Japanese Encephalitis: Defining the Risks and New Vaccine Options
Abstract & Commentary
By Mary-Louise Scully, MD
Dr. Scully is Director, Travel and Tropical Medicine Center, Sansum Clinic, Santa Barbara, CA.
Dr. Scully reports no financial relationships relevant to this field of study.
Synopsis: Assessment of Japanese Encephalitis risk in travelers remains a challenge for travel medicine providers, but the availability of a new vaccine and recent relevant publications may help to improve our ability to more clearly define and avert this risk.
Sources: Hatz C, Werlein J, Mutsch M, et al. Japanese encephalitis: Defining risk incidence for travelers to endemic countries and vaccine prescribing from the UK and Switzerland. J Travel Med 2009;16:200-203. Buhl MR, Lindquist L. Japanese encephalitis in travelers: Review of cases and seasonal risk. J Travel Med 2009;16:217-219.
Hatz and colleagues estimated risk of Japanese encephalitis (JE) in travelers using data on United Kingdom and Swiss travelers to JE risk areas, and the respective JE vaccine usage in these countries for the year 2004. Only an estimated 0.16% to 0.3% of U.K. and Swiss travelers to such areas were vaccinated against JE, indicating that more than 99% traveled to JE risk areas without vaccination. Despite this, there were no surveillance reports of JE cases. Overall, only 40 cases of JE infection (soldiers and relatives of expatriates excluded) have been reported in travelers during the past 30 years. This results in a JE risk incidence of 1.3 per year in 7.1 million European travelers of the 17 million European travelers who are at a potential risk of JE infection.
Buhl and Lindquist reviewed the details of 21 of the 40 JE cases reported in travelers between 1978 and 2008. These 21 cases occurred between 1992-2008, and of these 21 cases, at least half were among short-term travelers. Thirteen of the 21 cases were either fatal or associated with permanent neurologic sequelae. Three of the cases were actually in short-term travelers such as a "typical tourist" visit to Bali, including a 51-year-old male who died of JE infection after only a 12-day trip to Bali. Also, 6 of the 21 cases were infected in southern Thailand, and 4 of these cases were in December, i.e., outside the rainy season. In analyzing their data, these authors estimate the risk for JE among Nordic travelers to Thailand to be at least in the order of 1 in 400,000 travelers.
Commentary
These papers attest to the complexity of defining a traveler's risk of JE infection — a disease that clearly occurs infrequently in travelers, yet with sometimes devastating and even fatal results. JE is the leading cause of viral encephalitis in Asia, with 30,000-50,000 cases reported annually. It is estimated that of all individuals infected, around 1% will develop clinical disease, of whom one-third will die, and one-third will develop permanent neurological sequelae. Japanese encephalitis virus often is transmitted by Culex mosquitoes, and Culex tritaeniorhyncus is the principal vector in most of Asia. This mosquito feeds at night, mainly outdoors, and in rural areas, especially rice-irrigated areas, but also on the outskirts of urban areas.
More than a decade ago, the Centers for Disease Control and Prevention (CDC) reviewed cases of JE among expatriates and travelers between 1978-1992.1 In total, there were 24 cases, of which 16 cases were travelers (i.e., excluding soldiers or relatives of expatriates). The CDC concluded that the overall risk of JE for travelers to areas of JE risk was less than 1 case per 1,000,000 travelers. However, if travel was to a rural area during the season of JE risk, the risk rose to an estimated range of 1 case per 5000 to 1 case per 20,000 per week. The relatively rare occurrence of JE in travelers coupled with the potential adverse events after the mouse brain-derived JE vaccine resulted in the CDC recommendation for JE vaccine to be given to travelers who would be staying more than 30 days in a JE risk area during a transmission season or for shorter-term travelers whose itineraries might put them at increased risk of exposure.
For many years, the only vaccine available for travelers from Europe and the Western hemisphere was a mouse brain-derived, inactivated vaccine, given on a schedule of days 0, 7, and 30. Although the vaccine had been administered to millions of resident Asians before being given to travelers, in the first years of use in travel clinics, a new pattern of adverse events was reported such as urticaria, angioedema, and respiratory distress. It was postulated that these reactions might be related to small amounts of gelatin that were used as a stabilizer in the vaccine. An additional concern to travel practioners was that these reactions could appear as delayed events after vaccination. Therefore, it was advised that if possible the vaccine series should be completed 10 days before departure in case of a delayed adverse effect.
In 2006, the manufacturer discontinued production of the mouse brain-derived vaccine, although remaining stockpiles are still available for use in children. In March 2009, a new Vero-cell-derived, inactivated JE virus SA14-14-2 vaccine was approved in the United States and likely also will be approved for use in the European Union as well. The new vaccine, licensed under the brand name IXIARO®, is formulated without gelatin, animal proteins, or thimerosal. The new vaccine has the advantage of requiring just two doses, versus three for the older vaccine. In a randomized controlled industry-sponsored study, two 0.5 mL intramuscular doses (day 0, 28) of the new inactivated vaccine were found to be non-inferior to three doses of mouse-derived vaccine with respect to proportion of patients achieving a protective level of neutralizing antibody.2 Common adverse events were similar in both groups and included headache, myalgias, influenza-like illness, and fatigue. However, the new vaccine did have fewer local side effects at the injection site (pain, hardening, swelling, and redness) than the mouse-derived vaccine (about 2% vs 14%, respectively). Of note, none of the 400+ patients in either group had any hypersensitivity reactions such as angioedema or difficulty breathing. Since the number of recipients of the new vaccine to date is relatively limited (fewer than 5000 subjects), post marketing data for both adverse events and efficacy will be very important.
The duration of neutralizing antibody of the new Vero-cell-derived vaccine has been documented out to a year (95% seroconversion rate at 6 months and 83% seroconversion rate at 12 months), but as of yet there is no recommendation for timing of booster doses.3 The new vaccine is licensed in the United States for ages 17 and older, and Phase III studies in children are in progress. Unfortunately, the cost to even purchase the vaccine is very high ($195.00 per dose!), likely placing the vaccine out of reach for use in many travelers on a tight budget, especially those who might stand to benefit most — students, aid workers, volunteers, and those returning home to visit friends and relatives (VFRs). Another JE vaccine, a single-dose, live, attenuated vaccine (ChimeriVax-JE) also is under development for travelers and those living in endemic areas, especially children. Phase III trials in children in the Philippines and Thailand are in progress.
In an earlier publication, Shlim and Solomen also addressed the difficult issue of risk assessment for JE by trying to determine sub-groups of travelers at greatest risk based on their specific travel and work plans while in an endemic area;4 for example, persons spending time in rural areas, especially near rice paddies and farm animals, aid workers, missionaries, students, researchers, adventure travelers, and expatriates planning on living in a JE-endemic country. Yet the more recent case reports show that JE cases can occur, albeit rarely, on short-term visits to risk areas, even outside classical transmission seasons, and in areas considered more typical "tourist" destinations (i.e., southern Thailand and Bali). A recent report published by the CDC in July 2009 describes three more previously unpublished cases of JE in U.S. travelers.5 All were Asian immigrants or family members who traveled to live or visit friends or relatives (VFRs). This might suggest VFRs traveling back to Asian countries are another high-risk group to target for JE prevention.
The new ACIP provisional guidelines for JE vaccination now will include the consideration of JE vaccination for short-term travelers to endemic areas during transmission season if travel is outside of an urban area and the activities of the travelers will increase their risk of exposure to JE.6 It also includes consideration for vaccination in travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel as well as travelers to an area with an ongoing JE outbreak.
All travelers to Asia should be made aware of the risk of JE and counseled in the appropriate use of personal protection measures against mosquito bites. The use of bed nets, insect repellents, and protective clothing and avoidance of high-risk exposure times should be stressed. As the geographic areas of other vector-borne diseases such as malaria often overlap with JE risk areas, this discussion of personal protection measures is important during all pre-travel visits.
For persons living in endemic areas and travelers to those areas, the development of new JE vaccines is indeed welcome. Clearly, there is no easy formula to apply in the case of JE risk and, therefore, our role as travel medicine providers is to perform individual risk assessment. In the end, when we are considering JE risk (or yellow fever, rabies, or measles, for that matter), there is no substitute for a one-on-one discussion with each traveler to assess his or her personal risk of acquiring a given disease versus the potential of an adverse event from vaccination.
References
- Centers for Disease Control and Prevention. Inactivated Japanese encephalitis virus vaccine: Recommendations of the advisory committee on immunization practices (ACIP). MMWR 1993;42(RR-1):6.
- Tauber E, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: A non-inferiority, phase III, randomized controlled trial. Lancet 2007;370:1847-53.
- 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.
- Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: Exploring the limits of risk. Clin Infect Dis 2002;35:183-188.
- Centers for Disease Control and Prevention. Japanese encephalitis among three U.S. travelers returning from Asia, 2003-2008. MMWR 2009;58(27):737-740.
- ACIP Provisional Recommendations for the Use of Japanese Encephalitis Vaccine http://www.cdc.gov/vaccines Accessed 9/11/2009.
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