approach for suppressing viral gene expression and represents a promising antiviral strategy. Here, we designed small interfering RNAs (siRNAs) targeting selected regions of essential JEV genes, including prM, NS1, NS3, and NS5, and evaluated their antiviral efficacy in HeLa cells. Individual siRNAs reduced viral protein expression and infectious virus production while maintaining more than 85% cell viability. A multi-target siRNA cocktail reduced viral replication to approximately 5–6% of the scrambled control level and preserved cell viability after JEV infection. Neither individual siRNAs nor the cocktail produced a detectable increase in protein kinase R phosphorylation relative to the scrambled control under the conditions tested. These findings support the feasibility of multi-target RNAi-mediated suppression of JEV replication in vitro and provide a basis for further evaluation of RNAi-based antiviral approaches against related flaviviruses.
2026-01-28 | Opportunities and Challenges of mRNA and VLP Technologies for Pan-Flavivirus Vaccine Development: Focus on Conserved Quaternary Epitope Conformations.
Mosquito-borne flaviviruses, including Dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Yellow fever virus (YFV), and Zika virus (ZIKV), continue to present a significant threat to public health worldwide. In 2024, these viruses accounted for 11,717 reported cases in the United States and more than 7.6 million cases globally. As of early 2025, according to CDC data, 1830 cases of dengue had already been reported, with 1584 transmitted locally within the U.S. Despite the considerable burden that these diseases pose, no specific antiviral treatments exist. A very limited number of virus-specific vaccines have been licensed, such as those for YFV, JEV, and, with specific constraints, for DENV. To date, no pan-flavivirus vaccine is available. This review examines the potential of emerging vaccine platforms-particularly messenger RNA and virus-like particles-as promising tools in the pursuit of a broadly protective flavivirus vaccine. We analyze current strategies for inducing cross-neutralizing immune responses and discuss how these technologies could support the presentation of conserved quaternary epitope conformations, which are increasingly recognized as critical targets for establishing potent immune responses. We review key advances in virology, immune response, and immunogen delivery systems to highlight the potential for developing a pan-flavivirus vaccine.
2025-10-25 | RNAi therapeutics targeting Japanese encephalitis virus: Gene targets, delivery platforms, and translational barriers.
Japanese encephalitis virus (JEV), a neurotropic flavivirus, is a leading cause of viral encephalitis in Asia, particularly affecting children and causing significant morbidity and mortality. Despite the availability of vaccines and vector control strategies, their limited efficacy against emerging genotypes and incomplete coverage necessitate alternative antiviral approaches. RNA interference (RNAi) has emerged as a promising therapeutic modality by exploiting post-transcriptional gene silencing to inhibit viral replication. Notably, conserved viral genes-such as capsid (C), envelope (E), NS3, and NS5-represent optimal RNAi targets across JEV genotypes due to their essential roles in the viral life cycle and minimal sequence variability. Recent advances in delivery platforms, including lipid nanoparticles, lentiviral vectors, and artificial microRNAs, have significantly improved RNAi stability, blood-brain barrier (BBB) penetration, and cell-specific targeting. Comparative insights from related flaviviruses such as Dengue and Zika have further informed effective RNAi design. Preclinical studies have demonstrated potent antiviral effects, with >90 % suppression of viral RNA, substantial reductions in brain viral load, and enhanced survival in murine models. However, clinical translation remains challenged by delivery efficiency, immune activation, off-target effects, and the potential for viral escape mutations. This review summarizes the current landscape of RNAi-based therapeutics for JEV, emphasizing conserved gene targets, delivery innovations, and translational hurdles, and outlines future directions for integrating RNAi into next-generation antiviral strategies.
other
2026-08-22 | Annexin A2 facilitates Japanese encephalitis virus replication by regulating endocytosis and intracellular transport in PK15 cells.
Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes severe encephalitis in humans and reproductive disorders in pigs. However, the host factors that regulate JEV infection and replication remain incompletely understood. In this study, we used porcine kidney cells (PK15) infected with the attenuated JEV strain SA14-14-2 to identify host proteins interacting with the JEV envelope (E) protein by immunoprecipitation coupled with LC-MS/MS. Annexin A2 (ANXA2) was identified as a candidate host factor associated with JEV infection. ANXA2 expression was increased during JEV infection, and co- immunoprecipitation confirmed its association with the JEV E protein. Inhibition of ANXA2 with antibody reduced JEV RNA replication in a dose-dependent manner. To further define its function, ANXA2 knockout (KO) PK15 cells were generated using CRISPR/Cas9. Compared with wild-type cells, ANXA2-KO cells showed significantly reduced viral RNA accumulation, especially during the early stage of JEV infection (2-6hpi), when the viral entry and initiates replication, lower JEV E protein expression, and decreased progeny virus titers. In addition, ANXA2 deficiency altered the expression of clathrin-mediated endocytosis- related genes and proteins, including CLTC, CLTB, AP2M1, and EPS15, and affected Akt phosphorylation during early infection. Fluorescence recovery after photobleaching analysis (FRAP) of DiD-labeled JEV particles indicated impaired intracellular transport in ANXA2-KO cells. these findings identify ANXA2 as a host factor that promotes JEV infection and replication, at least in part by regulating clathrin-mediated endocytosis and intracellular transport. ANXA2 may represent a potential target for future antiviral strategies against JEV.
2026-07-18 | Engineered Extracellular Vesicle-Delivered CRISPR/Cas13d for Alleviating Japanese Encephalitis Virus-Induced Brain Injury
This research investigates an engineered extracellular vesicle (EV)-based strategy for delivering programmable CRISPR/Cas13d components across the blood–brain barrier (BBB) to inhibit Japanese encephalitis virus (JEV) infection. We developed RVG-functionalized targeted engineered EVs, termed TEEVs, for brain-targeted delivery of high-fidelity RfxCas13d mRNA and JEV-targeting CRISPR RNAs (crRNAs). The CD63–L7Ae/C/D box system was used to actively enrich Cas13d mRNA and tandem crRNAs within EVs, while RVG surface functionalization was introduced to enhance BBB crossing and uptake by target cells. In vitro, TEEVs showed greater cellular uptake than non-targeted engineered EVs and crossed the BBB-like endothelial barrier in a Transwell co-culture model. TEEVs also suppressed JEV replication and preserved barrier integrity. In vivo biodistribution analyses showed enhanced brain accumulation following intravenous administration. In a lethal mouse model of JEV infection, TEEV treatment reduced brain viral loads, inflammatory responses, BBB disruption, and neuropathological injury and improved survival.
2026-07-02 | FcγRIIA signalling as a host-associated determinant of endosomal trafficking and antibody-dependent enhancement in flavivirus infection.
Antibody-dependent enhancement (ADE) is a major determinant of disease severity in flavivirus infections, yet the host-associated factors that regulate the transition from antibody-mediated uptake to productive infection remain incompletely defined. Fc gamma receptor IIA (FcγRIIA/CD32A), an activating Fc receptor expressed on myeloid cells, represents a key host determinant linking pre-existing immunity to viral entry pathways. Here, we investigated how FcγRIIA signalling influences intracellular trafficking and ADE efficiency across dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). Using BHK-21 cells expressing either wild-type FcγRIIA (WT) or a cytoplasmic-truncated variant lacking the immunoreceptor tyrosine-based activation motif (ITAM), we show that immune-complex internalization occurs independently of the cytoplasmic domain, but that signalling competence significantly modulates downstream infection efficiency. WT cells generally showed higher ADE efficiency, whereas cytoplasmic-truncated receptors preserved ADE activity but showed virus-dependent reductions in enhancement magnitude. FcγRIIA signalling altered the intracellular routing of virus-antibody complexes. WT receptors promoted rapid trafficking from EEA1-positive early endosomes to Rab7-positive late endosomes, whereas signalling-deficient receptors displayed delayed progression and increased association with IRAP- and Rab14-positive compartments. These trafficking differences correlated with virus-specific patterns of enhancement, with DENV showing the strongest dependence on late endosomal maturation, while ZIKV and JEV utilized more flexible or alternative pathways. Transcriptomic analysis revealed minimal differences between WT and truncated receptors at later time points, indicating that FcγRIIA primarily modulates early post-entry events rather than sustained transcriptional responses. Collectively, these findings identify FcγRIIA signalling as a host-associated determinant that regulates the intracellular fate of virus-antibody complexes and influences ADE efficiency through modulation of endosomal trafficking dynamics. The work provides a mechanistic framework linking host receptor signalling to variability in infection outcomes under conditions of pre-existing immunity, with implications for understanding disease heterogeneity and optimizing vaccine and antibody-based interventions.
2026-05-22 | Immunity-oriented drug strategies for viral encephalitis: Acyclovir, antiepileptics and corticosteroids in neurological intensive care.
Viral encephalitis (VE), is a life-threatening neurological disorder marked by inflammation of brain parenchyma, driven by direct viral cytotoxicity and host immune-mediated injury. Globally, its incidence ranges from 1.4 to 13.8 cases per 100,000 individuals annually, with significant morbidity and mortality in endemic regions such as India, among children. Neurotropic viruses including herpes simplex virus (HSV), Japanese encephalitis virus (JEV) and West Nile virus, enter central nervous system via hematogenous or neuronal routes, triggering viral replication, cytokine release and blood-brain barrier disruption, resulting in seizures, cerebral edema and long-term neurological deficits. Current management in neurological intensive care relies on immunity-oriented strategies: Acyclovir as first-line antiviral for HSV and varicella-zoster virus, antiepileptics to control seizures and limit secondary neuronal injury and corticosteroids to modulate harmful neuroinflammation and cerebral edema. Emerging therapies, including novel antivirals (favipiravir, remdesivir, brincidofovir), monoclonal antibodies, cytokine inhibitors (tocilizumab, anakinra) and B-cell/plasma cell-targeted agents (rituximab, daratumumab), offer promise by simultaneously addressing viral replication and immune dysregulation. Personalized biomarker-guided integrating pathogen-directed and host-targeted therapies may optimize outcomes, reduce neuronal injury and improve recovery. This review underscores the importance of a multidimensional, immunity-oriented treatment paradigm, highlighting both established and emerging strategies to enhance prognosis and long-term neurological functions in patients with viral encephalitis.
2026-04-17 | Human antibodies against West Nile and related orthoflaviviruses.
West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease. No specific prophylaxis or treatment exists for WNV or related orthoflavivirus infections, and the determinants of human disease severity remain poorly understood. Here, we report that neutralizing autoantibodies against type I interferons do not impair antiviral antibody development. Among the fully human monoclonal antibodies with potent neutralizing activity against WNV that were discovered, W010 targets a unique epitope within the envelope protein domain III (EDIII) and confers both pre- and post-exposure protection in a murine WNV model, even when interferon signaling is impaired. A second protective antibody, W014, exhibits broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.
proteins
2026-09-29 | MAVS maintains mitochondrial import competence and also limits RNA virus replication independently of interferon signaling.
Intrinsic, cell-autonomous antiviral defenses can restrict infection without involving paracrine interferon (IFN) programs. Previous studies have demonstrated the importance of intact mitochondrial homeostasis in antiviral immunity. Mitochondrial antiviral signaling (MAVS) protein is a critical adaptor molecule in the RLR pathway that regulates IFN production in response to RNA viral infections. Here, we identify a potent intrinsic antiviral immunity that is orchestrated through stable mitochondria. We further identify MAVS as a regulator of mitochondrial import machinery whose activity is required for an IFN-independent antiviral state. Loss of MAVS leads to severe mitochondrial fragmentation, depolarization, and mitophagy, accompanied by diminished mitochondrial bioenergetics and protein import. Mechanistically, MAVS maintains mitochondrial integrity by maintaining the expression and assembly of the translocase of the outer membrane complex and sustaining the abundance of its core components. Restoration of MAVS expression reverses these defects and reinstates a robust antiviral state. Remarkably, this mitochondrial-driven immunity efficiently restricts SARS-CoV-2 replication even under IFN-deficient conditions and operates alongside the IFN pathways during infection by RNA viruses, such as the Japanese encephalitis virus. Our findings reveal a mitochondrial maintenance function of MAVS that operates in parallel to, and independently of, canonical interferon signaling during RNA virus infection. These findings highlight mitochondrial integrity as a common determinant behind a broad, collective antiviral immunity that involves both intrinsic and IFN-dependent mechanisms.IMPORTANCEHow do mitochondria contribute to the intrinsic cellular antiviral defense even when the primary immune arsenal is silenced? This work reveals that MAVS, long known for triggering interferon, acts as a vital bridge that stabilizes mitochondria to impart a potent intrinsic antiviral state against RNA viruses. We show that MAVS serves as a structural guardian of the organelle, a function it orchestrates by stabilizing the translocase of the outer membrane complex, the essential gateway for mitochondrial protein import. When MAVS is lost or targeted by viruses like SARS-CoV-2 and Japanese encephalitis virus (JEV), this gateway collapses, leading to organelle failure that viruses exploit. Crucially, we demonstrate that MAVS can restrict viral replication entirely independently of traditional interferon signaling. This discovery shifts our understanding of MAVS from a simple signal transducer to a multidimensional protector. By safeguarding the cell's "powerhouse," MAVS provides a fundamental layer of intrinsic immunity that remains active even when other immune responses are evaded.
2026-09-23 | SAMSN1 restricts Japanese encephalitis virus replication by recruiting TRIM21 to degrade viral proteins and activate the interferon pathway.
Japanese encephalitis virus (JEV), a zoonotic mosquito-transmitted flavivirus, induces human encephalitis and swine reproductive diseases. No antiviral drugs or treatments exist for flavivirus infections, which cause severe symptoms. Even though some host proteins can suppress flavivirus proliferation, the virus can inhibit this antiviral effect. This study identified a host protein SAMSN1 (SAM domain, SH3 domain, and nuclear localization signal 1; also referred to as HACS1, SLY2, and NASH1) having antiviral activity during JEV replication. SAMSN1 was upregulated during JEV infection. The expression of SAMSN1 inhibits JEV replication by binding and degrading JEV-encoded nonstructural proteins (NS1, NS5) through the proteasome and the SAMSN1-TRIM21-p62 autophagy protein degradation pathways. SAMSN1 induced expression of type I interferon through the RIG-I/MyD88-TBK1-IRF3 axis in the JEV infection process. Current findings reveal a novel role of SAMSN1 in inhibiting JEV replication and proliferation, through viral protein degradation and interferon pathway upregulation.
2026-09-16 | Travel vaccination in senior travelers: current evidence, challenges, and prevention.
The substantial number of older adults undertaking international travel has increased the relevance of pre-travel prevention in this population. However, vaccination strategies in this group require consideration of immune aging, baseline status, medication use, and travel-related exposure. This narrative review summarizes the current evidence on vaccination in senior travelers, with particular attention to the vaccines most relevant to this population, the differences in the strength of evidence across vaccines, and the clinical factors that should guide pre-travel decision-making. Routine vaccines, including influenza, COVID-19, pneumococcal, respiratory syncytial virus, herpes zoster, and tetanus-diphtheria vaccines, constitute an essential part of pre-travel assessment, whereas travel-specific vaccines, such as hepatitis A, hepatitis B, typhoid, rabies, Japanese encephalitis, tick-borne encephalitis, and cholera, should be considered according to the destination, itinerary, expected exposure, and time before departure. Yellow fever vaccination represents a particular clinical challenge because advancing age is associated with a greater risk of serious vaccine-associated adverse events, making individualized risk‒benefit assessment essential. Recently introduced dengue and chikungunya vaccines should also be considered on an individualized basis, taking into account exposure risk, potential benefits, comorbidities, and the current limitations of the available evidence. The review also highlights the importance of integrating vaccination with non-vaccine preventive strategies, including food and water precautions, vector avoidance, and hygiene measures. Although the evidence base has expanded, important uncertainties remain, particularly because age-specific data are limited and frail older adults remain underrepresented in clinical studies. Overall, pre-travel care for senior travelers should be comprehensive, exposure-based, and individualized according to the clinical profile and travel characteristics of each traveler.
2026-08-13 | NLRC5 restricts Japanese encephalitis virus replication and neuroinflammation by interacting with the viral NS3 protein in an IFN-γ-dependent manner.
NLRC5 is a known activator of MHC class I genes and a regulator of type I interferon activity. Although its expression increases in brains infected with Japanese encephalitis virus (JEV), its specific contribution to JEV pathogenesis and neuroinflammation remains unclear. We utilised in vitro cell cultures, in silico modelling, and in vivo mouse knockdown models of NLRC5 to investigate its impact on JEV replication, antiviral immune responses, central nervous system (CNS) inflammation, and overall disease progression. JEV infection upregulated NLRC5 expression in the brain, microglia, and non-neuronal cells, but not in neuronal cells. However, NLRC5 expression could be induced in neuroblastoma cells via IFN-γ treatment. Experimental modulation demonstrated that the typical antiviral restriction of JEV replication by IFN-γ is lost in NLRC5-deficient cells. Evaluation of stable cell lines expressing different NLRC5 variants showed that cytoplasmic retention and NLRC5 leucine-rich repeats (LRRs) are essential for viral restriction. Mechanistically, in silico modelling, co-immunoprecipitation, and immunofluorescence confirmed that NLRC5 binds directly to the viral NS3 protein in an LRR-dependent manner. In mouse models, in vivo knockdown of NLRC5 in the brain significantly accelerated clinical disease progression, heightened mortality, and triggered uncontrolled viral replication, indicated by elevated viral titers and NS3/NS1 expression. This viral surge induced severe neuroinflammation, as evidenced by significantly elevated levels of ASC and cleaved caspase-3 in NLRC5-deficient brains. These findings demonstrate that NLRC5 functions as a cell-type-specific antiviral regulator during JEV infection. It suppresses viral replication by directly binding to and degrading the viral NS3 protein. Loss of NLRC5 impairs IFN-γ-mediated antiviral restriction, leading to enhanced viral replication, severe neuroinflammation, and accelerated disease progression in vivo.
2026-06-22 | Integrative modelling of innate immune response dynamics during virus infection.
Positive-sense RNA viruses that constitute a large class of human pathogens employ various strategies to suppress and evade host immune defenses. Understanding the dynamic interaction between the viral life cycle and immune signaling is crucial to designing effective antiviral strategies. Although significant progress has been made, quantitative models that can accurately capture the intricate interactions and the intertwined dynamics during viral infection of cells remain missing. In this study, we develop a comprehensive mathematical model that integrates the intracellular viral life cycle with key cellular innate immune pathways, including RIG-I-mediated detection and JAK-STAT signaling. The model provides mechanistic insights into long-standing observations, capturing both virus-specific dynamics and innate immune response, and the key components driving their coupled dynamics. For example, a comparison of viruses shows how the Japanese Encephalitis virus undergoes a dramatic reduction in viral load in cells, due to its rapid replication that robustly activates the RIG-I pathway, in contrast to the poor immune control of Hepatitis C virus. More importantly, our model demonstrates how virus-host interactions exhibit a sharp transition boundary behavior, where minor differences in immune strength or viral suppression capacity can determine whether infections resolve or persist. We propose that ISG mRNA translation and viral replication predominantly dictate these bimodal infection outcomes. Additionally, the model not only recapitulates IFN desensitization but also identifies the molecular players involved. We demonstrate how our model's ability to capture IFN dynamics allows us to predict optimal timing and dosing strategies for interferon-based prophylactic therapies. Together, our approach reveals fundamental features that govern the delicate balance between the establishment of infection and immune control in RNA virus infections.
vaccines
2026-09-13 | Immunogenicity of a Vero cell-adapted Japanese encephalitis attenuated virus strain SA14-14-2 VC6.
To develop a Vero cell-adapted Japanese encephalitis (JE) SA14-14-2 strain for the production of JE SA14-14-2 live attenuated vaccine (LAV) using Vero cells as the substrate, the SA14-14-2 PHKC strain was adapted to Vero cells and subjected to plaque purification followed by clone selection. A highly attenuated strain, SA14-14-2 VC6, was isolated, whose phenotypic and genotypic characteristics were highly consistent with those of its parental strain SA14-14-2 PHKC. Immunogenicity assays demonstrated that the VC6 strain exhibited comparable immunogenicity to the parental SA14-14-2 strain. Under the experimental conditions used in this study, the VC6 strain induced stronger neutralizing antibody (NAb) responses, protection against intraperitoneal (i.p.) or intracerebral (i.c.) challenge with wild-type JE virus (JEV), viremia inhibition, and cellular immune responses than the chimeric JE-CV vaccine. Collectively, these findings indicate that the SA14-14-2 VC6 retains the immunogenic properties of the parental SA14-14-2 strain after adaptation to Vero cells and warrants further preclinical evaluation before its potential use in Vero cell-based JE vaccine development.
2026-08-05 | Japanese Encephalitis in Bangladesh: A Decade of Hospital-Based Sentinel Surveillance, 2007-2016
Japanese encephalitis (JE) is a mosquito-borne flavivirus disease amplified by pigs and transmitted by Culex mosquitoes breeding in irrigated rice paddies -- a One Health disease at the intersection of livestock husbandry, agriculture, and human health. This study compiles a decade of hospital-based sentinel surveillance data for Bangladesh into a single reproducible summary. No public API or dashboard exists for this disease, and no second published source was found to cross-validate the data against -- disclosed explicitly, unlike the companion HPAI, rabies, and Nipah virus analyses in this series. Key findings: (1) of 6,525 tested acute meningitis-encephalitis syndrome patients at four sentinel hospitals (Rangpur, Rajshahi, Chittagong, Khulna), 548 (8%) were confirmed JE cases, 2007-2016; (2) cases spanned 36 of 64 districts (56%), concentrated in the northwest; (3) 193 cases (35%) were aged 15 years or younger; (4) cases were sharply seasonal -- 436 (80%) had onset July-November, peaking in October, consistent with monsoon-driven Culex mosquito breeding in rice paddies; (5) approximately 50% of pigs in the Rajshahi catchment were JEV-seropositive by age 3, direct evidence of the amplifying-host cycle; (6) the apparent case rise after 2010 coincides with the Rangpur site joining surveillance that year, likely reflecting expanded capacity rather than purely rising incidence. Data source: transcribed with full citation from Paul et al. (2020, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2020.07.026). All analysis code and data are available at: https://github.com/khalilurrrahmanridoykhan/bangladesh-je-2007-2016
2026-07-07 | Japanese encephalitis in Nepal: closing the adult immunity gap.
Japanese encephalitis (JE) in Nepal is undergoing an epidemiological shift from a predominantly pediatric, Terai-centered disease to a geographically broader threat affecting susceptible adults. Despite successful childhood vaccination, the 2025 resurgence, with 175 confirmed cases and 34 deaths, exposed a major immunity gap among older cohorts, particularly adults over 40 years. Expanding transmission into hill districts and higher-altitude areas, likely influenced by climate variability, land-use change, and vector ecology, further challenges existing control strategies. Because JE overlaps clinically and radiologically with other endemic encephalitides, rapid laboratory confirmation is essential. Nepal's emerging adult vaccination policy should be integrated with climate-informed surveillance, One Health data systems, vector control, and survivor rehabilitation before future monsoon-driven outbreaks.
2026-07-04 | Japanese Encephalitis With a Characteristic Neuropathological Distribution Following Early MRI-Based Diagnosis: An Autopsy Case.
Japanese encephalitis (JE) is a mosquito-borne viral infection of the central nervous system for which no specific antiviral treatment is available. We report the case of a 79-year-old man residing in Kumamoto Prefecture, southwestern Japan, with JE who presented with fever, impaired consciousness, and respiratory failure, and subsequently died of multiple organ failure despite early supportive care. Magnetic resonance imaging (MRI) revealed characteristic bilateral thalamic lesions, leading to an early clinical suspicion of JE before serological confirmation. Neuropathological findings, particularly, the involvement of the thalamus, substantia nigra, hippocampus, and anterior horn of the spinal cord, were consistent with previously reported cases of JE, while also demonstrating a broader distribution of lesions than suggested by antemortem MRI. As most cases of JE occur in unvaccinated individuals, vaccination should be considered in middle-aged and older adults, particularly, those with low antibody titers against the JE virus.
2026-06-26 | Nucleotide variations in 3' untranslated region contribute to the enhanced virulence and replication efficiency of reemerging Japanese encephalitis virus genotype V.
Japanese encephalitis virus, a major causative agent of viral encephalitis in Asia, is classified into five genotypes. Genotype V (GV) has reemerged after more than 50 years of apparent absence, following identification of the sole GV isolate - the Muar strain - in 1952. Newly reemerged GV strains are genetically distinct from the ancestral Muar strain. In this study, we compared virulence and replication efficiency between the newly reemerged XZ0934 strain and the ancestral Muar strain. Viral titers in cultured cells, as well as viremia and mortality in mice infected with the XZ0934 strain, were significantly higher than those observed with the Muar strain, indicating enhanced virulence and replication efficiency of the XZ0934 strain. Multiple nucleotide variations in the 3' untranslated region (3'UTR) were identified between the XZ0934 and Muar strains; such variations contributed to the increased virulence and replication efficiency of the XZ0934 strain. These nucleotide variations resulted in substantial differences in the stem - loop (SL) I, SLII, and 3'SL structures of the 3'UTR and led to differential production of subgenomic flaviviral RNA (sfRNA). The variations also were responsible for differential inhibition of type I interferon production in vitro and in vivo between the two strains. These effects collectively contributed to the enhanced virulence and replication efficiency of the XZ0934 strain relative to the Muar strain. Our findings provide insight into the role of genetic variation in determining virulence and replication efficiency between newly reemerged and ancestral GV strains, as well as the molecular basis underlying GV virus reemergence.
small molecules
2026-09-28 | Targeting the catalytic ATP-binding site of Japanese Encephalitis Virus RNA-dependent RNA polymerase using integrated structure-based drug discovery.
Despite current advances, Japanese Encephalitis Virus (JEV) still poses a considerable risk because effective antiviral drugs are lacking. The RdRp protein is the main component of viral genome replication and therefore a primary target for antiviral drug development. In this study, we applied a drug discovery protocol with multiple parameters to identify RdRp inhibitors. Using a pharmacophore model, ligand-based screening of the ADMET-like Screening Compound Library, which had more than 448,000 molecules, was carried out, and 102,496 hits were generated. The three-level docking cascade, namely HTVS, SP, and XP, together with an initial MM-GBSA calculation, was used to identify F6548-1309, F0877-0123, and F1683-2814 as candidate inhibitors due to their good binding affinities. Further optimization was done through density functional theory (DFT), and the reactivity and electronic stability of the candidates were studied. Five independent Molecular dynamics (MD) simulations with random velocities were carried out to ensure accuracy and reproducibility. The MD simulations revealed that the candidates were dynamically stable. Furthermore, the PCA and FEL showed the candidates' conformational stability. This indicates that the selected compounds have stronger binding affinity to RdRp than the reference compound CHEMBL464432.
2026-09-04 | PTBP1 at the host-virus interface: mechanistic roles in viral RNA translation, replication, and immune modulation.
Viruses require the involvement of host RNA binding proteins for completion of important steps of their life cycle. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein found ubiquitously which performs important regulatory functions like alternative splicing, RNA stability, RNA localization, and translation by virtue of its four RRMs and shuttling between nucleus and cytoplasm. There is increasing evidence showing that many viruses make use of such regulatory roles of PTBP1 to facilitate their gene expression and replication. This review describes the existing mechanistic knowledge about the PTBP1 functions during viral infection, paying attention to the role of PTBP1 in viral RNA translation, viral RNA genome replication, and regulation of host antiviral response. Special attention is paid to the regulation by PTBP1 of IRES-dependent translation of enteroviruses and hepatitis C virus, as well as to the PTBP1 contribution to RNA stabilization, long-distance RNA interactions, and genome cyclization of flaviviruses such as dengue virus and Japanese encephalitis virus. Recent data on the PTBP1 function in coronavirus RNA metabolism are discussed as well. Furthermore, the role of PTBP1 in being both proviral and antiviral is reviewed in terms of innate immunity signalling pathways, stress granule biology, and virus-host interaction. Finally, we will explore the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein.
2026-08-27 | AMPK-Orchestrated Metabolic Reprogramming in Some Flavivirus Infections: Mechanisms and Therapeutic Opportunities.
5'-Adenosine monophosphate-activated protein kinase (AMPK) is the principal cellular energy sensor that coordinates metabolic adaptation by balancing anabolic and catabolic pathways in response to energic stress. Beyond its canonical role in maintaining energy homeostasis, AMPK has emerged as a central regulator of host-pathogen interactions by integrating lipid metabolism, autophagy, mitochondrial dynamics, oxidative stress, and innate immune signaling. Flaviviruses, including dengue virus, Zika virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus, extensively remodel host metabolism to establish productive infection. As a master regulator of cellular metabolism, AMPK can either restrict or facilitate flavivirus replication in a context-dependent manner by regulating lipid droplet biogenesis, fatty acid synthesis and beta-oxidation, autophagy, mitochondrial homeostasis, and interferon-mediated antiviral responses. Conversely, flaviviruses actively manipulate AMPK signaling and its downstream metabolic networks to promote endoplasmic reticulum remodeling, replication organelle biogenesis, energy production, and immune evasion. In this review, we summarize recent advances in understanding the multifaceted roles of AMPK during flavivirus infection, with an emphasis on its regulation of metabolic reprogramming, organelle remodeling, and antiviral immunity. We further discuss the therapeutic potential of pharmacologically targeting AMPK and its downstream pathways as a host-directed strategy for broad-spectrum antiviral intervention against flaviviruses.
2026-08-20 | CYLD restricts Japanese encephalitis virus pathogenic progression via blocking viral replication and virus-triggered GSDMD-dependent pyroptosis in neural cells.
Japanese encephalitis virus (JEV), a typical mosquito-borne neurotropic pathogen, triggers neuronal cell death and robust inflammatory responses within the central nervous system, posing severe threats to public health and animal husbandry worldwide. The host protein cylindromatosis (CYLD) acts as a vital deubiquitinating enzyme and negatively modulates a spectrum of inflammatory signaling cascades via its deubiquitinase activity; nevertheless, its functional role and underlying mechanism during JEV infection remain poorly defined. The present study was designed to explore the regulatory effects and molecular mechanism of CYLD in JEV replication as well as virus-elicited neuronal pyroptosis. Our results revealed that JEV infection markedly downregulated endogenous CYLD expression in a time-dependent fashion. Functional validation experiments demonstrated that CYLD overexpression remarkably restrained JEV replication, while CYLD knockdown exerted the opposite pro-viral effect, and such regulatory functions were independent of the interferon signaling pathway. Additionally, ectopic CYLD expression effectively mitigated JEV-triggered neuronal pyroptosis, whereas CYLD deficiency significantly exacerbated this pyroptotic process. Notably, the inhibitory effects of CYLD on viral replication and neuronal pyroptosis were completely abrogated by the application of deubiquitinase activity-deficient mutants and truncated CYLD constructs, confirming that the biological functions of CYLD are strictly dependent on its deubiquitinase active domain. Consistently, in vivo mouse infection models further validated the critical involvement of CYLD in JEV pathogenicity. Mechanistically, combined in vivo and in vitro assays illustrated that CYLD alleviates JEV-induced neuronal pyroptosis through targeted inhibition of the JNK/p38 MAPK signaling pathway and subsequent suppression of downstream NLRP3 inflammasome activation. Collectively, this study for the first time identifies CYLD as a pivotal negative regulator of neuronal pyroptosis upon JEV infection. CYLD exerts prominent neuroprotective effects and restricts JEV replication via suppressing NLRP3 inflammasome-dependent pyroptosis, which sheds new light on the molecular pathogenesis of Japanese encephalitis and provides a promising novel therapeutic target for the prevention and clinical treatment of JEV encephalitis.
2026-08-13 | Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses.
Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.
oligonucleotides
2026-09-30 | Human Infection with Japanese Encephalitis Virus Genotype V, China, 2025.
Japanese encephalitis virus genotype V (JEV GV) has caused multiple cases of viral encephalitis in South Korea. We report a human case of JEV GV in China, confirmed by serology, sequencing, and quantitative reverse transcription PCR. We confirm JEV GV infection in China, highlighting the persistent threat of this virus.
2026-09-30 | Viral RNA-Targeting Locked Nucleic Acid Gapmers: Design and In Vitro Evaluation.
Recurrent viral outbreaks, such as coronavirus disease 2019 (COVID-19), seasonal influenza, and flavivirus infections, highlight the urgent need for rapid-response therapies against viral diseases. These outbreaks are mainly caused by viruses with RNA genomes. Accordingly, antisense oligonucleotides (ASOs), which bind target RNA in a sequence-specific manner to modulate its functions, represent a promising modality for developing antiviral agents. Recent studies, particularly those on RNase H-recruiting ASOs incorporating the nucleic acid analogue locked nucleic acid (LNA), known as LNA gapmers, have demonstrated effective antiviral activity via targeted viral RNA degradation. Since the approval of fomivirsen, the first ASO drug targeting cytomegalovirus RNA, in 1998, the development of LNA gapmers has positioned viral RNA degradation as a promising approach for clinical application. Here, using Japanese encephalitis virus (JEV), a flavivirus of major public health concern, as a model system, we describe a step-by-step protocol for the design and in vitro evaluation of the antiviral efficacy and cytotoxicity of JEV RNA-targeting LNA gapmers. The approaches presented here provide a basis for the design and screening of antiviral LNA gapmers and can be applied to other viruses.
2026-09-06 | A rational multi-target RNA interference approach for effective suppression of Japanese encephalitis virus replication
Japanese encephalitis virus (JEV), a major cause of viral encephalitis in the Asia–Pacific region, remains a significant public health concern due to suboptimal vaccine coverage and the lack of approved antiviral therapies. RNA interference (RNAi) provides a sequence-specific approach for suppressing viral gene expression and represents a promising antiviral strategy. Here, we designed small interfering RNAs (siRNAs) targeting selected regions of essential JEV genes, including prM, NS1, NS3, and NS5, and evaluated their antiviral efficacy in HeLa cells. Individual siRNAs reduced viral protein expression and infectious virus production while maintaining more than 85% cell viability. A multi-target siRNA cocktail reduced viral replication to approximately 5–6% of the scrambled control level and preserved cell viability after JEV infection. Neither individual siRNAs nor the cocktail produced a detectable increase in protein kinase R phosphorylation relative to the scrambled control under the conditions tested. These findings support the feasibility of multi-target RNAi-mediated suppression of JEV replication in vitro and provide a basis for further evaluation of RNAi-based antiviral approaches against related flaviviruses.
2026-01-28 | Opportunities and Challenges of mRNA and VLP Technologies for Pan-Flavivirus Vaccine Development: Focus on Conserved Quaternary Epitope Conformations.
Mosquito-borne flaviviruses, including Dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Yellow fever virus (YFV), and Zika virus (ZIKV), continue to present a significant threat to public health worldwide. In 2024, these viruses accounted for 11,717 reported cases in the United States and more than 7.6 million cases globally. As of early 2025, according to CDC data, 1830 cases of dengue had already been reported, with 1584 transmitted locally within the U.S. Despite the considerable burden that these diseases pose, no specific antiviral treatments exist. A very limited number of virus-specific vaccines have been licensed, such as those for YFV, JEV, and, with specific constraints, for DENV. To date, no pan-flavivirus vaccine is available. This review examines the potential of emerging vaccine platforms-particularly messenger RNA and virus-like particles-as promising tools in the pursuit of a broadly protective flavivirus vaccine. We analyze current strategies for inducing cross-neutralizing immune responses and discuss how these technologies could support the presentation of conserved quaternary epitope conformations, which are increasingly recognized as critical targets for establishing potent immune responses. We review key advances in virology, immune response, and immunogen delivery systems to highlight the potential for developing a pan-flavivirus vaccine.
2025-10-25 | RNAi therapeutics targeting Japanese encephalitis virus: Gene targets, delivery platforms, and translational barriers.
Japanese encephalitis virus (JEV), a neurotropic flavivirus, is a leading cause of viral encephalitis in Asia, particularly affecting children and causing significant morbidity and mortality. Despite the availability of vaccines and vector control strategies, their limited efficacy against emerging genotypes and incomplete coverage necessitate alternative antiviral approaches. RNA interference (RNAi) has emerged as a promising therapeutic modality by exploiting post-transcriptional gene silencing to inhibit viral replication. Notably, conserved viral genes-such as capsid (C), envelope (E), NS3, and NS5-represent optimal RNAi targets across JEV genotypes due to their essential roles in the viral life cycle and minimal sequence variability. Recent advances in delivery platforms, including lipid nanoparticles, lentiviral vectors, and artificial microRNAs, have significantly improved RNAi stability, blood-brain barrier (BBB) penetration, and cell-specific targeting. Comparative insights from related flaviviruses such as Dengue and Zika have further informed effective RNAi design. Preclinical studies have demonstrated potent antiviral effects, with >90 % suppression of viral RNA, substantial reductions in brain viral load, and enhanced survival in murine models. However, clinical translation remains challenged by delivery efficiency, immune activation, off-target effects, and the potential for viral escape mutations. This review summarizes the current landscape of RNAi-based therapeutics for JEV, emphasizing conserved gene targets, delivery innovations, and translational hurdles, and outlines future directions for integrating RNAi into next-generation antiviral strategies.
other
2026-08-22 | Annexin A2 facilitates Japanese encephalitis virus replication by regulating endocytosis and intracellular transport in PK15 cells.
Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes severe encephalitis in humans and reproductive disorders in pigs. However, the host factors that regulate JEV infection and replication remain incompletely understood. In this study, we used porcine kidney cells (PK15) infected with the attenuated JEV strain SA14-14-2 to identify host proteins interacting with the JEV envelope (E) protein by immunoprecipitation coupled with LC-MS/MS. Annexin A2 (ANXA2) was identified as a candidate host factor associated with JEV infection. ANXA2 expression was increased during JEV infection, and co- immunoprecipitation confirmed its association with the JEV E protein. Inhibition of ANXA2 with antibody reduced JEV RNA replication in a dose-dependent manner. To further define its function, ANXA2 knockout (KO) PK15 cells were generated using CRISPR/Cas9. Compared with wild-type cells, ANXA2-KO cells showed significantly reduced viral RNA accumulation, especially during the early stage of JEV infection (2-6hpi), when the viral entry and initiates replication, lower JEV E protein expression, and decreased progeny virus titers. In addition, ANXA2 deficiency altered the expression of clathrin-mediated endocytosis- related genes and proteins, including CLTC, CLTB, AP2M1, and EPS15, and affected Akt phosphorylation during early infection. Fluorescence recovery after photobleaching analysis (FRAP) of DiD-labeled JEV particles indicated impaired intracellular transport in ANXA2-KO cells. these findings identify ANXA2 as a host factor that promotes JEV infection and replication, at least in part by regulating clathrin-mediated endocytosis and intracellular transport. ANXA2 may represent a potential target for future antiviral strategies against JEV.
2026-07-18 | Engineered Extracellular Vesicle-Delivered CRISPR/Cas13d for Alleviating Japanese Encephalitis Virus-Induced Brain Injury
This research investigates an engineered extracellular vesicle (EV)-based strategy for delivering programmable CRISPR/Cas13d components across the blood–brain barrier (BBB) to inhibit Japanese encephalitis virus (JEV) infection. We developed RVG-functionalized targeted engineered EVs, termed TEEVs, for brain-targeted delivery of high-fidelity RfxCas13d mRNA and JEV-targeting CRISPR RNAs (crRNAs). The CD63–L7Ae/C/D box system was used to actively enrich Cas13d mRNA and tandem crRNAs within EVs, while RVG surface functionalization was introduced to enhance BBB crossing and uptake by target cells. In vitro, TEEVs showed greater cellular uptake than non-targeted engineered EVs and crossed the BBB-like endothelial barrier in a Transwell co-culture model. TEEVs also suppressed JEV replication and preserved barrier integrity. In vivo biodistribution analyses showed enhanced brain accumulation following intravenous administration. In a lethal mouse model of JEV infection, TEEV treatment reduced brain viral loads, inflammatory responses, BBB disruption, and neuropathological injury and improved survival.
2026-07-02 | FcγRIIA signalling as a host-associated determinant of endosomal trafficking and antibody-dependent enhancement in flavivirus infection.
Antibody-dependent enhancement (ADE) is a major determinant of disease severity in flavivirus infections, yet the host-associated factors that regulate the transition from antibody-mediated uptake to productive infection remain incompletely defined. Fc gamma receptor IIA (FcγRIIA/CD32A), an activating Fc receptor expressed on myeloid cells, represents a key host determinant linking pre-existing immunity to viral entry pathways. Here, we investigated how FcγRIIA signalling influences intracellular trafficking and ADE efficiency across dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). Using BHK-21 cells expressing either wild-type FcγRIIA (WT) or a cytoplasmic-truncated variant lacking the immunoreceptor tyrosine-based activation motif (ITAM), we show that immune-complex internalization occurs independently of the cytoplasmic domain, but that signalling competence significantly modulates downstream infection efficiency. WT cells generally showed higher ADE efficiency, whereas cytoplasmic-truncated receptors preserved ADE activity but showed virus-dependent reductions in enhancement magnitude. FcγRIIA signalling altered the intracellular routing of virus-antibody complexes. WT receptors promoted rapid trafficking from EEA1-positive early endosomes to Rab7-positive late endosomes, whereas signalling-deficient receptors displayed delayed progression and increased association with IRAP- and Rab14-positive compartments. These trafficking differences correlated with virus-specific patterns of enhancement, with DENV showing the strongest dependence on late endosomal maturation, while ZIKV and JEV utilized more flexible or alternative pathways. Transcriptomic analysis revealed minimal differences between WT and truncated receptors at later time points, indicating that FcγRIIA primarily modulates early post-entry events rather than sustained transcriptional responses. Collectively, these findings identify FcγRIIA signalling as a host-associated determinant that regulates the intracellular fate of virus-antibody complexes and influences ADE efficiency through modulation of endosomal trafficking dynamics. The work provides a mechanistic framework linking host receptor signalling to variability in infection outcomes under conditions of pre-existing immunity, with implications for understanding disease heterogeneity and optimizing vaccine and antibody-based interventions.
2026-05-22 | Immunity-oriented drug strategies for viral encephalitis: Acyclovir, antiepileptics and corticosteroids in neurological intensive care.
Viral encephalitis (VE), is a life-threatening neurological disorder marked by inflammation of brain parenchyma, driven by direct viral cytotoxicity and host immune-mediated injury. Globally, its incidence ranges from 1.4 to 13.8 cases per 100,000 individuals annually, with significant morbidity and mortality in endemic regions such as India, among children. Neurotropic viruses including herpes simplex virus (HSV), Japanese encephalitis virus (JEV) and West Nile virus, enter central nervous system via hematogenous or neuronal routes, triggering viral replication, cytokine release and blood-brain barrier disruption, resulting in seizures, cerebral edema and long-term neurological deficits. Current management in neurological intensive care relies on immunity-oriented strategies: Acyclovir as first-line antiviral for HSV and varicella-zoster virus, antiepileptics to control seizures and limit secondary neuronal injury and corticosteroids to modulate harmful neuroinflammation and cerebral edema. Emerging therapies, including novel antivirals (favipiravir, remdesivir, brincidofovir), monoclonal antibodies, cytokine inhibitors (tocilizumab, anakinra) and B-cell/plasma cell-targeted agents (rituximab, daratumumab), offer promise by simultaneously addressing viral replication and immune dysregulation. Personalized biomarker-guided integrating pathogen-directed and host-targeted therapies may optimize outcomes, reduce neuronal injury and improve recovery. This review underscores the importance of a multidimensional, immunity-oriented treatment paradigm, highlighting both established and emerging strategies to enhance prognosis and long-term neurological functions in patients with viral encephalitis.
2026-04-17 | Human antibodies against West Nile and related orthoflaviviruses.
West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease. No specific prophylaxis or treatment exists for WNV or related orthoflavivirus infections, and the determinants of human disease severity remain poorly understood. Here, we report that neutralizing autoantibodies against type I interferons do not impair antiviral antibody development. Among the fully human monoclonal antibodies with potent neutralizing activity against WNV that were discovered, W010 targets a unique epitope within the envelope protein domain III (EDIII) and confers both pre- and post-exposure protection in a murine WNV model, even when interferon signaling is impaired. A second protective antibody, W014, exhibits broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.
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Drug Discovery Landscape
3 orphan drug designations for Japanese encephalitis, including 1 approved therapy.
3 orphan drug designations for Japanese encephalitis, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Japanese encephalitis vaccine, inactivated, adsorbed [IXIARO] | vaccines | FDA | Approved | Intercell AG |
Japanese encephalitis vaccine (inactivated, adsorbed) [Ixiaro] | vaccines | EMA | [INACTIVE] Intercell AG | |
Japanese encephalitis vaccine (live, attenuated) | vaccines | FDA | — | Glovax Co., Ltd. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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