IXIARO®: A New Japanese Encephalitis Vaccine
Special Commentary
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
Japanese encephalitis virus (JEV), a flavivirus, is transmitted by rice field-breeding mosquitoes who have fed on wild birds, the natural hosts, and domestic pigs, which serve as amplifying hosts.1 Japanese encephalitis due to JEV is estimated to be the cause of 10,000-15,000 deaths in Asia annually, with significant residual neurological deficits in approximately one-third of survivors. Countries that have had major epidemics in the past, but that have controlled the disease primarily by vaccination include China, Korea, Japan, Taiwan, and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia.2 Travelers visiting endemic areas may be at risk, depending on the season, proximity to rural areas, and outdoor activities pursued. In the United States, an inactivated mouse brain-derived vaccine, JE-VAX®, has been available, but its use was limited, in large part because of associated adverse events, including urticaria, angioedema, and respiratory distress, which often occurred as late as two weeks after vaccination. JE-VAX® is no longer an option since it was recently discontinued and the availability of remaining stocks is severely limited and diminishing. The estimated remaining 4,500 doses of JE-VAX® is being reserved by Sanofi Pasteur for use in younger children. Fortunately, we now have an alternative, at least for adults.
A new inactivated vaccine, IXIARO®, has been demonstrated to have immunogenicity similar to JEVAX®, with a similar overall safety profile and with somewhat improved tolerability at the site of injection. It is adjuvanted with aluminum hydroxide and contains no gelatin or animal proteins (or thimerosal). Grown in Vero cells, administration of this vaccine in clinical trials resulted in protective antibody titers 56 days after vaccination in 99% of subjects with two doses.3 After six months, 95% still had protective levels, but this proportion diminished to 83% after one year.4 In 24 subjects 65 years of age or older, the seroconversion rate was 95.8%. The duration of protection is unknown.
IXIARO® was approved by the FDA on March 30, 2009, for use in individuals 17 years of age and older. The CDC Advisory Committee on Immunization Practices (ACIP) has updated previous recommendations and, importantly, expanded its use to short-term travelers going to non-urban areas with significant outdoor exposure during the transmission season. These do not, however, become official CDC recommendations until they are published in MMWR, and this has not yet occurred. Nonetheless, the ACIP recommendations included the following:
- Travelers to countries where the virus is endemic should be advised of the risks of Japanese encephalitis and the importance of measures to reduce mosquito bites.
- Vaccination is recommended for travelers who plan to spend a month or longer in endemic areas during transmission season.2
- Vaccination should be considered for short-term travelers to endemic areas during transmission season2 if they will travel outside of an urban area and their activities will increase the risk of exposure to the virus.
- Vaccination is not recommended for short-term travelers whose visit will be restricted to urban areas or times outside the transmission season.
- Vaccination with regular follow-up to ensure protection is recommended for laboratory personnel who work with live, wild-type strains of the virus.
IXIARO®, which must stored at 2°-8° C, is administered as two intramuscular doses 28 days apart; the second dose should be received at least one week prior to potential exposure to JEV. Coadministration of hepatitis A vaccine does not affect the immunogenicity of IXIARO®. The most frequently encountered adverse events of vaccination, occurring in > 10% of recipients, are headache, myalgia, and injection site pain and tenderness. While appearing safe in clinical trials, caution must be exerted, since the vaccine was tested in fewer than 5,000 subjects, and unexpected adverse reactions may emerge with wider experience.
Those most susceptible to severe manifestations of JEV infection include children < 10 years of age, and IXIARO® has not been approved by the FDA for individuals < 17 years of age. In child travelers who will be at significant risk of JEV infection, it may be possible to access the remaining doses of JE-VAX® until they are depleted or they become outdated in the spring of 2011. Aggressive measures to prevent mosquito exposure, important for all travelers, will assume greater importance in children .
References
- Duggan ST, Plosker GL. Japanese encephalitis vaccine (inactivated, adsorbed) [IXIARO®]. Drugs. 2009;69:115-122.
- Risk of Japanese encephalitis by country, region, and season. http://www.cdc.gov/ncidod/dvbid/jencephalitis/risk-table.htm
- Tauber, E. et al. Safety and immunogenicity of a Vero-cell derived, inactivated Japanese encephalitis vaccine: a non-inferiority, Phase III, randomized control trial. Lancet. 2007;370[9602]:1847-1853. 1-12, 2007.
- Schuller, E., et al. Long-term immunogenicity of the new Vero cell-derived, inactivated Japanese encephalitis virus vaccine IC51: six and 12 month results of a multicenter follow-up phase 3 study. Vaccine. 2008;26:4382-4386.
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