Japanese encephalitis (JE) causes over 15,000 deaths a year of children in southeast Asia. Three vaccines are licensed against the Japanese encephalitis virus. The inactivated mouse-brain derived JE vaccine is available on the international market. Primary hamster kidney (PHK) cell derived inactivated and live attenuated JE vaccines are widely used in China. A comparison between the inactivated mouse-brain derived vaccine and the PHK-derived live attenuated vaccine showed similar immunogenicity (84-100% seroconversion after 3 doses vs. 94-100% seroconversion after 2 doses), efficacy (91% with two doses vs. 97% with two doses), and incidence of minor side effects. The inactivated JE vaccine was associated with rare incidence of severe allergic reactions and neurological complications. The live attenuated vaccine is a better JE vaccine option for countries endemic for JE because of its shorter dosage schedule and low cost.

The use of vaccines and mosquito control has helped lead to a decrease in incidence of JE (Sohn, 2000). Currently, there are three licensed JE vaccines. A formalin-inactivated JE vaccine is used worldwide. The Research Institute of Microbial Diseases (Biken) at Osaka University in Japan is one of the main manufacturers of this vaccine. Although the vaccine has been licensed in Japan since 1954, the vaccine was just licensed in the US in 1992 (ACIP, 1993). This mouse brain derived vaccine is prepared using the Nakayama-NIH strain (other manufacturers use the Beijing-1 strain). The inactivated vaccine is the only JE vaccine available on the international market. Two other JE vaccines are licensed in China. An inactivated JE vaccine derived from primary hamster kidney (PHK) cells is often used. In the past ten years, a live, attenuated vaccine derived from PHK cells and produced from the SA14-14-2 viral strain has begun to replace the inactivated vaccine because of its low cost (Hennessy et al., 1996). This vaccine, licensed in 1988 in China, has been distributed to over 100 million children (Tsai, 1994).

Dosage schedules differ for endemic and non-endemic regions. Children in endemic areas may need fewer doses because of previous immunity or subsequent exposures to flaviviruses that boost antibody levels (ACIP, 1993). In endemic areas, the inactivated Biken vaccine is administered subcutaneously in two 0.5-mL doses one to four weeks apart. Primary vaccination varies from the age of 18 months in Thailand to 3 years in Japan. Boosters often are given one year after primary vaccination and at intervals of 3 years thereafter (Tsai, 1994). In non-endemic regions, the Advisory Committee on Immunization Practices (ACIP) recommends a three-dose regimen on days 0, 7, and 30 with a booster given at one year and every three years thereafter (ACIP, 1993). A recent study of US soldiers found that a three-dose regimen on days 0,7, and 14 was also sufficiently immunogenic (Defraites et al., 1999). Normal administration in China consists of a 0.5-mL dose at years 1 and 2. A final booster is given in year six (Hennessy et al., 1996).

Japanese encephalitis immunogenicity studies define protection and seroconversion as neutralizing antibody titers greater or equal to 1:10 (Tsai, 1994). Inactivated JE vaccine showed high seroconversion rates after 2 doses in endemic areas and after 3 doses in non-endemic areas. Live attenuated vaccine showed high seroconversion rates after 1 or 2 doses in endemic areas.

Several other studies of US and British military populations and US inhabitants show that seroconversion is much higher after 3 doses than after 2 doses. One study of 1152 subjects in Nepal, tested 75 subjects for immune response. Of the 47 seronegative subjects given 3 doses, 42 (89%) seroconverted. Of the 14 seronegative subjects given 2 doses, 5 seroconverted (35%). Although this is a distinct difference (the study did not give statistical analysis), the study groups consisted of different populations. The 3-dose study group consisted of American soldiers and Gurkha soldiers while the 2-dose study group consisted of Nepalese male civilians (Henderson, 1984). The demographics were not given, so the groups could be significantly different. Other confounds or small sample size could also explain the difference.

Several small Chinese studies have shown 85% to 100% seroconversion after one dose. After 12 months only 31% remained seroconverted (Tsai, 1994). A Korean study of 68 seronegative children ages one to three years showed high short-term seroconversion rates (96%) at four weeks after one dose of the vaccine. Sixteen seropositive children also showed significant increases in geometric mean titer (GMT) (Sohn et al., 1999). Long term follow-up and a non-vaccinated control would have strengthened the study.

Both vaccines have been found to have 90 to 97% efficacy rates.

In 1965, initial studies in Taiwan showed that two doses had 80% efficacy in protecting patients the first year after vaccination (Tsai, 1994). A placebo-controlled, blinded, randomized study performed in Thailand from November 1984 to December 1986 showed 91% efficacy (95% CI – 70 to 97 percent) for 2 doses of vaccine. The researchers split 65,224 children ages 1 to 14 years into a monovalent (Nakayama strain) JE vaccine group, a bivalent (Nakayama and Beijing-1 strains), and a placebo (tetanus toxoid) group. They administered two doses at a seven-day interval. Eleven cases of JE occurred in the placebo group (n=21,516, 51 per 100,000) and one case of JE occurred in each of the vaccine groups (n=21,628, n=22,080, 5 per 100,000 for each) (Hoke et al., 1988). The strengths of this study include a placebo control, two years of observation, and huge sample size. The researchers took special measures to find mild or not hospitalized cases by conducting a post study census and serological testing follow-up. But there should have been a general population control to see what the baseline JE rate was without intervention.

Trials in Chinese children with a two dose administration a year apart yielded protection rates from 98 to 100 percent with high confidence intervals (Tsai, 1994). A retrospective study was done on all cases of encephalitis from 1993 in Sichuan Province, China. 1299 matched controls of similar age (mean age: 4.7 years) were found from the villages of the 56 cases. The researchers obtained vaccine histories and compared the two groups. Of the 56 cases, 38 had no previous vaccination, 11 had one dose vaccination, 6 had two dose vaccination, and 1 had three dose vaccination. Administration of one dose was found to have an 80% efficacy (95% CI – 44 to 93%) and administration of two doses were found to have an efficacy of 97.5% (95% CI – 86 to 99.6%) (Hennessy et al., 1996). This study depended on unreliable vaccine histories and did not mention when the vaccinations were given. Time since last vaccination would be very important in determining the effectiveness of the vaccine. Ideally, the researchers would have done a prospective study with appropriate controls, but the ethical obligations of treatment make this impossible. One solution is to maintain surveillance of a large population and compare the JE incidence rate with traditional incidence rates.

Severe allergic reactions and neurological complications have been associated with the inactivated vaccine. Both the inactivated and live attenuated vaccine are associated with mild symptoms.

Since 1989, several reports of adverse reactions associated with JE vaccination have emerged in Australia, Canada, and Denmark (Nazareth et al., 1994). A letter to the editor in the October 5, 1991 The Lancet describes three cases of severe adverse events following JE vaccination in Australia. Severe rashes and swelling occurred within three days of the second dose of vaccination. No other medications or vaccinations were given at the same time. The vaccines came from the same batch. Twenty-seven other mild adverse events were reported in 1990 and 1991. Because there is no active surveillance in Australia, the actual numbers may be higher than reported (Ruff et al., 1991). Another report from Denmark describes the increase in incidence of urticaria, angioedema, and other allergic reactions after the first reported incidence in 1989. High rates of adverse reactions were associated with specific batches (up to 15 per 10,000 vaccinations). 1992 and 1993 were the worst years. Sixty-seven percent of reactions required medical treatment (Plesner and Ronne, 1997). Both of these surveillance studies were very thorough in considering other factors. A general population control would have been useful, but the generally rare incidence of urticaria supported the association with vaccination. In addition, allergic reactions were associated with vaccination in three separate countries. A group in the UK reported no genuine systemic adverse reactions after interviewing respondents to a retrospective questionnaire. The researchers concluded that, "JE vaccines are not associated with a significant risk of systemic allergic reactions" (Nazareth et al., 1994). However, both the interview and questionnaire depended on recall data. Only 21% of questionnaire recipients responded. The study might have missed adverse events through their methodology.

Although minor symptoms have been reported in association with administration of the live attenuated vaccine, no serious complications have been reported in the administration of over one hundred million doses (Tsai, 1994). A study of 26,239 subjects in Chengdu, China determined the short-term safety of the vaccine. During normal vaccinations in 1995, 13,275 children received the vaccine and 12,964 children did not receive the vaccine. The patients that did not get vaccinated received the vaccine after a one-month observation period. Events as rare as 3 in 10,000 could be detected. No difference was found in incidence of adverse events between the two groups. There were no cases of encephalitis, meningitis, or anaphylaxis. 266 vaccinated subjects were observed on days 1,2,3, and 7 after vaccination. Fever occurred in 13 subjects. No other severe adverse events were observed (Liu et al., 1997). The enormous sample size and existence of a control strengthened this study. But the study period is very short. There is no evidence of long-term safety. In addition, the study is limited to children in an endemic area. Many reported severe adverse effects with inactivated JE vaccination occurred in adults in non-endemic areas.

The study of over 65,000 children in Thailand was one of the most thorough studies on the protective efficacy of the inactivated JE vaccine. The placebo control was key in the convincing power of study. Unfortunately, giving placebo to over 21,000 children with the availability of a widely used vaccine deprived the children of the standard of care. Japan had used the vaccine for over twenty years. It had been licensed in Denmark since 1983. With vaccination, eleven children could have been protected from life-endangering encephalitis. One of the children died and most of the others had severe neurological damage upon examination two or three years later (Hoke et al., 1988). The researchers had a responsibility to vaccinate those children.

The live attenuated vaccine has comparable immunogenicity and protective efficacy to the inactivated vaccine. Its shorter dosage schedule and low production cost ($0.02/dose-$0.03/dose) (Hennessy et al., 1996) make it a desirable option for endemic countries in southeast Asia . The price of the inactivated vaccine is almost $5/dose in Asia compared to $0.75/dose for the live attenuated vaccine (Liu et al., 1997). The next step is to license the live attenuated vaccine in countries outside of China. The vaccine could first be implemented in those countries with endemic JE who could otherwise not afford an extensive JE vaccination program. Long-term studies on efficacy, immunogenicity, and severe adverse effects in non-endemic populations would make it a more convincing option for travelers. In 1998, three doses of JE vaccine cost $192 in the US (web page: ESR, 1998). A cheaper vaccine would be attractive to frequent travelers. Further studies on long-term immunogenic protection would help determine ideal booster schedules. Although careful surveillance can be difficult, it must be maintained to determine the continued safety of each of these vaccines.