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Japanese encephalitis (JE) is a significant public health concern in Asia, particularly in children, where vaccination plays a crucial role in prevention. In this study, we investigated the immunogenicity and safety of two different live-attenuated JE vaccines used as primary and booster doses. Fifty healthy participants aged 1-3 years, who were primed with the chimeric JE vaccine IMOJEV® a year earlier, received a booster dose of the SA14-14-2 JE vaccine CD.JEVAX®. To evaluate the immune response, JE-neutralizing antibody titers were assessed on day 0 (pre-booster), day 30, and annually from 1 to 5 years post-booster using the 50% plaque reduction neutralization test (JEPRNT50). The assessment revealed strong immunogenicity 30 d post-booster, with a geometric mean titer of 2092.4 [95% confidence interval (CI): 1473.9-2970.5] and a seroprotection rate of 100%, which gradually decreased to 97.5% at 5 years post-booster. No severe adverse events were observed. The most common reaction within 7 d of vaccination was fever (20%; 95% CI: 10.7-32.3). These results indicate that a booster dose of CD.JEVAX® elicits a strong immune response in children previously vaccinated with IMOJEV® while maintaining a good safety profile, thus supporting the interchangeability of these two live-attenuated JE vaccines. Registered at www.thaiclinicaltrials.org (TCTR ID: TCTR20221102003), our study suggests that CD.JEVAX® can be a viable option for booster vaccination in JE prevention programs, potentially enhancing vaccine flexibility and accessibility.

Vaccination remains the sole effective strategy for combating Japanese encephalitis (JE). Both inactivated and live attenuated vaccines exhibit robust immunogenicity. However, the production of these conventional vaccine modalities necessitates extensive cultivation of the pathogen, incurring substantial costs and presenting significant biosafety risks. Moreover, the administration of live pathogens poses potential hazards for individuals or animals with compromised immune systems or other health vulnerabilities. Subsequently, ongoing research endeavors are focused on the development of next-generation JE vaccines utilizing nanoparticle (NP) platforms. This systematic review seeks to aggregate the research findings pertaining to NP-based vaccine development against JE. A thorough literature search was conducted across established English-language databases for research articles on JE NP vaccine development published between 2000 and 2023. A total of twenty-eight published studies were selected for detailed analysis in this review. Of these, 16 studies (57.14%) concentrated on virus-like particles (VLPs) employing various structural proteins. Other approaches, including sub-viral particles (SVPs), biopolymers, and both synthetic and inorganic NP platforms, were utilized to a lesser extent. The results of these investigations indicated that, despite variations in the usage of adjuvants, dosages, NP types, antigenic proteins, and animal models employed across different studies, the candidate NP vaccines developed were capable of eliciting enhanced humoral and cellular adaptive immune responses, providing effective protection (70-100%) for immunized mice against lethal challenges posed by virulent Japanese encephalitis virus (JEV). In conclusion, prospective next-generation JE vaccines for humans and animals may emerge from these candidate formulations following further evaluation in subsequent vaccine development phases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Adugna, Niu, Guan, Du, Yang, Tian and Yin.)

In 2022, the largest ever virgin soil outbreak of Japanese encephalitis (JE) occurred in Australia resulting in 45 reported human cases of JE, with seven fatalities. Japanese encephalitis virus (JEV) was detected in 84 piggeries across Australia. In response, states implemented targeted vaccination programs for those individuals at the highest risk of JEV exposure. A mixed methods approach, including geospatial mapping of JEV vaccine distribution in Queensland, a case series of Queensland human cases and interviews with Queensland Health staff, assessed the JEV vaccination response program. Five notified human cases were reviewed, with three having occupational outdoor risk and local travel-related exposure. Vaccine coverage ranged from 0 to 7.4 doses per 100 people after 12 months of the program. The highest uptake was in southern Queensland, where 95% of the state's commercial pig population is located. The vaccination program was limited by a heavy reliance on general practitioners, vast geographical distribution of eligible populations, difficulties mobilising and engaging eligible cohorts, and suboptimal One Health collaboration. Population and climate factors make it possible for the virus to become endemic. Targeted vaccination programs remain an important strategy to protect people at the highest risk of exposure, however, program improvements are required to optimize vaccine accessibility.

Background: We explored the impact of prior yellow fever (YF) or Japanese encephalitis (JE) vaccination on the efficacy of Takeda's dengue vaccine candidate, TAK-003., Methods: Children 4-16 years of age were randomized 2:1 to receive TAK-003 or placebo and were under active febrile surveillance. Symptomatic dengue was confirmed by serotype-specific reverse-transcription polymerase chain reaction. YF and JE vaccination history was recorded., Results: Of the 20 071 children who received TAK-003 or placebo, 21.1% had a YF and 23.9% had a JE vaccination history at randomization. Fifty-seven months after vaccination, vaccine efficacy (95% confidence interval) was 55.7% (39.7%-67.5%) in those with YF vaccination, 77.8% (70.8%-83.1%) for JE vaccination, and 53.5% (45.4%-60.4%) for no prior YF/JE vaccination. Regional differences in serotype distribution confound these results. The apparent higher vaccine efficacy in the JE vaccination subgroup could be largely explained by serotype-specific efficacy of TAK-003. Within 28 days of any vaccination, the proportions of participants with serious adverse events in the YF/JE prior vaccination population were comparable between the TAK-003 and placebo groups., Conclusions: The available data do not suggest a clinically relevant impact of prior JE or YF vaccination on TAK-003 performance. Overall, TAK-003 was well-tolerated and efficacious in different epidemiological settings. Clinical Trials Registration.  NCT02747927., Competing Interests: Potential conflicts of interest. S. B., M. R., I. E., S. T., E. L., V. T., N. F., and D. W. are permanent employees of the Takeda group of companies and may hold Takeda stock/stock options. A. B. and I. L. were permanent employees of Takeda and held Takeda stock/stock options at the time of the trial. H. F. was a consultant for Takeda Vaccines and previous employee of Takeda Vaccines, Inc. D. W. is an inventor of the international patent applications WO2017179017, WO2021/034349, and WO2020/051334 currently pending in several jurisdictions worldwide and being the basis of various granted patents. The institutions of principal investigators received a research grant from Takeda to conduct this study. X. S.-L., P. K., and L. B. have served as advisory board members for Takeda. P. K. has received funding for attending meetings. E. D. M. has participated in an advisory board for Takeda. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Japanese encephalitis (JE), caused by the Japanese encephalitis virus (JEV), is a highly threatening disease with no specific treatment. Fortunately, the development of vaccines has enabled effective defense against JE. However, re-emerging genotype V (GV) JEV poses a challenge as current vaccines are genotype III (GIII)-based and provide suboptimal protection. Given the isolation of GV JEVs from Malaysia, China, and the Republic of Korea, there is a concern about the potential for a broader outbreak. Under the hypothesis that a GV-based vaccine is necessary for effective defense against GV JEV, we developed a pentameric recombinant antigen using cholera toxin B as a scaffold and mucosal adjuvant, which was conjugated with the E protein domain III of GV by genetic fusion. This GV-based vaccine antigen induced a more effective immune response in mice against GV JEV isolates compared to GIII-based antigen and efficiently protected animals from lethal challenges. Furthermore, a bivalent vaccine approach, inoculating simultaneously with GIII- and GV-based antigens, showed protective efficacy against both GIII and GV JEVs. This strategy presents a promising avenue for comprehensive protection in regions facing the threat of diverse JEV genotypes, including both prevalent GIII and GI as well as emerging GV strains.

Japanese encephalitis (JE) is preventable using the affordable, effective, and safe live attenuated SA 14-14-2 JE vaccine (CD-JEV). We used a Markov model to evaluate the cost-effectiveness of 1 dose of CD-JEV compared with no vaccination in 3 vaccination strategies in Bangladesh: subnational campaign and routine immunization, subnational campaign and national routine immunization, and national routine immunization alone. For input parameters, we gathered information from a cost-of-illness study, medical literature, government documents, and expert opinions. The base-case analysis estimated that a subnational campaign for children <15 years of age and routine immunization over 20 birth cohorts in Rajshahi, Rangpur, and Chattogram yielded (in 2021 US dollars) a cost of $82.2 million, $981/disability-adjusted life years averted, $9,964/case averted, and $49,819/death averted (societal perspective). We projected CD-JEV vaccination would be cost-effective across cost perspectives and vaccination strategies in Bangladesh, yielding an incremental cost-effectiveness ratio of approximately one third of per capita national gross domestic product.

Problem: The first known locally acquired cases of Japanese encephalitis virus (JEV) infection in New South Wales (NSW), Australia, were identified in March 2022. NSW Health (the state entity for health care in NSW), with its partner agencies, conducted a serological survey to identify the prevalence of JEV antibody responses in high-risk communities in NSW., Context: JEV infection is rare in Australia; therefore, vaccination is not recommended for the majority of Australians. Less than 1% of JEV infections in humans result in clinical disease., Action: We conducted a cross-sectional serological survey of all age groups in five townships within NSW between June and July 2022. A summary report of the serosurvey methods and results was previously published by NSW Health. In this report, we describe the operations and lessons learned from rapidly gathering serological survey evidence to inform the public health management of JEV infection in NSW, within a country with well established health infrastructure., Lessons Learned: Resource limitations had to be addressed pragmatically during this field epidemiology research. Community participation varied between towns. The knowledge of local public health staff was important for identifying appropriate locations for clinics and community engagement activities. The consistency of data collection needs to be emphasized when multiple teams are involved. Data quality assurance issues were limited during this survey, owing to ease of communication in the field with the coordinating research team. When possible, allowing additional time for community engagement and staff orientation would be beneficial before implementing a similar survey. Further consideration of reporting serology results during the study design stage might have prevented the need for manual processing upon study completion., Discussion: This serological survey highlights that a well trained and coordinated public health workforce can provide important, timely evidence when faced with an emerging public health issue., Competing Interests: The authors have no conflicts of interest to declare., ((c) 2024 The authors; licensee World Health Organization.)

Vaccines represent a significant milestone in the history of human medical science and serve as the primary means for controlling infectious diseases. In recent years, the geographical distribution of Japanese encephalitis viruses (JEV) of various genotypes has become increasingly complex, which provides a rationale for the development of safer and more effective vaccines. The advent of subunit and nucleic acid vaccines, especially propelled by advancements in genetic engineering since the 1980s, has accelerated the application of novel adjuvants. These novel vaccine adjuvants have diversified into toll-like receptor (TLR) agonists, complex adjuvants, nanoparticles and so on. However, the efficacy of adjuvant combinations can vary depending on the host system, disease model, or vaccine formulation, sometimes resulting in competitive or counteractive effects. In our previous study, we constructed a pJME-LC3 chimeric DNA vaccine aimed at inducing an immune response through autophagy induction. Building on this, we investigated the impact of the TLR7/8 agonist imiquimod (IMQ) and the TLR9 agonist CpG ODN 1826 as adjuvants on the immunogenicity of the Japanese encephalitis chimeric DNA vaccine. Our findings indicate that the combination of the pJME-LC3 vaccine with IMQ and CpG ODN 1826 adjuvants enhanced the innate immune response, promoting the maturation and activation of antigen-presenting cells in the early immune response. Furthermore, it played a regulatory and optimizing role in subsequent antigen-specific immune responses, resulting in effective cellular and humoral immunity and providing prolonged immune protection. The synergistic effect of IMQ and CpG ODN 1826 as adjuvants offers a novel approach for the development of Japanese encephalitis nucleic acid vaccines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Japanese encephalitis (JE) virus is the leading cause of vaccine-preventable encephalitis and a significant cause of disability in Asia and the western Pacific. Many countries have introduced JE vaccination programs, including several low resource countries following WHO's prioritization of JE vaccination in 2006. We sought to characterize the public health impact of JE vaccination programs., Methodology/principal Findings: JE case data and vaccination coverage rates, were requested from country health officials in 23 JE endemic countries and Chinese Taipei. Additional data were extracted from meeting presentations and published literature. JE incidence was compared before and after vaccination using a minimum three year period pre and post program introduction or expansion. Data suitable for analysis were available for 13 JE-endemic countries and Chinese Taipei, for either all age groups or for children aged under 15 years only. Five countries and Chinese Taipei introduced vaccine prior to 2006 and the all-age JE incidence was reduced by 73-100% in about 5-20 years following introduction. Six countries have introduced JE vaccine since 2006, and JE incidence in children aged younger than 15 years has been reduced by 14-79% as of 2015-2021. JE-specific data were unavailable before introduction in Thailand and Vietnam, but vaccination programs reduced acute encephalitis incidence by 80% and 74%, respectively. Even in the programs with greatest impact, it took several years to achieve their results., Conclusions/significance: JE vaccination has greatly reduced JE in 13 JE-endemic countries and Chinese Taipei. Highest impact has been observed in countries that introduced prior to 2006, but it often took roughly two decades and substantial resources to achieve that level of success. For greatest possible impact, more recently introducing countries and funding agencies should commit to continuous improvements in delivery systems to sustain coverage after initial vaccine introduction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Japanese encephalitis virus (JEV) is a major threat to human health. Bangladesh is considering introducing a JEV vaccine; however, the investment case is hampered by a limited understanding of key aspects of JEV ecology. We conducted a seroprevalence study in a high-incidence region using an assay that limits cross-reactivity with dengue virus. We also trapped mosquitoes and collected information about potential host species. We used mathematical models to recover risk factors for infection and underlying probabilities of severe disease and death. We observed 19.0% [95% confidence interval (CI):17.1 to 21.1] of JEV antibodies. On average, 0.7% (95% CI: 0.2 to 2.0) of the susceptible population gets infected yearly, with pig proximity being the main human infection risk factor. Our traps captured 10 different mosquito species that have been linked with JEV transmission. We estimated that 1 in 1000 infections results in severe disease, 1 in 10,000 results in death, and 76% of severe cases are missed by surveillance.

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are antigenically related flaviviruses that co-circulate in many countries/territories. The interaction between the two viruses needs to be determined. Recent findings by ourselves and other labs showed that JEV-elicited antibodies (Abs) and CD8 + T cells exacerbate and protect against subsequent ZIKV infection, respectively. However, the impact of JEV envelope (E) protein domain III (EDIII)-induced immune responses on ZIKV infection is unclear. We show here that sera from JEV-EDIII-vaccinated mice cross-react with ZIKV-EDIII in vitro, and transfer of the same sera to mice significantly decreases death upon lethal ZIKV infection at a dose-dependent manner. Maternally acquired anti-JEV-EDIII Abs also significantly reduce the mortality of neonatal mice born to JEV-EDIII-immune mothers post ZIKV challenge. Similarly, transfer of ZIKV-EDIII-reactive IgG purified from JEV-vaccinated humans increases the survival of ZIKV-infected mice. Notably, transfer of an extremely low volume of JEV-EDIII-immune sera or ZIKV-EDIII-reactive IgG does not mediate the Ab-mediated enhancement (ADE) of ZIKV infection. Similarly, transfer of JEV-EDIII-elicited CD8 + T cells protects recipient mice against ZIKV challenge. These results demonstrate that JEV-EDIII-induced immune components including Abs and T cells have protective roles in ZIKV infection, suggesting EDIII is a promising immunogen for developing effective and safety JEV vaccine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

On 12 September 2022, a 10-year-old female in Paracelis municipality, Mountain Province, the Philippines, without travel history outside the municipality, experienced acute onset of fever and a change in mental status with disorientation, an altered level of consciousness and new onset of seizures. She was hospitalized at the district hospital from 1 to 3 October 2022, before being transferred to the regional hospital. As diphtheria was originally suspected, the investigation team reviewed records and reports and interviewed key informants to gather additional information and organize case finding and contact tracing. The patient's condition was laboratory-confirmed for Japanese encephalitis virus infection. An environmental survey was carried out at the patient's residence to check for the presence of vectors and contributing factors. Exemplifying inadequate vaccination coverage for Japanese encephalitis virus in Mountain Province, the patient had not been vaccinated against the disease. It is recommended that vaccination campaigns be immediately implemented in the affected area and the surveillance system be strengthened for early detection and prompt response to the emergence of cases and outbreaks. Overall, the investigation highlighted the importance of strong surveillance and response systems for early detection and control of diseases, such as Japanese encephalitis virus. It also underscores the need for comprehensive vaccination programmes to prevent outbreaks and protect vulnerable populations., Competing Interests: The authors have no conflicts of interest to declare., ((c) 2024 The authors; licensee World Health Organization.)

Abstract: Japanese encephalitis, caused by the JE virus transmitted by mosquitoes, is the most common type of epidemic encephalitis in Asia. It is endemic in most of South and Southeast Asia, but the number of cases can vary greatly between areas. While many infections do not lead to disease, the symptomatic cases can be very severe and life-threatening. It mainly affects children, whereas adults are generally immune to the disease due to either being infected in childhood or receiving vaccination. However, individuals who are not immune, such as travelers from non-endemic countries, are susceptible to the disease when exposed to the virus for the first time, regardless of age. Without antiviral treatment options, vaccination is the only strategy to establish effective protection against Japanese encephalitis.

Short-chain fatty acids (SCFAs) are gut microbial metabolic derivatives produced during the fermentation of ingested complex carbohydrates. SCFAs have been widely regarded to have a potent anti-inflammatory and neuro-protective role and have implications in several disease conditions, such as, inflammatory bowel disease, type-2 diabetes, and neurodegenerative disorders. Japanese encephalitis virus (JEV), a neurotropic flavivirus, is associated with life threatening neuro-inflammation and neurological sequelae in infected hosts. In this study, we hypothesize that SCFAs have potential in mitigating JEV pathogenesis. Postnatal day 10 BALB/c mice were intraperitoneally injected with either a SCFA mixture (acetate, propionate, and butyrate) or PBS for a period of 7 days, followed by JEV infection. All mice were observed for onset and progression of symptoms. The brain tissue was collected upon reaching terminal illness for further analysis. SCFA-supplemented JEV-infected mice (SCFA + JEV) showed a delayed onset of symptoms, lower hindlimb clasping score, and decreased weight loss and increased survival by 3 days ( p < 0.0001) upon infection as opposed to the PBS-treated JEV-infected animals (JEV). Significant downregulation of inflammatory cytokines TNF-α, MCP-1, IL-6, and IFN-Υ in the SCFA + JEV group relative to the JEV-infected control group was observed. Inflammatory mediators, phospho-NF-kB (P-NF-kB) and iba1, showed 2.08 ± 0.1 and 3.132 ± 0.43-fold upregulation in JEV versus 1.19 ± 0.11 and 1.31 ± 0.11-fold in the SCFA + JEV group, respectively. Tissue section analysis exhibited reduced glial activation (JEV group─42 ± 2.15 microglia/ROI; SCFA + JEV group─27.07 ± 1.8 microglia/ROI) in animals that received SCFA supplementation prior to infection as seen from the astrocytic and microglial morphometric analysis. Caspase-3 immunoblotting showed 4.08 ± 1.3-fold upregulation in JEV as compared to 1.03 ± 0.14-fold in the SCFA + JEV group and TUNEL assay showed a reduced cellular death post-JEV infection (JEV-6.4 ± 1.5 cells/ROI and SCFA + JEV-3.7 ± 0.73 cells/ROI). Our study critically contributes to the increasing evidence in support of SCFAs as an anti-inflammatory and neuro-protective agent, we further expand its scope as a potential supplementary intervention in JEV-mediated neuroinflammation.

Dengue vaccine candidates have been shown to improve vaccine safety and efficacy by altering the residues or accessibility of the fusion loop on the virus envelope protein domain II (DII FL ) in an ex vivo animal study. The current study aimed to comprehensively investigate the impact of DII FL mutations on the antigenicity, immunogenicity, and protective efficacy of Japanese encephalitis virus (JEV) virus-like particles (VLPs) in mice. We found the DII FL G106K/L107D (KD) and W101G/G106K/L107D (GKD) mutations altered the binding activity of JEV VLP to cross-reactive monoclonal antibodies but had no effect on their ability to elicit total IgG antibodies in mice. However, JEV VLPs with KD or GKD mutations induced significantly less neutralizing antibodies against JEV. Only 46% and 31% of the KD and GKD VLPs-immunized mice survived compared to 100% of the wild-type (WT) VLP-immunized mice after a lethal JEV challenge. In passive protection experiments, naïve mice that received sera from WT VLP-immunized mice exhibited a significantly higher survival rate of 46.7% compared to those receiving sera from KD VLP- and GKD VLP-immunized mice (6.7% and 0%, respectively). This study demonstrated that JEV DII FL is crucial for eliciting potently neutralizing antibodies and protective immunity against JEV., Importance: Introduction of mutations into the fusion loop is one potential strategy for generating safe dengue and Zika vaccines by reducing the risk of severe dengue following subsequent infections, and for constructing live-attenuated vaccine candidates against newly emerging Japanese encephalitis virus (JEV) or Japanese encephalitis (JE) serocomplex virus. The monoclonal antibody studies indicated the fusion loop of JE serocomplex viruses primarily comprised non-neutralizing epitopes. However, the present study demonstrates that the JEV fusion loop plays a critical role in eliciting protective immunity in mice. Modifications to the fusion loop of JE serocomplex viruses might negatively affect vaccine efficacy compared to dengue and zika serocomplex viruses. Further studies are required to assess the impact of mutant fusion loop encoded by commonly used JEV vaccine strains on vaccine efficacy or safety after subsequent dengue virus infection., Competing Interests: The authors declare no conflict of interest.

Background: Travel to Southeast Asia increases the likelihood of acquiring mosquito-borne Flavivirus infections such as dengue (DENV), Japanese encephalitis (JEV) and Zika viruses (ZIKV). Expatriates are long-term travellers who have a higher risk of mosquito-borne illness at their destination country. The purpose of this study was to evaluate the seroprevalence of DENV, JEV and ZIKV infections and the determinants contributing to seropositivity among expatriates living in Thailand., Methods: A cross-sectional study was performed from December 2017 to February 2020. Expatriates from non-Flavivirus endemic countries were recruited. 5 mL of blood was collected for DENV 1-4, JEV and ZIKV antibody testing by plaque reduction neutralization test (PRNT50). Individuals with vaccination histories or diagnoses for dengue, Japanese encephalitis, yellow fever and tick-borne encephalitis were excluded., Results: Among 254 participants, most participants (83.1%) were male, the mean age was 65 years and the median duration of stay in Thailand was 6 years. Seroprevalence rate of any Flavivirus, non-specific DENV, DENV1-4, JEV and ZIKV were 34.3, 30.7, 20.5, 18.1, 18.9, 10.6, 4.7 and 2.8%, respectively. The presence of neutralizing antibodies against DENV1-4 positively correlates with the duration of stay in Thailand. DENV seropositivity was associated with living in urban areas (aOR 2.75, 95% CI 1.36-5.57). Expatriates were unlikely to have detectable anti-JEV antibodies regardless of time spent in a JEV-endemic area. No risk factors were identified that were significantly associated with JEV or ZIKV seropositivity. Only 48.4% received pre-travel counselling services, while only 18.9% visited a travel medicine specialist., Conclusions: A high proportion (34.3%) of long-term expatriates living in Thailand were seropositive for flavivirus, mainly from dengue (30.7%). To minimize risk, travel medicine practitioners should provide adequate pre-travel health risk information on mosquito-borne flavivirus infection and offer advice on mosquito bite prevention strategies. Dengue vaccine might be considered in high-risk travellers such as long-term expatriate., (© International Society of Travel Medicine 2024. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Usutu virus (USUV) is an emerging arthropod-borne flavivirus that has expanded into multiple European countries during the past several decades. USUV infection in human has been linked to severe neurological complications, and no vaccine is now available against USUV. In this work, we develop a live-attenuated chimeric USUV vaccine (termed ChinUSUV) based on the full-length infectious cDNA clone of the licensed Japanese encephalitis virus (JEV) vaccine strain SA14-14-2. In vitro studies demonstrate that ChinUSUV replicates efficiently and maintains its genetic stability. Remarkably, ChinUSUV exhibits a significant attenuation phenotype in multiple mouse models even compared with the licensed JEV vaccine. A single immunization with ChinUSUV elicits potent IgG and neutralizing antibody responses as well as T cell response. Passive transfer of sera from ChinUSUV-immunized mice confers significant protection against lethal homologous challenge in suckling mice. Taken together, our results suggest that ChinUSUV represents a potential USUV vaccine candidate that merits further development., Competing Interests: Declaration of competing interest C.F.Q., Y.Q. and Z.J.W. have filed a patent related to the major findings reported in this study. The remaining authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Japanese encephalitis virus (JEV) causes acute Japanese encephalitis (JE) in humans and reproductive disorders in pigs. There are ~68 000 cases of JE worldwide each year, with ~13 600-20 400 deaths. JE infections have a fatality rate of one-third, and half of the survivors experience permanent neurological sequelae. The disease is prevalent throughout the Asia-Pacific region and has the potential to spread globally. JEV poses a serious threat to human life and health, and vaccination is currently the only strategy for long-term sustainable protection against JEV infection. However, licensed JEV vaccines are not effective against all strains of JEV. To date, there are no drugs approved for clinical use, and the development of anti-JEV drugs is urgently needed. Natural products are characterized by a wide range of sources, unique structures, and low prices, and this paper provides an overview of the research and development of anti-JEV bioactive natural products., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Introduction: Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes encephalitis and other morbidity in Southeast Asia. Since February 2022, geographically dispersed JEV human, animal and vector detections occurred on the Australian mainland for the first time. This study will determine the prevalence of JEV-specific antibodies in human blood with a focus on populations at high risk of JEV exposure and determine risk factors associated with JEV seropositivity by location, age, occupation and other factors., Method: Samples are collected using two approaches: from routine blood donors (4153 samples), and active collections targeting high-risk populations (convenience sampling). Consent-based sampling for the latter includes a participant questionnaire on demographic, vaccination and exposure data. Samples are tested for JEV-specific total antibody using a defined epitope-blocking ELISA, and total antibody to Australian endemic flaviviruses Murray Valley encephalitis and Kunjin viruses., Analysis: Two analytic approaches will occur: descriptive estimates of seroprevalence and multivariable logistic regression using Bayesian hierarchical models. Descriptive analyses will include unadjusted analysis of raw data with exclusions for JEV-endemic country of birth, travel to JEV-endemic countries, prior JEV-vaccination, and sex-standardised and age-standardised analyses. Multivariable logistic regression will determine which risk factors are associated with JEV seropositivity likely due to recent transmission within Australia and the relative contribution of each factor when accounting for effects within the model., Ethics: National Mutual Acceptance ethical approval was obtained from the Sydney Children's Hospitals Network Human Research Ethics Committee (HREC). Local approvals were sought in each jurisdiction. Ethical approval was also obtained from the Australian Red Cross Lifeblood HREC., Dissemination: Findings will be communicated to participants and their communities, and human and animal health stakeholders and policy-makers iteratively and after final analyses. Understanding human infection rates will inform procurement and targeted allocation of limited JEV vaccine, and public health strategies and communication campaigns, to at-risk populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Japanese encephalitis (JE) is a severe infectious disease of the central nervous system. Vaccination with Vero cell culture-derived vaccines may effectively reduce JE incidence., Research Design and Methods: In this single-center, randomized, blinded, positive-controlled clinical trial in China involving 600 healthy infants aged 6-11 months, participants were divided into experimental and control groups administered JEV-PI and JEV-LI, respectively. Antibody titers were determined after 0- and 7-day immunization schedules. A booster dose followed 12 months later., Results: After primary vaccination and before booster vaccination, the positive conversion rate, geometric mean titer (GMT), and geometric mean increase (GMI) of JEV-PI-neutralizing antibodies exceeded those of JEV-LI. After booster immunization, the GMT and GMI of JEV-PI were higher than those of JEV-LI. After primary immunization, the local, systemic, and overall adverse reactions were of grades 1 and 2, with a low incidence of grade 3. After booster immunization, these differences were mainly grades 1 and 2, with no differences between JEV-PI and JEV-LI., Conclusion: JEV-PI is a promising vaccine as infants acquired long-lasting and highly neutralizing immune antibodies after inoculation with JEV-PI., Trial Registration: The trial was registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj = 203130; registration number: ChiCTR2300074692; registration date: 14/08/2023).

Japanese encephalitis virus is a mosquito-borne member of the Flaviviridae family. JEV is the leading cause of viral encephalitis in Asia and is characterized by encephalitis, high lethality, and neurological sequelae in survivors. The virus also causes severe disease in swine, which are an amplifying host in the transmission cycle, and in horses. US agricultural authorities have recently recognized the threat to the swine industry and initiated preparedness activities. Other mosquito-borne viruses exotic to the Western Hemisphere have been introduced and established in recent years, including West Nile, Zika, and chikungunya viruses, and JEV has recently invaded continental Australia for the first time. These events amply illustrate the potential threat of JEV to US health security. Susceptible indigenous mosquito vectors, birds, feral and domestic pigs, and possibly bats, constitute the receptive ecological ingredients for the spread of JEV in the US. Fortunately, unlike the other virus invaders mentioned above, an inactivated whole virus JE vaccine (IXIARO ® ) has been approved by the US Food and Drug Administration for human use in advance of a public health emergency, but there is no veterinary vaccine. This paper describes the risks and potential consequences of the introduction of JEV into the US, the need to integrate planning for such an event in public health policy, and the requirement for additional countermeasures, including antiviral drugs and an improved single dose vaccine that elicits durable immunity in both humans and livestock.

Objective: The incidence of Japanese Encephalitis (JE) in Bali Province remains high, and is one among the highest in Indonesia. The Indonesian Government initiated the JE vaccination campaign followed by a JE vaccine introduction program in Bali Province in 2018. The JE vaccination program then has been fully integrated into the provincial routine immunization program since 2019. We conducted a retrospective economic analysis of JE vaccination program in Bali Province, Indonesia; considering multiple vaccination strategies., Methods: We conducted a cost-effectiveness analysis using a decision analytic model comparing two vaccination strategies with no vaccination from the societal and government perspectives. These vaccination strategies were: (1) JE vaccination campaign and introduction program, and (2) a routine JE vaccination program. We compared costs and outcomes for three hypothetical cohorts of 100,000 children followed from birth to the age of 10 years, with impacts measured throughout the child's life-time. We measured the economic consequences as costs per case, per death, and per disability-adjusted life year (DALY) averted., Results: A routine JE immunization program was the most cost-effective strategy with a cost per DALYs averted of US$ 212.59 and US$ 94.09 from the government and societal perspectives respectively. In contrast, costs per DALYs averted through the JE vaccination campaign and introduction strategy was US$ 1,473.53 and US$ 1,224.20 from the government and societal perspectives respectively., Conclusions: Both JE vaccination strategies are cost-effective but they are not cost-saving when compared to no immunization program., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anak Agung Sagung Sawitri reports financial support and administrative support were provided by Directorate General Prevention and Control of Disease, Ministry of Health, Republic of Indonesia. Sofya Umi Labiba, Anak Agung Sagung Sawitri reports financial support was provided by GAVI Alliance., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors have declared that no competing interests exist.

Introduction: Taiwan introduced a two-dose inactivated Japanese encephalitis (JE) mouse brain-derived (JE-MB) vaccine into routine childhood immunization in 1968, with booster vaccination implemented in 1974 and 1983. In 2017, JE-MB vaccine was replaced by a two-dose live-attenuated chimeric vaccine (JE-CV). After implementation of JE vaccination programs, JE cases have shifted from children to adults. In this study, we described the JE epidemiology and identify high-risk groups to further inform vaccine policy., Methodology/principal Findings: We extracted data from Taiwan's notifiable disease surveillance database, vital statistics, and employment statistics from 2010 to 2022. Diagnosis of JE was confirmed by JE seroconversion, a four-fold increase in virus-specific antibodies, a positive JE viral nucleic-acid test, or JE virus isolation. From 2010 to 2022, a total of 313 cases of JE were diagnosed, resulting in an overall incidence rate of 0.10 cases per 100,000 person-years and a mortality rate of 0.006 per 100,000 population per year. Among these patients, 64% were male, and the median age was 51 years (range 0-82). Compared with people born in or after 1976 (vaccinated with four doses of JE-MB vaccine or two doses of JE-CV), those born in or before 1962 (unvaccinated) and those born during 1963-1975 (vaccinated with two or three doses of JE-MB vaccine) had a 4.2-fold (95% confidence interval [CI] 3.0-5.7) and 5.9-fold (95% CI 4.3-8.1) higher risk of JE, respectively. The relative risk of working in agriculture, forestry, fishing, or animal husbandry, compared to other occupations, was 5.0 (95% CI 3.5-7.0)., Conclusions/significance: In Taiwan, individuals born before 1976 and those employed in agriculture, forestry, fishing, or animal husbandry had a higher risk of JE. We recommend JE vaccination for people in these high-risk groups who have not been fully vaccinated or have an unknown vaccination history., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Japanese encephalitis (JE) is a vector-borne viral disease that causes acute encephalitis in children. Although vaccines have been developed against the JE virus (JEV), no effective antiviral therapy exists. Our study shows that inhibition of poly(ADP-ribose) polymerase 1 (PARP1), an NAD + -dependent (poly-ADP) ribosyl transferase, protects against JEV infection. Interestingly, PARP1 is critical for JEV pathogenesis in Neuro-2a cells and mice. Small molecular inhibitors of PARP1, olaparib, and 3-aminobenzamide (3-AB) significantly reduce clinical signs and viral load in the serum and brains of mice and improve survival. PARP1 inhibition confers protection against JEV infection by inhibiting autophagy. Mechanistically, upon JEV infection, PARP1 PARylates AKT and negatively affects its phosphorylation. In addition, PARP1 transcriptionally upregulates PTEN, the PIP3 phosphatase, negatively regulating AKT. PARP1-mediated AKT inactivation promotes autophagy and JEV pathogenesis by increasing the FoxO activity. Thus, our findings demonstrate PARP1 as a potential mediator of JEV pathogenesis that can be effectively targeted for treating JE., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The current production of the Japanese encephalitis virus (JEV) vaccine is based on animal cells, where various risk factors for human health should be resolved. This study used a transient expression system to express the chimeric protein composed of antigenic epitopes from the JEV envelope (E) protein in Nicotiana benthamiana . JEV multi-epitope peptide (MEP) sequences fused with FLAG-tag or 6× His-tag at the C- or N-terminus for the purification were introduced into plant expression vectors and used for transient expression. Among the constructs, vector pSK480, which expresses MEP fused with a FLAG-tag at the C-terminus, showed the highest level of expression and yield in purification. Optimization of transient expression procedures further improved the target protein yield. The purified MEP protein was applied to an ICR mouse and successfully induced an antibody against JEV, which demonstrates the potential of the plant-produced JEV MEP as an alternative vaccine candidate.

Purpose of Review: Vaccinations have been pivotal in lowering the global disease burden of vaccine-preventable encephalitides, including Japanese encephalitis, tick-borne encephalitis, measles encephalitis, and rabies encephalitis, among others., Recent Findings: Populations vulnerable to vaccine-preventable infections that may lead to encephalitis include those living in endemic and rural areas, military members, migrants, refugees, international travelers, younger and older persons, pregnant women, the immunocompromised, outdoor, healthcare and laboratory workers, and the homeless. There is scope for improving the availability and distribution of vaccinations, vaccine equity, surveillance of vaccine-preventable encephalitides, and public education and information., Summary: Addressing these gaps in vaccination strategies will allow for improved vaccination coverage and lead to better health outcomes for those most at risk for vaccine-preventable encephalitis., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We estimated the incidence of Japanese encephalitis (JE) and acute encephalitis syndrome (AES) following routine immunization with the live-attenuated SA 14-14-2 JE vaccine., Methods: We implemented enhanced surveillance of AES and JE hospitalizations in endemic districts in Maharashtra and Telangana States during 2015-2016 and 2018-2020. We estimated incidence and compared differences in the incidence of JE and AES between two states, and vaccinated and unvaccinated districts during two study periods. We also considered secondary data from public health services to understand long-term trends from 2007 to 2020., Results: The annual AES incidence rate of 2.25 cases per 100,000 children in Maharashtra during 2018-2020 was significantly lower than 3.36 cases per 100,000 children during 2015-2016. The six JE-vaccinated districts in Maharashtra had significantly lower incidence rates during 2018-2020 (2.03, 95% CI 1.73-2.37) than in 2015-16 (3.26, 2.86-3.70). In addition, the incidence of both JE and AES in two unvaccinated districts was higher than in the vaccinated districts in Maharashtra. Telangana had a lower incidence of both JE and AES than Maharashtra. The AES incidence rate of 0.95 (0.77-1.17) during 2018-2020 in Telangana was significantly lower than 1.67 (1.41-1.97) during 2015-2016., Conclusions: The annual incidence rate of Japanese encephalitis was < 1 case per 100,000 children. It indicated accelerated control of Japanese encephalitis after routine immunization. However, the annual incidence of acute encephalitis syndrome was still > 1 case per 100,000 children. It highlights the need for improving surveillance and evaluating the impacts of vaccination., (© 2023. The Author(s).)

Mainland China included Japanese encephalitis (JE) vaccine in the national immunization program in 2008 to control the JE epidemic. However, Gansu province in Western China experienced the largest JE outbreak since 1958 in 2018. We conducted a retrospective epidemiological study to explore the causes of this outbreak. We found that adults aged ≥20 years (especially those in rural areas) were the main JE cases in Gansu Province, with a significant increase in the JE incidence in older adults aged ≥60 years in 2017 and 2018. In addition, JE outbreaks in Gansu Province were mainly located in the southeastern region, while the temperature and precipitation in Gansu Province were gradually increasing in recent years, which made the JE epidemic areas in Gansu Province gradually spread to the western of Gansu Province. We also found that adults aged ≥20 years in Gansu Province had lower JE antibody positivity than children and infants, and the antibody positivity rate decreased with age. In the summer of 2017 and 2018, the density of mosquitoes (mainly the Culex tritaeniorhynchus) in Gansu Province was significantly higher than in other years, and the genotype of JEV was mainly Genotype-G1. Therefore, in the future JE control in Gansu Province, we need to strengthen JE vaccination for adults. Moreover, strengthening mosquito surveillance can provide early warning of JE outbreaks and the spread of epidemic areas in Gansu Province. At the same time, strengthening JE antibody surveillance is also necessary for JE control., (© 2023 Wiley Periodicals LLC.)

Objective　Following the case of a 10-month-old with Japanese encephalitis in Chiba in 2015, the Chiba Pediatric Association and Chiba Medical Association recommended that children receive the Japanese encephalitis vaccine at six months of age. In this study, we investigated early vaccinations and standard vaccinations of children in a patient outbreak area. Additionally, we examined changes in the timing of vaccination initiation and the acquisition and maintenance of protective immunity before and after the early vaccination recommendation.Methods　With the cooperation of the medical institution designated for Type II Infectious Diseases, which treated affected children in 2015, the history and timing of vaccinations for children who visited the hospital between October 2018 and March 2020 were investigated, and serum samples were collected. The data obtained in this study and the Ministry of Health, Labour and Welfare's Community Health Service Report were used to investigate the timing of vaccinations. Neutralizing antibody titers in serum were quantified with the focus measurement method and examined with respect to the number of vaccinations, doses, and number of days since vaccination.Results　A total of 154 samples were obtained, with 89 from the vaccinated group and 65 from the unvaccinated group. There was no difference in the percentage of children based on the age of first vaccination between Japan, Chiba Prefecture, and the study subjects until FY2015, but from FY2016 onward, the percentage of children vaccinated early was higher among the study subjects, as well as for children from Chiba Prefecture and Japan, in that order. The antibody possession rate by vaccination frequency was 9.2% for the unimmunized, 87.5% for those vaccinated once, 95.1% for those vaccinated twice, and 100% for those vaccinated three times. In the group vaccinated twice, antibody titers of children who received half the vaccine dose were significantly lower than those of children who received the normal dose.Conclusion　In the districts targeted in this study, significantly more children under three years of age were vaccinated before the early vaccination recommendation, suggesting the effectiveness of that recommendation. In addition, the high rate of antibody positivity among unvaccinated children suggests that it is important to promote early vaccination in areas at high risk for Japanese encephalitis. In this study, there was no evidence of attenuation of antibody titers over time after early immunization, but the possibility remains that the children who completed early immunization received a booster due to pathogen exposure and maintained antibody titers, given that Japanese encephalitis was endemic in the target area.

Japanese encephalitis (JE) is becoming an increasingly important issue among adults. The reasons for this are multifactorial. During the past decades, new areas of Japanese encephalitis virus (JEV) transmission have occurred in several locations, most notably in a markedly expanded area of Australia during 2021-2022. When JEV enters new areas, cases in adults frequently occur. This is unlike the typical pattern in endemic areas where the burden of disease is in children because most adults are protected through natural immunity following earlier exposure to the virus. Even in endemic areas, JEV has become relatively more important in adults because improved JE control through childhood immunization programs has resulted in a substantial decrease in pediatric JE cases and thus more prominence of adult JE cases. Finally, increases in tourism to JE risk areas have resulted in more exposure of adult travelers, who are usually non-immune, to infection in JE risk areas. In this review we describe the increasing importance of JE in adults in some areas and then consider the comparative clinical presentation and severity of illness among children and adults.

Background: Acute encephalitis syndrome (AES) is a major public health concern in India, and the Japanese Encephalitis (JE) virus is the most common cause of viral encephalitis in Asia affecting children under the age of 15 years. In India, despite the introduction of the JE vaccine (SA-14-14-2) in the immunization programme, JE continues to account for 15-20% of AES cases to date. This study evaluates the immunogenicity of live attenuated SA-14-14-2 JE vaccine in terms of persistence of the humoral response after two doses., Methods: A cross-sectional study was conducted among 266 children belonging to one of the JE endemic regions of Uttar Pradesh, India. Blood samples were taken from children (2-10 years) and grouped according to the duration (in years) after two doses of the vaccine (5 groups with a class interval of 2 years). Informed written consent was obtained from the parents/guardians. All the samples collected were tested for the presence of anti-JEV-specific IgG antibodies by enzyme-linked immunosorbent assay (ELISA) and further confirmed by micro neutralization test (MNT) and immunofluorescence assays., Results: Of the 266 samples tested by ELISA for anti-JEV-specific IgG antibodies, 260 (97.74%) were negative and 6 (2.26%) were equivocal. The geometric mean immune status ratio across the five groups, 0-2 years (n = 59), 2-4 years (n = 73), 4-6 years (n = 65), 6-8 years (n = 48) and 8-10 years (n = 21) post-two doses of SA-14-14-2 JE vaccine was 1.143, 1.059, 1.138, 1.075 and 1.130, respectively, and the geometric mean titre obtained from MNT across the five groups was 10.77, 8.400, 8.453, 9.517 and 9.674, respectively., Conclusion: The study showed a decreasing trend of anti-JEV specific IgG antibody titres across the five groups based on the duration following two doses of SA-14-14-2 vaccine. The results emphasize the significance of booster doses of vaccine for children living in endemic areas., (© International Society of Travel Medicine 2022. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Japanese encephalitis (JE) is endemic in Asia and the western Pacific. Vaccination is recommended for travellers to endemic regions, but the high cost of the vaccine is a major barrier to uptake., Methods: A quasi-experimental, pre-post intervention clinical trial without a control group was conducted to assess the immunogenicity and safety of intradermal (ID) JE vaccine. Healthy adults (18-45 years) received one dose of 0.1 mL (20% of standard dose) ID Imojev® (JE live attenuated chimeric vaccine, Sanofi-Aventis). Adverse events following immunization (AEFIs) were recorded 10 days post-vaccination. Blood samples were collected at baseline, 4 and 8 weeks post-vaccination. Neutralizing antibodies were measured using 50% plaque reduction neutralization test (PRNT50). Seroconversion was defined as PRNT50 titre ≥10. An in vitro study was also conducted to quantify the rate of decay of vaccine potency after reconstitution., Results: In total, 51 participants (72.6% females, median age 31 years), all non-reactive to JE virus at baseline were enrolled. Mild and moderate AEFIs were reported by 19.6% of participants; none required medical attention or interfered with normal daily activities. All participants seroconverted at 4 weeks (GMT 249.3; 95%CI:192.8-322.5) and remained seropositive at 8 weeks (GMT 135.5; 95%CI:104.5-175.6). Vaccine potency declined at a rate of 0.14 log plaque-forming units/0.5 mL per hour., Conclusions: In healthy adults, a single 0.1 mL ID dose of Imojev was safe and immunogenic, at least in the short term. Reconstituted vials of Imojev vaccine may not retain their potency after 6 hours. Fractional JE ID vaccination could be a cheaper yet effective alternative for short-term travellers. Further studies need to investigate the immune response in a wider age range of individuals and the long-term immunogenicity of fractional JE ID vaccines., Clinical Trials Registration: ACTRN12621000024842., (© International Society of Travel Medicine 2022. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC; Ixiaro) was approved in the United States in 2009. The previous JE vaccine, an inactivated mouse brain-derived vaccine, had been associated with rare, but serious, allergic and neurologic adverse events (AE). Studies and AE surveillance have supported JE-VC's safety, but one evaluation among military personnel found elevated hypersensitivity and neurologic AE rates. However, co-administration of multiple vaccines to some personnel might have affected results. We retrospectively compared rates of hypersensitivity and neurologic AEs within 28 days following vaccination of military personnel with JE-VC or parenteral Vi capsular polysaccharide typhoid vaccine administered without other vaccines from July 1, 2011, through August 31, 2019. Rates of most events were similar between the vaccines. Only delayed hypersensitivity reactions occurred more frequently following JE-VC (rate ratio: 4.2, 95 % CI 1.2-15.3; p = 0.03), but rates were low for both vaccines. These results support JE-VC's safety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Flavivirus infections pose a significant global health burden underscoring the need for the development of safe and effective vaccination strategies. Available flavivirus vaccines are from time to time concomitantly delivered to individuals. Co-administration of different vaccines saves time and visits to health care units and vaccine clinics. It serves to provide protection against multiple pathogens in a shorter time-span; e.g., for individuals travelling to different endemic areas. However, safety and immunogenicity-related responses have not been appropriately evaluated upon concomitant delivery of these vaccines. Therefore, we performed an open label, non-randomized clinical trial studying the safety and immunogenicity following concomitant delivery of the yellow fever virus (YFV) vaccine with tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JE) virus vaccines., Methods and Findings: Following screening, healthy study participants were enrolled into different cohorts receiving either TBEV and YFV vaccines, JEV and YFV vaccines, or in control groups receiving only the TBEV, JEV, or YFV vaccine. Concomitant delivery was given in the same or different upper arms for comparison in the co-vaccination cohorts. Adverse effects were recorded throughout the study period and blood samples were taken before and at multiple time-points following vaccination to evaluate immunological responses to the vaccines. Adverse events were predominantly mild in the study groups. Four serious adverse events (SAE) were reported, none of them deemed related to vaccination. The development of neutralizing antibodies (nAbs) against TBEV, JEV, or YFV was not affected by the concomitant vaccination strategy. Concomitant vaccination in the same or different upper arms did not significantly affect safety or immunogenicity-related outcomes. Exploratory studies on immunological effects were additionally performed and included studies of lymphocyte activation, correlates associated with germinal center activation, and plasmablast expansion., Conclusions: Inactivated TBEV or JEV vaccines can be co-administered with the live attenuated YFV vaccine without an increased risk of adverse events and without reduced development of nAbs to the respective viruses. The vaccines can be delivered in the same upper arm without negative outcome. In a broader perspective, the results add valuable information for simultaneous administration of live and inactivated flavivirus vaccines in general., Trial Registration: Eudra CT 2017-002137-32., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sandberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The intron-based stabilization approach is a very useful strategy for construction of stable flavivirus infectious clones. SA 14 -14-2 is a highly attenuated Japanese encephalitis (JE) live vaccine strain that has been widely used in China since 1989. To develop safe and effective recombinant vaccines with SA 14 -14-2 as a backbone vector, we constructed the DNA-based infectious clone pCMW-JEV of SA 14 -14-2 using the intron-based stabilization approach and acquired the rescued virus rDJEV, which retained the biological properties of the parental virus. Unexpectedly, a rescued virus strain with altered virulence, designated rHV-DJEV, was accidentally acquired in one of the transfection experiments. rHV-DJEV showed up to 10 5 -fold increased neurovirulence compared with the SA 14 -14-2 parental strain. Genome sequencing showed that the inserted introns were still present in the genome of rHV-DJEV. Therefore, we think that the intron-based stabilization approach should be used with caution in vaccine development and direct iDNA immunization., (© 2023. The Author(s).)

Background: Acute encephalitis syndrome (AES) is an infection of the central nervous system with high case-fatality rates. Japanese encephalitis virus (JEV) is the most common vaccine preventable cause of AES in Asia and part of the Western Pacific. In 2003, the JE vaccine was introduced into Thailand's National Immunization Program and expanded to all provinces. This study reviews data from the national surveillance system on the incidence of AES, including Japanese encephalitis in Thailand to guide surveillance, control, and prevention strategies., Materials and Methods: We collected data on all patients diagnosed with AES and reported to the Bureau of Epidemiology, Ministry of Public Health, Thailand, from 2003 to 2019., Results: A total of 9566 AES patients and 266 death cases were reported during these 17 years. Six hundred and forty-two (6.7%) patients were JE with 16 deaths. The incidence of AES increased from 0.47-0.51-1.36 cases per 100,000 population with a preponderance of cases in adults. CFR reduced from 6.25% - 6.94% in 2003-2005 to 0.78% in 2019. AES cases occurred all year round in all the age groups with a male predilection JE vaccination coverage had reached 83% by 2019. The patients were mainly from the north-eastern region of Thailand., Conclusion: Integrated surveillance regular monitoring, strengthening, and making immunization sustainable is required to improve and maintain progress toward JE control and prevention.

Aim: To develop a vaccine candidate for Japanese encephalitis virus (JEV), for which an effective and safe vaccine is urgently needed. Materials & methods: A vaccine candidate based on domain III of the JEV envelope protein and lumazine synthase (EDIII-LS) was prepared by coupling multivalent ED III to a self-assembling nanoparticle of LS through genetic fusion and self-assembly. Results: High enrichment of ED III was achieved based on the self-assembly of an EDIII-LS polymer. EDIII-LS strongly promoted dendritic cells' internalization and presentation compared with ED III monomer. The cellular and humoral immune responses provoked by EDIII-LS were remarkably higher than those caused by ED III in mice, and conferred complete protection against JEV challenge. Conclusion: The study of ED III-based nanoparticles suggests an effective approach against JEV.

We aimed to estimate the coverage of Japanese encephalitis (JE) vaccination in central India to help explain the continued occurrence of JE disease despite routine vaccination. We implemented a 30-cluster survey for estimating the coverage of JE vaccination in the medium-endemic areas implemented with JE vaccination in central India. The parents were enquired about the uptake of the JE vaccine by their children aged 2-6 years, followed by verification of the immunization cards at home along with reasons for non-vaccination. Vaccination coverage was reported as a percentage with 95% confidence intervals (CI). We estimated high coverage of live-attenuated SA 14-14-2 JE vaccination in Maharashtra (94.8%, 95% CI: 92.7-96.3) and Telangana (92.8%, 95% CI: 90.0-94.9). The vaccination card retention was 90.3% in Maharashtra and 70.4% in Telangana state. There were no gender differences in coverage in both states. A similar level of JE vaccination coverage was observed during the year 2013-2021 in both states. In Maharashtra, the maximum age-wise coverage was 96.6% in the >60 months age category, whereas in Telangana it was in the <24 months age category (97.2%). The timeliness of JE vaccination was appropriate and similar in both states. We found a very good agreement between JE and measles-rubella vaccinations administered simultaneously. The reasons for non-vaccination were the shortage of vaccines and the parental migration for work. The coverage of JE vaccination was high in medium-endemic regions in central India. Vaccination effectiveness studies may help further explain the continued incidence of JE., (© 2022 Wiley Periodicals LLC.)

Japanese encephalitis (JE) is a vector-borne neurotropic disease caused by Japanese encephalitis virus (JEV) associated with high mortality rate distributed from Eastern and Southern Asia to Northern Queensland (Australia). The challenges in early detection and lack of point-of-care biomarkers make it the most important Flavivirus causing encephalitis. There is no specific treatment for the disease, although vaccines are licenced. In this review, we focussed on point-of-care biomarkers as early detection tools and developing the effective therapeutic agents that could halt JE. We have also provided molecular details of JEV, disease progression, and its pathogenesis with recent findings which might bring insights to overcome the disease burden., (© 2022 John Wiley & Sons Ltd.)

Japanese encephalitis (JE) disease among children continues in central India despite vaccination implemented in the routine immunization program. Therefore, we planned to estimate the JE vaccination effectiveness among children by undertaking a 1:2 individually-matched population-based case-control study from August 2018 to October 2020. The laboratory-confirmed JE cases aged 1-15 years were enrolled along with neighborhood controls without fever and encephalitis matched on the residence area, age and sex. The JE vaccination history was enquired from parents and verified independently from the vaccination cards available at home and records at health facilities. We enrolled 35 JE cases and 70 matched controls. The vaccination effectiveness of 86.7% (95% confidence interval [CI]: 30.8-94.7) was estimated on the per-protocol analysis of 31 case-control sets. The screening method provided an effectiveness of 89.5% (CI: 78.9-94.7) on using the population vaccination coverage of 90% reported earlier in the same area. In conclusion, JE vaccination offered a moderate level of protection among children in JE medium-endemic central India, similar to reports from high-endemic areas in India. The operational aspects of vaccination program implementation need to be evaluated to assess the impact of vaccination on the disease burden of JE in medium-endemic regions of India., (© 2022 Wiley Periodicals LLC.)

Japanese encephalitis is the main cause of viral encephalitis in Asia. In a previous single-arm vaccine trial, an inactivated chromatographically purified Japanese encephalitis Vero cell vaccine (CVI-JE; JEVAC TM ) was safe and immunogenic in 152 Thai children aged 1-3 years receiving a 2-dose primary immunization and booster dose 1 year later. We conducted a 5-year follow-up assessment of the persistence of the immune response the 144 children remaining in this cohort after first booster dose. Immunity was assessed by 50% plaque reduction neutralization test annually for up to 5 years post-booster. Seroprotection rates (95%CI) decreased from 100% (97.1-100) at 1 year post-booster to 93% (85.0-98.3) at 5 years post-booster. No serious vaccine-related adverse events or Japanese encephalitis infections were reported. A 2-dose primary immunization and booster 1 year later with CVI-JE provided long-lasting immunity in the majority of children.

Limited information is available about post-marketing safety of Japanese encephalitis (JE) vaccines. Using data from SmartVax, an active surveillance system for monitoring vaccine safety, adverse events following immunizations (AEFIs) were compared between the two JE vaccines available in Australia (a chimeric live attenuated vaccine [Imojev] and a Vero cell-derived inactivated vaccine [JEspect]). Data from 2756 patients (1855 Imojev and 901 JEspect) were included. Overall (7.0%), systemic (2.8%), and local (1.9%) AEFIs were uncommon. There were no significant differences in the odds of overall (OR = 1.27; 95%CI: 0.91-1.77), systemic (OR = 1.23; 95%CI: 0.74-2.06), or local (OR = 1.20; 95%CI: 0.65-2.22) AEFIs with Imojev compared to JEspect. There was an increase in odds of overall AEFI in patients aged <5 years (OR = 2.39; 95%CI: 1.10-5.19) compared to those aged >50 years. Both JE vaccines available in Australia are safe and well tolerated. Odds of AEFIs were age-dependent, young children should be carefully observed for AEFIs after vaccination.

Japanese encephalitis virus (JEV) genotype V (GV) emerged in China in 2009, then South Korea, and has since spread to other regions in Asia and beyond, raising concern about its pathogenicity and the cross-protection offered by JEV vaccines against different genotypes. In this study, we replaced the structural proteins (C-prM-E) of an attenuated genotype I (GI) SD12-F120 strain with those of a virulent GV XZ0934 strain to construct a recombinant chimeric GI-GV JEV (JEV-GI/V) strain to determine the role of the structural proteins in virulence and cross-protection. The recombinant chimeric virus was highly neurovirulent and neuroinvasive in mice. This demonstrated the determinant role of the structural proteins in the virulence of the GV strain. Intracerebral or intraperitoneal inoculation of mice with JEV-GI/V-E5 harboring a combination of substitutions (N47K, L107F, E138K, H123R, and I176R) in E protein, but not mutants containing single substitution of these residues, resulted in decreased or disappeared mortality, suggesting that these residues synergistically, but not individually, played a role in determining the neurovirulence and neuroinvasiveness of the GV strain. Immunization of mice with attenuated strain JEV-GI/V-E5 provided complete protection and induced high neutralizing antibody titers against parental strain JEV-GI/V, but partial cross-protection and low cross-neutralizing antibodies titers against the heterologous GI and GIII strains in mice, suggesting the reduced cross-protection of JEV vaccines among different genotypes. Overall, these findings suggested the essential role of the structural proteins in determination of the virulence of GV strain, and highlighted the need for a novel vaccine against this newly emerged strain. IMPORTANCE The GV JEV showed an increase in epidemic areas, which exhibited higher pathogenicity in mice than the prevalent GI and GIII strains. We replaced a recombinant chimeric GI-GV JEV (JEV-GI/V) strain to determine the role of the structural proteins in virulence and cross-protection. It was found that the essential role of the structural proteins is to determinethe virulence of the GV strain. It is also suggested that there is reduced cross-protection of JEV vaccines among different genotypes, which provides basic data for subsequent JEV prevention, control, and new vaccine development.