Japanese Encephalitis Vaccine

Abstract & Commentary

Synopsis: Although Japanese encephalitis rarely occurs in travelers, certain groups and subsets of individuals have a risk of infection that can reach 1 in 5000 travelers per week. It is crucial to recognize those with increased risk, and to seriously consider immunizing them in order to prevent the potentially devastating sequelae of Japanese encephalitis.

Source: Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: Exploring the limits of risk. Clin Infect Dis. 2002;5:183-188.

This excellent review highlights a number of important issues regarding Japanese encephalitis (JE) infection. The CDC estimates the risk of acquiring JE to be < 1 in 1,000,000 travelers visiting endemic areas. However, for travelers spending significant periods of time in risk areas during transmission season, the risk greatly increases from 1 in 5000 to 1 in 20,000 travelers per week. Mortality from the disease is 30-40%, and 50% of survivors will likely have permanent neuropsychiatric sequelae.

JE virus is carried by Culex mosquitoes. The infection rates among mosquitoes found in areas of known hyperendemicity is 3% at most. While symptomatic illness usually occurs in < 1 in 250 persons when bitten by infected mosquitoes, during a study of American service personnel in Korea, 1 in 25 infections did lead to symptomatic illness.

Cases that have occurred in tourists include the following data:

The JE vaccine that is used in travelers is the Biken product, an inactivated mouse brain-derived vaccine. Vaccine efficacy is 91% and 2 doses provide 80% seroconversion rates. Severe neurological reactions have been reported in 1-2.3 per 1,000,000 recipients of the vaccine in Japan. Mucocutaneous reactions occur in approximately 1-17 per 10,000 recipients, and neurological symptoms in 0.1-2.3 per 10,000 recipients in Denmark. One fatality occurred in a vaccine recipient from among more than 10,000,000 recipients in the United States and Japan. The sum of all types of adverse events is estimated at 15 per 100,000 recipients in the United States. Urticaria and angioedema are estimated to occur in 6.3 per 100,000 recipients, also in the United States.

Comment by Lin H. Chen, MD

JE is a mosquito-borne flavivirus infection closely related to the West Nile virus, Saint Louis encephalitis, and Murray Valley encephalitis viruses. More than 10,000 cases of JE occur annually.1 Epidemics occur more frequently in temperate regions of east Asia, but southern and southeast Asia also continue to be endemic regions for this disease. JE is transmitted by Culex mosquitoes, and the risk of being bitten is greatest around rice paddies where the mosquitoes breed. Following an incubation period of 1-2 weeks, a small proportion of infections (1 in 25 to 1 in 1000) become symptomatic.1 Presenting symptoms include fever, headache, and malaise, followed by neurologic signs including seizures, paralyses, paresis, ataxia, cranial nerve defects, and sensory derangements. As pointed out by Shlim and Solomon, about one third of all symptomatic cases are fatal, and half of the remainder develop long-term neurologic sequelae.

Twenty-four cases of travelers and expatriates who acquired JE from 1978-1992 were summarized in Recommendations of the Advisory Committee on Immunization Practices (ACIP) in 1993.2 From these data the CDC derived the overall risk of JE in travelers visiting endemic areas to be < 1 in 1,000,000.

The JE vaccine has been shown to be immunogenic and safe using the 0, 7, 14-day or 0, 7, 30-day schedule,3 but need for booster doses of JE vaccine is not clearly defined. Antibodies following immunization with JE vaccine have been shown to persist for 3 years.4 A booster dose is generally considered after 3 years if the traveler continues to be at risk, although the ACIP recommendations state that boosters may be given after 2 years.2 Since there are no studies to define the need for further booster doses, Shlim and Solomon suggest the options of giving another booster after 3 years or measuring the serum JE neutralizing antibody levels to ensure protection is still present.

Initial reports of adverse reactions to the JE vaccine commonly described urticaria and angioedema, but there were also cases that showed respiratory distress.5,6 Some reactions occurred several days to 2 weeks following immunizations. Two patterns of systemic immediate-type reactions have emerged. One type presents as urticaria and angioedema and is associated with the presence of IgE antibodies directed against gelatin.7 The other type presents with cardiovascular symptoms including hypotension and cyanosis.7 There appears to be a correlation between adverse reactions to the JE vaccine and a predisposition to allergies in the recipient, younger age, and female gender.8

Reported rates of adverse events have been quite variable from country to country. Post-marketing surveillance data noted total adverse events to be 2.8 per 100,000 doses in Japan compared with 15 per 100,000 doses in the United States.9 Systemic hypersensitivity reactions were reported in 0.8 per 100,000 doses in Japan, compared with 6.3 per 100,000 doses in the United States. Serious neurological adverse events were reported in 0.2 per 100,000 doses in Japan, significantly lower than the rates reported from Denmark.

Shlim and Solomon’s succinct statement concerning those populations for whom the travel medicine practitioner might consider the JE vaccine most relevant is as follows: "persons who will be spending time living in a village setting near rice paddies and farm animals during a season of transmission; soldiers who will be on maneuvers in an area of endemicity during the season of risk. . . aid workers, missionaries, students, and researchers whose work will involve spending time in an area of endemicity during the season of risk; bicyclists, backpackers, and other adventure travelers whose itinerary is uncertain but may include significant time in areas of endemicity; expatriates taking up residence in a country in which JE is endemic. . . and travelers who request the vaccine after the risk of JE has been discussed, even if the travel medicine practitioner feels the risk is low."

References

1. Shope RE. Other flavivirus infections. In: Tropical Infectious Diseases. Guerrant RL, Walker DH, Weller PF, eds. Philadelphia, Pa: Churchill Livingstone; 1999: 1275-1279.

2. CDC. Inactivated Japanese encephalitis virus vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 1993;42(RR-1):1-15.

3. Defraites RF, et al. Japanese encephalitis vaccine (inactivated, BIKEN) in US soldiers: Immunogenicity and safety of vaccine administered in two dosing regimens. Am J Trop Med Hyg. 1999;61:288-293.

4. Gambel JM, et al. Japanese encephalitis vaccine: Persistence of antibodies up to 3 years after a 3-dose primary series. J Infect Dis. 1995;171:1074.

5. Andersen MM, Ronne T. Side-effects with Japanese encephalitis vaccine. Lancet. 1991;337:1044.

6. Ruff TA, Eisen D, Fuller A. Adverse reactions to Japanese encephalitis vaccine. Lancet. 1991;338:881-882.

7. Sakaguchi M, Inouye S. Two patterns of systemic immediate-type reactions to Japanese encephalitis vaccines. Vaccine. 1998;16:68-69.

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

9. 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.

Dr. Chen is Clinical Instructor, Harvard Medical School, Director, Travel Resource Center, Mt. Auburn Hospital, Cambridge, Mass.

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