Japanese B Encephalitis Vaccination

abstract & commentary

Synopsis: Hypersensitivity reactions after vaccination in the United States with Japanese B encephalitis vaccine were reported, in a passive surveillance system, with an incidence of 6.3 per 100,000 doses.

Source: Takahashi H, et al. Adverse events after Japanese encephalitis vaccination: Review of post-marketing surveillance data from Japan and the United States. Vaccine 2000; 18:2963-2969.

All reports of adverse events possibly due to administration of Japanese B encephalitis vaccine (JEV) in the United States between its licensure in December 1992 and the end of 1998 received by the Vaccine Adverse Event Reporting System (VAERS) were analyzed.

More than 813,000 doses of vaccine were administered during the period analyzed and 122 adverse event reports were received by VAERS. Vaccine from at least 42 different lots were received by the recipients who were the subjects of reporting, whose mean age was 42 years (range, 2-64 years). The symptoms most commonly reported, and accounting for 69% of patients, were headache, pruritus, rash, fever, nausea, urticaria, vasodilatation, and dizziness.

One recipient developed Guillain-Barré syndrome 17 days after JEV and five weeks after a dose of rabies vaccine—as well as one week after an episode of gastroenteritis; recovery was complete. A 22-month-old child had a febrile seizure three days after receiving twice the recommended dose of JEV. These were the only two possibly related neurologic adverse events, resulting in a total incidence of 0.2 per 100,000 doses.

Angioedema and/or urticaria occurred in 51 (42%) subjects (6.3/100,000 doses) with onset by the third day after vaccination in 51%. Among 52 patients for whom a detailed history was available, systemic urticaria and/or angioedema developed after the first dose in 23 (55%). One-half required an emergency room visit and six were hospitalized.

A similar analysis of reports to Japan’s National Adverse Reaction Reporting System (NARRS) related to vaccine administered from April 1996, through October 1998, was performed. The frequency of systemic hypersensitivity reactions was only 0.8 per 100,000 doses.

Comment by Stan Deresinski, MD, FACP

Japanese B encephalitis (JE) is an important arboviral infection acquired in rural areas, particularly rice and pig farming areas of Asia and Oceania where approximately 50,000 recognized cases are reported annually. Transmission, which is caused by the bite of Culex mosquitoes, is seasonal in most endemic areas. While only 0.1-5% of infections are clinically apparent, these have an associated mortality of 5-30% with approximately one-third of survivors suffering serious neurological sequelae.

The Biken vaccine, an inactivated product derived from mouse brain infected with the Nakayama-NIH strain of JE virus, was licensed for use in the United States in December 1992, and is the only JEV in use in this country. Shortly after its introduction, a pattern of adverse reactions consisting of urticaria and angioedema, not previously noted to be prevalent in Asian vaccinees, was detected in U.S. and Australian travelers to endemic areas. Furthermore, these reactions may be delayed for as long as two weeks after a JEV dose.

The lower rate of reactions noted in Japan may be due to several factors. Both used passive surveillance systems, but Japan’s NARRS accepts only events meeting predefined criteria while the U.S.’s VAERS accepts all reports and the vaccine differs in some components from that used in the United States.

A case-control study performed in Danes found that the main risk factors for such reactions were young age, female gender, and previous allergic skin reactions or hayfever.1 In a study of U.S. Marines, a history of urticaria or allergic rhinitis was associated with an increased probability of a vaccine reaction.

The nature of the reactogenic antigen in the vaccine is unclear. In addition to inactivated virus, the Biken vaccine contains gelatin and thiomerosal, but no detectable (< 2 ng/mL) myelin basic protein. Some studies have reported the presence of anti-gelatin IgE in the serum of vaccinees with acute hypersensitivity reactions.2

A study of JE vaccination of U.S. Marine personnel found a reaction rate of 10.3 per 10,000 doses, an incidence that is an order of magnitude greater than that reported by Takahasi and colleagues using a passive surveillance system.3 The frequency of reactions has been taken into account in the recommendations of the U.S. Public Health Service for its use in travelers. All travelers to endemic areas should, of course, take steps to avoid mosquito bites, such as the use of bed nets, insect repellents, and protective clothing, and the avoidance of outdoor activity, especially during twilight periods and in the evening. JE vaccination is recommended for individuals planning to spend at least one month in an endemic area (especially rural) during transmission season. The estimated risk of infection for residents of endemic rural areas is one per 20,000 per week, suggesting that a traveler spending a month in an endemic area may have a risk of one in 5000.

The increased risk of an adverse reaction in individuals with a history of urticaria must be taken into consideration in a decision to vaccinate. It is contraindicated in individuals with a prior history of reaction to JEV or those with hypersensitivity to neural or rodent proteins or to thiomerosal. Pregnant women should be vaccinated only when it is estimated that the risk of immunization is less than the risk of infection with JE virus.

Three doses are given subcutaneously: 1.0 mL each on days 0, 7, and 30. In circumstances in which less time is available, it may be administered on days 0, 7, and 14, although this is somewhat less efficacious (80% protection) than the longer schedule. In either case, the last dose should be given at least 10 days prior to the start of travel in order to assure the development of adequate immunity and to monitor for delayed adverse reactions. Vaccine recipients should be observed for 30 minutes after vaccine receipt. Children 1-3 years of age receive 0.5 mL on the same schedule; there are no data on safety and efficacy in younger infants. Booster doses may be administered after two years.


1. Plesner A, Ronne T, Wachmann H. Case-control study of allergic reactions to Japanese encephalitis vaccine. Vaccine 2000;18:1830-1836.

2. Sakaguchi M, et al. Systemic immediate-type reactions to gelatin included in Japanese encephalitis vaccines. Vaccine 1997;15:121-122.

3. Berg SW, et al. Systemic reactions in U.S. Marine Corps personnel who received Japanese encephalitis vaccine. Clin Infect Dis 1997;24:265-266.