Japanese encephalitis vaccine

General information

Japanese encephalitis is an important arboviral disease in man in Japan, China, Korea, Thailand, India, Nepal, Sri Lanka, and Vietnam. In 1954, Japanese encephalitis vaccine of the mouse brain type for human use was licensed in Japan. However, there was strong criticism of mouse brain vaccine, and in 1965 the Nippon Institute of Biological Products and the Biken Foundation implemented more advanced purification procedures, such as alcohol precipitation and ultracentrifugation.

Three types of Japanese encephalitis vaccine are currently produced:

• 1.

  mouse brain-derived inactivated vaccine, commercially available;

• 2.

  cell culture-derived inactivated vaccine;

• 3.

  cell culture-derived attenuated vaccine, produced and used exclusively in China.

The Chinese cell culture-derived inactivated vaccine is produced in primary hamster kidney cells; a highly purified Vero cell culture-derived inactivated vaccine is under clinical development in France. A Chinese live-attenuated vaccine is also produced in primary hamster kidney cells. The efficacy of one dose is 80%, and the efficacy of two doses, given 1 year apart, is 97.5%; this vaccine was evaluated in a randomized trial in 26 239 children, half of whom received the vaccine and half served as controls, and its adverse effects have been reviewed [ ].

Japanese encephalitis vaccine has been reviewed [ , ].

In 1965, a special surveillance team was formed by the Japanese Ministry of Health and Welfare to investigate adverse events following the administration of Japanese encephalitis vaccine. No severe adverse event was reported among 21 396 vaccinees of whom 18 401 were adolescents. Some mild reactions (fever, malaise, abdominal symptoms) were noted in 1.2% of the vaccinees. Using a countrywide hospital network, the surveillance team studied any severe neurological disease occurring within 1 month after receipt of the vaccine. During 1957–66, 26 cases (nine cases of meningitis, ten cases of convulsions, five cases of polyneuropathy, and two cases of demyelinization) were analysed. No evidence was provided showing a causative relation between these clinical syndromes and Japanese encephalitis immunization. The incidence of neurological disease was considered minor compared with the millions of doses distributed annually in Japan [ ].

With the exception of China, where a live attenuated vaccine is used, all countries practising immunization against Japanese encephalitis use formalin-inactivated mouse brain vaccines. Injection site reactions were reported in about 20%, and systemic adverse reactions (fever, headache, malaise, rashes, chills, myalgia, gastrointestinal symptoms) in 5–10% of vaccinees. More serious adverse events fall into two categories: allergic and neurological. Hypersensitivity reactions (urticaria, angioedema, and bronchospasm) are reported at an incidence of 0.2–0.6 per 1000 vaccinees. Most patients respond well to anti-allergic treatment. Anaphylaxis can be life-threatening, and at least three deaths have been attributed to the vaccine.

Since 1989, urticaria and/or angioedema of the extremities, face, and oropharynx, and respiratory distress have been reported from Europe, North America, and Australia as a new pattern of adverse effects. Collapse due to hypotension has required hospitalization in several cases, and erythema multiforme and erythema nodosum have also occurred; the reported rates of such adverse effects varied markedly in different countries (respective ranges 0.7–12 per 10 000 and 50–104 per 10 000). The vaccine constituents responsible for the adverse reactions have not yet been identified.

Comprehensive data on the epidemiological and virological situation in southeast Asia and Australia, control measures, vaccine production capacities, and different vaccines against Japanese encephalitis were provided in a supplementary volume of the journal Vaccine dealing with results presented at a WHO meeting held in Bangkok in 1998 [ ]. Adverse events after the use of inactivated mouse brain vaccine (the only vaccine that is currently licensed for international use) have been reviewed in detail [ ].

The Global Advisory Committee on Vaccine Safety (GACVS) has considered a report from an Indian expert panel that assessed cases of serious adverse events after immunization campaigns (including about 9.3 million children aged 1–15 years) with the live attenuated SA-14-14-2 Japanese encephalitis vaccine [ ]. A total of 65 serious adverse events were reported, 22 of which were fatal. Most of the serious adverse events were considered to be unrelated to the vaccine. Two clusters of encephalitis-like syndromes were detected; the cases in one cluster probably represented cases of natural Japanese encephalitis, and the cases in the second cluster were classified as acute encephalopathy syndrome of unknown cause. A thorough investigation into possible alternative causes was not conducted. The committee concluded that the type of clustering of encephalopathy/encephalitis cases made it unlikely that they had been related to the vaccine. The committee recommended that future immunization campaigns should be accompanied by better adverse event monitoring and investigations.

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