Allergic reactions to Japanese encephalitis vaccine

Anne-Marie Plesner
Immunology and Allergy Clinics of North America 2003, 23 (4): 665-97
The JEV widely is used in Asian countries each year and is an important vaccine for travelers to the East from other parts of the world. JE virus is a zoonotic disease with natural reservoirs and cannot be eliminated. Although a declining incidence of JE has been observed in Asia because of reduced transmission by agricultural approaches and vaccination, the most important control measure now, and in the future, is vaccination of humans against JE. The inactivated vaccine, produced from infected mouse-brain-derived tissue, is the only commercially available vaccine. There are several concerns with the use of this vaccine. It is expensive, requires two or three doses to achieve protective efficacy, and, in practice, requires further booster doses to maintain immunity. The apparent increase in allergic reactions in the first part of the 1990s has set focus on the safety of the JEV. A cheap, live attenuated SA 14-14-2 vaccine is used almost exclusively in China and parts of Korea, but there have been no trials of SA 14-14-2 vaccine outside JE endemic countries. The vaccine seems to be highly efficient, and few adverse events have been observed; however, PHK cells are used for the production of this vaccine, and these cells are not approved by the WHO. A satisfactory cell substrate is needed. A committee under the WHO has proposed that for the live JEV, there should be validity of the assays for retrovirus when applied to PHK cell substrate and validity of the mouse assays for neurovirulence. Further information should be reviewed on the long-term follow-up of recipients of the vaccine. Several new types of vaccines have reached the phase of clinical trials; however, studies remain to be completed. Until a new vaccine is available, the priority of surveillance of adverse events and the continuous reporting of such events to the users of the vaccines must be of importance. This fact is highlighted by the possibility of the varying frequency of adverse events with different batches over the years. The WHO offers information and recommendations for vaccines in the EPI and issues a series of updated papers on other vaccines that are of international public health importance (eg, JEV). The development of alternative efficient, safe, and appropriately priced JEVs is recommended, as is intensified surveillance of adverse events. Prospective vaccine studies of safety may be limited because of sample size and because rare adverse events may not be detected. Several new initiatives have been taken to improve surveillance of adverse events to vaccines within the past 10 years. In Japan, there is an increasing awareness of the importance of efforts taken to improve vaccine safety, and surveillance of adverse events and possibilities of compensation for vaccine-related injuries are in place. In Vietnam, a database to detect adverse events after vaccination has been established; the project involves active visits to data collectors at the vaccination sites. Comparative studies of adverse events, such as one recent study from Japan and the United States, are important for the evaluation of the reporting systems. The reporting rate for JEV adverse events from Japan was approximately one order of magnitude lower than that in the United States. Japan had strict predefined reporting criteria and time limits for observations. If time limits for the observation are too strict (eg, defining a possible neurologic reaction to occur within 1 week after vaccination), later reactions will not be included (eg, if ADEM is elicited by a vaccine, the symptoms cannot be expected to occur until weeks after the vaccination). The passive surveillance systems have limitations with an underreporting of adverse events, depending on clinical seriousness, temporal proximity to vaccination, awareness of healthcare workers, and tradition of reporting particular events. In developed countries, surveillance of adverse events is formalized, although not necessarily optimal. An increase in reporting would be expected when the reporting of adverse events is mandatory. Reports have been sent to VAERS, the Vaccine Safety Datalink Project, and the European Union Pharmacovigilance System. A Brighton collaboration has been implemented to enhance comparability of vaccine safety data. Public health authorities in specific countries, such as the CDC in the United States and the National Advisory Committee in Canada, regularly have published information on the JE situation in Asia and the preventive measures to be taken, including information on the vaccines and adverse reactions. The conventional recommendation is that travelers should be vaccinated if they will spend more than 1 month in a JE endemic area or in areas with epidemic transmission with even shorter periods. Although the risk for JE for short-term travelers is considered small (1 case per 1 million travelers per year), sporadic cases, including deaths, have been reported among tourists traveling to endemic areas. Risk for travelers in rural districts in the season of risk is considerably higher (range, 1 case per 5000 travelers to 1 case per 20,000 travelers per week). Doctors who advise travelers should be updated on the latest JE occurrences in Asia. Updates on the JE situation can be found on bulletins at or are available from the WHO or CDC. The allergic reactions primarily described after vaccination with the inactivated mouse-brain-derived JEV have been observed in several countries during the 1900s. Allergic reactions, including the mucocutaneous and neurologic reactions reported after JE vaccination, may vary in frequency, and these reactions should be evaluated meticulously yearly. This step enables recommendations, including information on possible side effects, to be given in an optimal way.

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