Japanese Encephalitis: Vaccination Strategies and Recommendations

Introduction:

Japanese encephalitis virus (JEV), a neurotropic member of the Flaviviridae family and Orthoflavivirus genus which also includes dengue, Zika, yellow fever, and West Nile viruses., remains a leading cause of viral encephalitis throughout Asia and the Western Pacific. 

Between 1998 and 2011, an estimated 67,900 cases of Japanese encephalitis (JE) occurred annually across 24 endemic countries, corresponding to an overall incidence of 1.8 per 100,000 population. Based on WHO surveillance data, published case reports, and national health statistics from endemic regions between 2017 and 2023, the reported incidence declined to 0.5–1 per 1,000,000 population. The estimated annual number of locally acquired cases ranged from approximately 4,668 in 2017 to 1,886 in 2022. However, underreporting remains likely, given variations in surveillance capacity and diagnostic infrastructure across endemic areas.

Transmission to humans occurs through the bites of infected Culex species, primarily C. tritaeniorhynchus, but also C. vishnui, C. gelidus, and C. pipiens.

The main vertebrate hosts—pigs and aquatic wading birds—serve as amplifying reservoirs, while humans are incidental, dead-end hosts, as person-to-person transmission does not occur (Figure 1).

Figure 1. Japanese Encephalitis Transmission Cycle:

Approximately 99% of JEV infections are asymptomatic. When symptomatic, following an incubation period of 4–14 days, individuals typically develop nonspecific prodromal symptoms such as high-grade fever, chills, headache, and myalgia, which may progress to neurological manifestations (encephalitis), including confusion, seizures, coma, and, in severe cases, death. The case-fatality rate among symptomatic patients is estimated at ~30%, and up to 50% of survivors experience long-term neurological sequelae. Currently, no specific antiviral treatment exists; management remains supportive.

Areas of Japanese Encephalitis:

WHO case reports, published case reports, and endemic country health control statistics from 2017 to 2023 revealed that there has been a decrease in the incidence of JE among both residents and travelers, but the majority of countries where the JEV is still endemic are popular travel destinations, including India, China, Vietnam, Myanmar, Malaysia, the Philippines, Thailand, Indonesia, and possibly north of Australia, South Korea, Pakistan, Brunei, Cambodia, and Papua New Guinea, among others.

Interestingly, India reported a notably high rate of Japanese encephalitis virus (JEV) infection among local residents between 2017 and 2021, with nearly 2,500 cases in 2019 alone. China followed with approximately 1,800 cases reported in 2018. Between 2017 and 2018, both the Philippines and Vietnam documented substantial case numbers—up to 361 and 313, respectively [4]. In contrast, Thailand reported consistently low case counts, with 14, 17, 8, 9, and 3 cases recorded annually from 2017 to 2022, respectively [8–10]. Overall, the incidence of JEV infection in Thailand, the Philippines, China, India, and Vietnam demonstrated a steady decline during the 2017–2022 period.

The decline in new JEV infections among residents can be attributed to several factors, including strengthened surveillance systems, the successful implementation of non-pharmaceutical interventions (NPIs), and changes in lifestyle patterns. Furthermore, the transformation of rural regions into peri-urban areas and the relocation or encroachment of pig farms near residential zones may also have influenced this downward trend.

Japanese Encephalitis Vaccine Implications for Travelers Visiting JE-Endemic Areas:

Over the past 30 years, the estimated annual incidence of JE among American travelers has been less than one case per one million individuals. The estimated risk of JEV infection during one month of travel to rural areas in the transmission season ranges between 1 in 5,000 and 1 in 200,000 per week. Among Swedish and Finnish travelers to Thailand, the risk—regardless of travel type or duration—was estimated at 1 per 257,000 to 1 per 400,000 travelers. Between 1973 and 2023, only 85 travel-associated JE cases were identified among travelers visiting endemic regions across 15 countries, none of whom had been vaccinated against JE. Of these, 26 cases occurred in travelers to Thailand, followed by Indonesia (13), the Philippines (11), China (9), Vietnam (4), Japan (4), and South Korea (2). Single cases were also reported in travelers to Myanmar, Malaysia, Taiwan, Singapore, Papua New Guinea, Hong Kong, Cambodia, and Nepal. However, because of the high case-fatality rate of JE once neurological symptoms develop—despite its low overall incidence—vaccination is recommended for certain travelers.

Japanese Encephalitis Vaccines:

Inactivated JE Vaccines:

A Vero cell–derived JE vaccine (JE-VC) from the attenuated SA-14-14-2 strain was introduced in 2009 (IXIARO® in the U.S., JESPECT® in Australia/New Zealand, JEEV® in India) and licensed for U.S. children ≥2 months in 2013. An accelerated two-dose regimen within one-week elicited seroconversion rates of 99–100%, comparable to the standard 28-day schedule. Seroprotection 10–12 months later was 94% in the accelerated group and 88% in the conventional group. For the standard schedule, seroprotection declined from 96% at one month to 48% at 24 months, with long-term antibodies persisting in ~82% at 60 months; in adults >65 years, protection decreased after six weeks. A single JE-VC dose achieved 41% seroconversion at day 28, rising to 100% after a 15-month booster, with 96% protection maintained at 76 months.

JENVAC®, licensed in India since 2014, uses the JEV Kolar-821564XY strain grown in Vero cells. Two doses 28 days apart produced >90% seroprotection, persisting >60% over two years. A single dose yielded 92.4% seroprotection at four weeks and >80% at two years.

Live attenuated JE vaccines:

Only two newly introduced live JE vaccines (JE-LVs) are currently available. The first, CD. JEVAX®, contains the attenuated SA 14-14-2 virus grown in hamster kidney cell culture. A single dose in children provided 94.5% effectiveness at six months and 96.2% at five years. The second, IMOJEV®, is a recombinant chimeric vaccine combining the yellow fever 17D-204 backbone with JE virus components, introduced in 2012. Neutralizing antibodies were detected in 99% of recipients 28 days post-vaccination, with seroprotection persisting at 93% for up to five years. Studies indicate that a single dose of IMOJEV® confers long-term protection in adults for at least ten years. It is currently licensed in Australia, Thailand, Malaysia, the Philippines, Hong Kong, and Singapore.

Vaccine Candidates in Development:

Recent studies have identified three promising JE vaccine candidates. Virus-like particles (VLPs): Produced in vitro using Pichia pastoris to express the JEV envelope protein, these VLPs induced strong humoral and cellular immune responses in mice and pigs, providing complete protection in immunodeficient mice and high neutralizing antibody titers in pigs even without an adjuvant. JEV-ΔNS1 live-attenuated strain: This replication-deficient variant, lacking the NS1 region, showed excellent safety, genetic stability, and reduced neurovirulence in mice. A single dose elicited robust immunity comparable to the SA14-14-2 vaccine. DNA vaccine (pV-JP3ME): Based on the virulent JEV P3 strain and subcloned into the pVAX1 vector, this candidate induced high IgG and neutralizing antibody levels in mice.

Japanese Encephalitis Vaccine Recommendations:

As a reminding, since JE vaccination does not induce herd immunity (humans are dead-end hosts), achieving and sustaining high vaccination coverage is essential for populations at risk of disease. Therefore, JE vaccination should be integrated into national immunization schedules in all areas where JE is considered a public health priority.

The WHO recommends the following dosing schedules and age of administration for JE vaccines:

• Live attenuated vaccine: A single dose administered at ≥8 months of age
• Live recombinant vaccine: A single dose administered at ≥9 months of age
• Inactivated Vero cell-derived vaccine: The primary series should follow the manufacturer’s guidance, typically involving two doses four weeks apart, with the first dose starting at ≥6 months of age in endemic areas

The need for a booster dose in endemic areas has not yet been clearly established for these vaccines.

The most effective immunization strategy in JE endemic areas involves a one-time campaign targeting the primary at-risk population, as defined by local epidemiology (typically children aged < 15 years of age). This should be followed by incorporation of JE vaccination into the routine childhood immunization program.

The CDC (USA): Travelers to areas with risk for Japanese encephalitis should discuss the need for vaccination with their healthcare provider. The discussion should include:

• risks related to the specific travel itinerary,
• likelihood of future travel to countries where Japanese encephalitis virus occurs,
• possible severe outcomes of Japanese encephalitis, and
• information about the vaccine including cost and possible side effects.

Japanese encephalitis vaccine is recommended for persons moving to a Japanese encephalitis-endemic country to live, longer-term (e.g., 1 month or longer) travelers, and frequent travelers to Japanese encephalitis-endemic areas.

Japanese encephalitis vaccine also should be considered for:

• shorter-term (e.g., less than 1 month) travelers with an increased risk of Japanese encephalitis based on planned travel duration, season, location, activities, and accommodations, and
• for travelers who are uncertain of specific duration of travel, destinations, or activities.

Japanese encephalitis vaccine is not recommended for travelers with very low risk itineraries, such as shorter-term travel limited to urban areas or travel that occurs outside of a well-defined Japanese encephalitis virus transmission season.

The European Medicines Agency (EMA) recommends the JE vaccine for individuals at risk of exposure to the virus, particularly in endemic areas.

Target Population:

• Travelers to regions where Japanese encephalitis is common, especially rural areas in Asia.
• Individuals working in laboratories handling the virus.
• Residents in endemic areas.
• Vaccination is recommended for those staying in endemic areas for an extended period or during outbreaks.

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