Japanese Encephalitis Virus: Ongoing Public Health Threat 

April 7, 2022

Introduction 

Japanese encephalitis virus (JEV) is the leading cause of vaccine-preventable encephalitis. JEV is a flavivirus (genus Flavivirus, family Flaviviridae) and shares a close genetic and antigenic relationship with West Nile virus, St. Louis encephalitis virus, and Murray Valley encephalitis virus (1). Most people infected with JE do not have symptoms or have only mild symptoms. However, a small percentage of infected people develop inflammation of the brain (encephalitis), with symptoms including sudden onset of headache, high fever, disorientation, coma, tremors, and convulsions (2). The case-fatality rate among those with encephalitis can be as high as 30%. Permanent neurologic or psychiatric sequelae can occur in 30%–50% of those with encephalitis (3); in fact, among survivors, about 30–50% have long-term neurologic sequelae with intellectual or physical disabilities. Nearly, 69,000 clinical cases of JE are estimated to occur globally each year, with approximately 13 600 to 20 400 deaths (4). 

Transmission and Characteristics

JEV is transmitted to humans through the bite of infected Culex species mosquitoes, particularly Culex tritaeniorhynchus and Culex annulirostris (Australia) (4). The virus is maintained in a cycle between mosquitoes and vertebrate hosts, primarily pigs and wading birds. Human cases typically occur in children (<14 years) in endemic areas while adults are also at risk in areas where epidemics occur, particularly by working in proximity to elements in the transmission cycle, such as near rice fields or domestic pigs (5). However, JEV is not transmitted from human to human. JEV transmission is seasonal. In temperate areas of Asia, human disease usually peaks in the summer and fall. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season (6). 

JE mostly affects people in Asia and parts of the Western Pacific, particularly in agricultural areas (2). However, the virus is currently infecting people as far south as the Australian state of Victoria. On March 4, 2022, Australia declared the JEV situation a Communicable Disease Incident of National Significance (7). JEV was detected and confirmed in piggeries in Victoria, Queensland, New South Wales, Victoria, and South Australia, with cases confirmed in animals in at least 24 piggeries in all of those states (8). As of March 31, 2022, there have been 34 human cases of JEV in Australia with 24 laboratory confirmed cases and 10 probable cases where the person has been linked epidemiologically and/or has symptoms of the disease and has laboratory suggestive evidence (9). Three people have died of JEV. The spread of JEV in south-eastern Australia has likely been driven by wet weather with excessive rainfall, flooding, and climate change. Flooding in Australia’s north triggered the migration of birds further south. These birds may have carried the JEV virus deep into Australia, where mosquito populations have recently increased due to the unusually warm weather. Subsequently, these mosquitoes would have transmitted the virus to pigs. Indeed, pigs have known to serve as the principal amplifying hosts for JEV in epidemic areas and are maintenance hosts in endemic areas (10). Australia’s response to the JEV situation includes mosquito surveillance and control measures, identification of those at direct risk, and the rollout of vaccines.  

JE mostly affects people in Asia and parts of the Western Pacific, particularly in agricultural areas (2).

High production costs, poor induction of long-term immunity, multiple dose regimen, and reports of adverse events have limited the use of inactivated vaccines (6).

Global recommendations for JEV control include the use of vaccines. Despite the availability of safe and effective vaccines, vaccination rates remain low in most countries where they are most urgently needed.

The 4 Vaccine Types

There are 4 main types of JEV vaccines currently in use: inactivated mouse brain-derived vaccines, inactivated Vero cell-derived vaccines, live attenuated vaccines, and live recombinant (chimeric) vaccines. High production costs, poor induction of long-term immunity, multiple dose regimen, and reports of adverse events have limited the use of inactivated vaccines (6). In contrast, live-attenuated vaccine (e.g., SA14-14-2) can be given in two to three doses during childhood and is relatively inexpensive (11). The SA14-14-2 vaccine has been widely used in China. As a live recombinant (chimeric) vaccine, ChimeriVax-JE was constructed from yellow fever virus 17D vaccine cDNA by replacement of the viral structural prM and E proteins with those of an attenuated JEV strain (12). ChimeriVax-JE is known to be safe and to elicit high titers of neutralizing antibodies after a single inoculation at very low doses, an advantage over existing inactivated vaccines that require multiple doses. The live-attenuated vaccine is immunogenic and induces long term immunity. However, the vaccine needs to be improved to provide broad protection against diverse genotypes of JEV (11). Currently, no specific therapeutics are available for the treatment of JEV. Hospitalization for supportive care and close observation is generally required (13). Rest, fluids, and use of pain relievers and medication to reduce fever may relieve some symptoms. Given the apparently paradoxical role of the immune system in Japanese encephalitis, a combination therapy comprising both anti-inflammatory and antiviral drugs has been suggested (14). In addition, JEV-specific monoclonal antibodies could be potential candidates for the treatment. 

Conclusion

There is a risk of JEV’s further expansion into new regions due to the lack of effective vector control programs, the geographic expansion of human-adapted mosquito species, and the possible impacts of climate change (6). Global recommendations for JEV control include the use of vaccines. Despite the availability of safe and effective vaccines, vaccination rates remain low in most countries where they are most urgently needed. The WHO recommends JEV immunization in all regions where the disease is a recognized public health priority and supports implementation (3). In case of vaccine shortages, partial dosing may be initiated. This leads to JEV vaccine introduction and large-scale JEV vaccination campaigns, and evaluation of JEV vaccine effectiveness and programmatic impact. Importantly, the limited resources and the difficulty in JEV diagnostics without cerebrospinal fluid samples in many JEV endemic countries has caused poor surveillance of JEV. Currently, underreporting has hindered understanding the local and global burden of JEV and establishing a risk assessment (15). Improvement of surveillance program and providing technical support will allow efficient monitoring of JEV outbreaks. 

Our GVN Team thanks Drs. Alexander Khromykh and Roy Hall (The Australian Infectious Disease Research Centre, Australia) for reviewing this manuscript and for providing us with invaluable comments and insights. 

References

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