Japanese Encephalitis can be devastating.

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.

Spatio-temporal epidemiology of Japanese encephalitis virus infection in pig populations of eastern Uttar Pradesh, India, 2013-2022.

AIMS: Japanese encephalitis (JE) is endemic in India. Although pigs are considered important hosts and sentinels for JE outbreaks in people, limited information is available on JE virus (JEV) surveillance in pigs. METHODS AND RESULTS: We investigated the spatio-temporal distribution of JEV seroprevalence and its association with climate variables in 4451 samples from pigs in 10 districts of eastern Uttar Pradesh, India, over 10 years from 2013 to 2022. The mean seroprevalence of IgG (2013-2022) and IgM (2017-2022) was 14% (95% CI 12.8-15.2) and 10.98% (95% CI 9.8-12.2), respectively. Throughout the region, higher seroprevalence from 2013 to 2017 was observed and was highly variable with no predictable spatio-temporal pattern between districts. Seroprevalence of up to 60.8% in Sant Kabir Nagar in 2016 and 69.5% in Gorakhpur district in 2017 for IgG and IgM was observed, respectively. IgG seroprevalence did not increase with age. Monthly time-series decomposition of IgG and IgM seroprevalence demonstrated annual cyclicity (3-4 peaks) with seasonality (higher, broader peaks in the summer and monsoon periods). However, most variance was due to the overall trend and the random components of the time series. Autoregressive time-series modelling of pigs sampled from Gorakhpur was insufficiently predictive for forecasting; however, an inverse association between humidity (but not rainfall or temperature) was observed. CONCLUSIONS: Detection patterns confirm seasonal epidemic periods within year-round endemicity in pigs in eastern Uttar Pradesh. Lack of increasing age-associated seroprevalence indicates that JEV might not be immunizing in pigs which needs further investigation because models that inform public health interventions for JEV could be inaccurate if assuming long-term immunity in pigs. Although pigs are considered sentinels for human outbreaks, sufficient timeliness using sero-surveillance in pigs to inform public health interventions to prevent JEV in people will require more nuanced modelling than seroprevalence and broad climate variables alone.

Incongruence between confirmed and suspected clinical cases of Japanese encephalitis virus infection.

Background: Japanese encephalitis (JE) is a notifiable infectious disease in China. Information on every case of JE is reported to the superior health administration department. However, reported cases include both laboratory-confirmed and clinically diagnosed cases. This study aimed to differentiate between clinical and laboratory-confirmed cases of Japanese encephalitis virus (JEV) infection, and improve the accuracy of reported JE cases by analyzing the acute-phase serum and cerebrospinal fluid of all reported JE cases in the Sichuan province from 2012 to 2022. Methods: All acute-phase serum and/or cerebrospinal fluid samples of the reported JE cases were screened for IgM(ImmunoglobulinM)to JEV using the enzyme-linked immunosorbent assay (ELISA), and the detection of the viral genes of JEV and 9 other pathogens including enterovirus (EV), using reverse transcription PCR was attempted. Epidemiological analyses of JE and non-JE cases based on sex, age, onset time, and geographical distribution were also performed. Results: From 2012 to 2022, 1558 JE cases were reported in the Sichuan province. The results of serological (JEV-specific IgM) and genetic testing for JEV showed that 81% (1262/1558) of the reported cases were confirmed as JEV infection cases (laboratory-confirmed cases). Among the 296 cases of non-JEV infection, 6 viruses were detected in the cerebrospinal fluid in 62 cases, including EV and the Epstein-Barr virus (EBV), constituting 21% (62/296) of all non-JE cases. Among the 62 non-JEV infection cases with confirmed pathogens, infections with EV and EBV included 17 cases each, herpes simplex virus (HSV-1/2) included 14 cases, varicella- zoster virus included 6 cases, mumps virus included 2 cases, and human herpes viruses-6 included 1 case. Additionally, there were five cases involving mixed infections (two cases of EV/EBV, one case of HSV-1/HSV-2, one case of EBV/HSV-1, and one case of EV/herpes viruses-6). The remaining 234 cases were classified as unknown viral encephalitis cases. Our analysis indicated that those aged 0-15 y were the majority of the patients among the 1558 reported JE cases. However, the incidence of laboratory-confirmed JE cases in the >40 y age group has increased in recent years. The temporal distribution of laboratory-confirmed cases of JE revealed that the majority of cases occurred from May to September each year, with the highest incidence in August. Conclusion: The results of this study indicate that there is a certain discrepancy between clinically diagnosed and laboratory-confirmed cases of JE. Each reported case should be based on laboratory detection results, which is of great importance in improving the accuracy of case diagnosis and reducing misreporting. Our results are not only important for addressing JE endemic to the Sichuan province, but also provide a valuable reference for the laboratory detection of various notifiable infectious diseases in China and other regions outside China.

Current Advances in Japanese Encephalitis Virus Drug Development.

Japanese encephalitis virus (JEV) belongs to the Flaviviridae family and is a representative mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans. Despite the availability of vaccines, JEV remains a major public health threat with the potential to spread globally. According to the World Health Organization (WHO), there are an estimated 69,000 cases of JE each year, and this figure is probably an underestimate. The majority of JE victims are children in endemic areas, and almost half of the surviving patients have motor or cognitive sequelae. Thus, the absence of a clinically approved drug for the treatment of JE defines an urgent medical need. Recently, several promising and potential drug candidates were reported through drug repurposing studies, high-throughput drug library screening, and de novo design. This review focuses on the historical aspects of JEV, the biology of JEV replication, targets for therapeutic strategies, a target product profile, and drug development initiatives.

Development of Colloidal Gold-Based Immunochromatographic Strips for Rapid Detection and Surveillance of Japanese Encephalitis Virus in Dogs across Shanghai, China.

Japanese encephalitis virus (JEV) causes acute encephalitis in humans and is of major public health concern in most Asian regions. Dogs are suitable sentinels for assessing the risk of JEV infection in humans. A neutralization test (NT) or an enzyme-linked immunosorbent assay (ELISA) is used for the serological detection of JEV in dogs; however, these tests have several limitations, and, thus, a more convenient and reliable alternative test is needed. In this study, a colloidal gold immunochromatographic strip (ICS), using a purified recombinant EDIII protein, was established for the serological survey of JEV infection in dogs. The results show that the ICSs could specifically detect JEV antibodies within 10 min without cross-reactions with antibodies against other canine viruses. The test strips could detect anti-JEV in serum with dilution up to 640 times, showing high sensitivity. The coincidence rate with the NT test was higher than 96.6%. Among 586 serum samples from dogs in Shanghai examined using the ICS test, 179 (29.98%) were found to be positive for JEV antibodies, and the high seropositivity of JEV in dogs in China was significantly correlated with the season and living environment. In summary, we developed an accurate and economical ICS for the rapid detection of anti-JEV in dog serum samples with great potential for the surveillance of JEV in dogs.

Seroprevalence of dengue, Japanese encephalitis and Zika among long-term expatriates in Thailand.

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.

Seroprevalence of Japanese encephalitis virus-specific antibodies in Australia following novel epidemic spread: protocol for a national cross-sectional study.

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.

Potential for emergence of Japanese encephalitis in the European Union.

BACKGROUND AND OBJECTIVE: No autochthonous human cases of Japanese encephalitis (JE) have been reported to date in the European Union (EU). In this study, we assess the likelihood of Japanese encephalitis virus (JEV) introduction and transmission within the EU and propose outbreak response measures. RISK ASSESSMENT: Given the global geographical distribution of JEV, the probability of virus introduction into the EU is currently very low, with viremic bird migration being the most plausible pathway of introduction. However, this likelihood would significantly increase if the virus were to become established in the Middle East, Caucasus, Central Asia or Africa. Considering the environmental conditions that are expected to be conducive for virus circulation, there is a high likelihood of virus transmission within the EU after its introduction in environmentally suitable areas. The spread of the virus within the EU would likely occur through the movement of wild birds, pigs and mosquitoes. MITIGATION: To mitigate or potentially contain the emergence of JE in the EU, early detection of both human and animal cases will be crucial.

Mosquito-borne diseases in India over the past 50 years and their Global Public Health Implications: A Systematic Review.

Mosquito-borne diseases (MBDs) pose a significant public health concern globally, and India, with its unique eco-sociodemographic characteristics, is particularly vulnerable to these diseases. This comprehensive review aims to provide an in-depth overview of MBDs in India, emphasizing their impact and potential implications for global health. The article explores distribution, epidemiology, control or elimination, and economic burden of the prevalent diseases such as malaria, dengue, chikungunya, Japanese encephalitis, and lymphatic filariasis, which collectively contribute to millions of cases annually. It sheds light on their profound effects on morbidity, mortality, and socioeconomic burdens and the potential for international transmission through travel and trade. The challenges and perspectives associated with controlling mosquito populations are highlighted, underscoring the importance of effective public health communication for prevention and early detection. The potential for these diseases to spread beyond national borders is recognized, necessitating a holistic approach to address the challenge. A comprehensive literature search was conducted, covering the past five decades (1972-2022), utilizing databases such as Web of Science, PubMed, and Google Scholar, in addition to in-person library consultations. The literature review analyzed 4,082 articles initially identified through various databases. After screening and eligibility assessment, 252 articles were included for analysis. The review focused on malaria, dengue, chikungunya, Japanese encephalitis, and lymphatic filariasis. The included studies focused on MBDs occurrence in India, while those conducted outside India, lacking statistical analysis, or published before 1970 were excluded. This review provides valuable insights into the status of MBDs in India and underscores the need for concerted efforts to combat these diseases on both national and global scales through consilience.

Cost of Acute and Sequelae Care for Japanese Encephalitis Patients, Bangladesh, 2011-2021.

Japanese encephalitis (JE) is associated with an immense social and economic burden. Published cost-of-illness data come primarily from decades-old studies. To determine the cost of care for patients with acute JE and initial and long-term sequelae from the societal perspective, we recruited patients with laboratory-confirmed JE from the past 10 years of JE surveillance in Bangladesh and categorized them as acute care, initial sequalae, and long-term sequelae patients. Among 157 patients, we categorized 55 as acute, 65 as initial sequelae (53 as both categories), and 90 as long-term sequelae. The average (median) societal cost of an acute JE episode was US $929 ($909), of initial sequelae US $75 ($33), and of long-term sequelae US $47 ($14). Most families perceived the effect of JE on their well-being to be extreme and had sustained debt for JE expenses. Our data about the high cost of JE can be used by decision makers in Bangladesh.

The detection of Japanese encephalitis virus in municipal wastewater during an acute disease outbreak.

AIM: To demonstrate the capability of wastewater-based surveillance (WBS) as a tool for detecting potential cases of Japanese Encephalitis Virus (JEV) infection in the community. METHODS AND RESULTS: In this study, we explore the potential of WBS to detect cases of JEV infection by leveraging from an established SARS-CoV-2 wastewater surveillance program. We describe the use of two reverse transcriptase quantitative polymerase chain reaction (RTqPCR) assays targeting JEV to screen archived samples from two wastewater treatment plants (WWTPs). JEV was detected in wastewater samples collected during a timeframe coinciding with a cluster of acute human encephalitis cases, alongside concurrent evidence of JEV detection in mosquito surveillance and the sentinel chicken programs within South Australia's Riverland and Murraylands regions. CONCLUSIONS: Current surveillance measures for JEV encounter multiple constraints, which may miss the early stages of JEV circulation or fail to capture the full extent of transmission. The detection of JEV in wastewater during a disease outbreak highlights the potential WBS has as a complementary layer to existing monitoring efforts forming part of the One Health approach required for optimal disease response and control.

Mosquito surveillance on U.S military installations as part of a Japanese encephalitis virus detection program: 2016 to 2021.

Japanese encephalitis virus (JEV) continues to circulate throughout Southeast Asia and the Western Pacific where approximately 3 billion people in 24 countries are at risk of infection. Surveillance targeting the mosquito vectors of JEV was conducted at four military installations on Okinawa, Japan, between 2016 and 2021. Out of a total of 10,426 mosquitoes from 20 different species, zero were positive for JEV. The most abundant mosquito species collected were Aedes albopictus (36.4%) followed by Culex sitiens (24.3%) and Armigeres subalbatus (19%). Statistically significant differences in mosquito species populations according to location were observed. Changes in land use over time appear to be correlated with the species and number of mosquitoes trapped in each location. JEV appears to be absent from mosquito populations on Okinawa, but further research on domestic pigs and ardeid birds is warranted.

Epidemiology and risk factors of Japanese encephalitis in Taiwan, 2010-2022.

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.

Cost-effectiveness analysis of Japanese Encephalitis (JE) vaccination program in Bali Province, Indonesia.

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.

The Surveillance of Acute Encephalitis Syndrome in Thailand, 2003-2019: A Perspective for Prevention and Control.

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.

Sero-molecular epidemiology of Japanese encephalitis virus in swine population of western Uttar Pradesh, India: Unraveling the geographical expansion of the virus.

BACKGROUND & OBJECTIVES: Swine is a good sentinel for forecast of Japanese encephalitis virus (JEV) outbreaks in humans. The present study was envisaged with objectives to know the sero-conversion period of JEV and to assess the prevalence of JEV in swine population of western Uttar Pradesh state of India. METHODS: A total of 252 swine serum samples were screened using IgM ELISA over the period of one year to determine the sero-conversion rate and compared seasonally to check the transmission peak of virus. Further, 321 swine blood and serum samples were collected from all seven divisions of western Uttar Pradesh to determine prevalence of JEV using real time RT-PCR and ELISA. RESULTS: Seasonal sero-conversion rate was high during monsoon and post-monsoon (32%) followed by winter (22.91%) and summer (10.71%) seasons. The sero-conversion was observed in all months indicating viral activity throughout the year in the region. The low degree of correlation was found between meteorological variables (day temperature, rainfall) and sero-conversion rate. A total of 52 samples (16.19%) were found positive by real time RT-PCR while sero-positivity of 29.91% was observed using IgG and IgM ELISA(s). The overall prevalence of JEV was 39.25%. INTERPRETATION & CONCLUSION: The presence of JEV was recorded throughout the year with peak occurrence during monsoon and post-monsoon season indicating that virus has spread its realm to western region of the state. The information generated in the present study will aid in initiating timely vector control measures and human vaccination program to mitigate risk of JEV infection in the region.

Infection of Feral Phenotype Swine with Japanese Encephalitis Virus.

Background: Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic flavivirus and the leading cause of pediatric encephalitis in the Asian Pacific region. The transmission cycle primarily involves Culex spp. mosquitoes and Ardeid birds, with domestic pigs (Sus scrofa domestica) being the source of infectious viruses for the spillover of JEV from the natural endemic transmission cycle into the human population. Although many studies have concluded that domestic pigs play an important role in the transmission cycle of JEV, and infection of humans, the role of feral pigs in the transmission of JEV remains unclear. Since domestic and feral pigs are the same species, and because feral pig populations in the United States are increasing and expanding geographically, the current study aimed to test the hypothesis that if JEV were introduced into the United States, feral pigs might play a role in the transmission cycle. Materials and Methods: Sinclair miniature pigs, that exhibit the feral phenotype, were intradermally inoculated with JEV genotype Ib. These pigs were derived from crossing miniature domestic pig with four strains of feral pigs and were used since obtaining feral swine was not possible. Results: The Sinclair miniature pigs became viremic and displayed pathological outcomes similar to those observed in domestic swine. Conclusion: Based on these findings, we conclude that in the event of JEV being introduced into the United States, feral pig populations could contribute to establishment and maintenance of a transmission cycle of JEV and could lead to the virus becoming endemic in the United States.