Background
Japanese Encephalitis (JE) program concerns a vector-borne disease of particular concern in Asia. IVI has received support from the Bill and Melinda Gates Children¡¯s Vaccine Program at PATH for a multi-country, multi-disciplinary program addressing JE and JE vaccines.

JE is a mosquito-borne flaviviral disease and is endemic to large areas of Asia. Despite the availability of JE vaccines, JE remains a major health problem, particularly among children in whom JE is associated with a high case-fatality rate (range: 10 - 30 percent) and permanent neurologic sequelae. Approximately 3 billion people (60 percent of the world¡¯s population) live in JE-endemic regions. From this region, national surveillance systems reported 25,000-50,000 JE cases annually. When JE encephalitis occurs, the clinical signs and symptoms are typically severe, with a 10 ? 30 percent fatality rate. Long-term post-JE illness-associated disability may be the most important component of JE disease burden. Studies of post-JE illness-associated disability based on short-term follow-up of case-patients have demonstrated neurologic sequelae in 25 - 75 percent of survivors following acute episodes of JE. However, because of poor quality surveillance, such numbers likely underestimate the true burden of disease. In many Asian countries, the disease burden due to JE remains unclear.

Several JE vaccines are now available and used in Asian countries (Table 1).

    Table 1: Summary of JE Vaccines currently available or in development.

JE virus vaccine is provided as part of the routine childhood immunization programs in China, Japan, Korea, and Thailand. However, for other countries in the endemic region, the vaccine is used on a limited basis in part because of vaccine cost, and a lack of knowledge regarding the severe morbidity and economic impact associated with JE illness and post-JE illness-associated disability. Additional concerns have also arisen regarding the safety and adverse events following immunization with the inactivated, mouse-brain derived vaccines, although such adverse events have not been systematically documented.

Goals
The goal of the JE program is to accelerate the development and introduction of existing and new JE vaccines to assist in preventing this devastating disease in JE-endemic countries. The immediate goal is to facilitate and evaluate the integration of existing JE vaccines into public health programs of JE-endemic countries. The program focuses in India, Indonesia, Thailand and Vietnam.

Projects
Prospective, active surveillance for Japanese encephalitis
For prospective, hospital-based surveillance, the program is underway in two field sites in India and Indonesia, where epidemics of JE have been reported but where routine JE immunization is absent. In India, several JE outbreaks have been reported but the total disease burden is not known. In Indonesia, JE incidence rates are unclear despite the presence of anti-JE serum antibodies in 90 - 100 percent of the swine. Neither India nor Indonesia has plans to launch JE immunization programs. The IVI program results, by documenting the magnitude of JE disease burden in certain areas that on do not routinely report JE disease, may have significant impact on policy decision-making regarding JE immunization in Asia.

Assessment of post-JE illness-associated disability
Comparative observations in a control group are essential to evaluate the proportion of cases with psychomotor retardation, fine motor deficits, and behavioral disorders. Thus, a controlled cohort design method is being employed. This project is conducted in Shanghai, China where infections with non-JE flaviviruses have not been observed and where the diagnostic specificity of routine immunodiagnostic tests for JE is high. JE cases previously diagnosed from 1973 through 1994 are being assembled from the Children¡¯s Hospital and the Pediatric Hospital of Shanghai. All subjects are examined by a neurologist with a battery of standardized neurobiological tests.

Cost-effectiveness analysis of JE immunization programs
There are few pharmacoeconomic studies of JE vaccine, and thus governments of JE-endemic countries have given little consideration to the economics of immunization when making public health decisions about control of JE. The JE Program is conducting cost-effectiveness analyses to guide the introduction of JE vaccine into the routine immunization programs of JE-endemic countries.

For cost-effectiveness analyses, the Program uses routinely available data as well as data on JE disease burden, disability, treatment costs, and vaccine protection collected in other components of the Program.

The cost-effectiveness analyses focus on current national JE immunization programs in China, Thailand, and Vietnam. These analyses take into account the costs of JE immunization, treatment savings for care of JE patients and post-JE sequelae, work time lost, and person-years lost following death.

Assessment of JE immunization policy
Finally, the JE Program is evaluating JE immunization policies. This portion of the program seeks to determine reasons for lack of a national JE vaccine program in a JE-endemic country - India. This project will also describe the actual use of JE vaccines in countries with such programs (China, Thailand and Vietnam). Data, published and unpublished, are being gathered for this component of the program. The methodology also consists of face-to-face interviews, focus group discussions, and reviews of documents. Face-to-face interviews are held with government immunization program managers, experts in JE and other infectious diseases, faculty of schools of public health, donor agency and international agency staff, and others, as appropriate. Focus group discussions examine current thinking about JE immunization programs and their likely trends, receptivity to new vaccines, and the possible special difficulties to be faced in obtaining regulatory approval for new vaccines. The documents to be collected include official policy statements, ministry of health background discussion papers, and academic papers, both published and unpublished. Several face-to-face interviews will be held with management of vaccine producers and suppliers. The interviews and discussions will generate information about perceptions of current and projected vaccine cost, disease burden, side-effects of the vaccine, and feasibility of local vaccine production.

IVI is carrying out this program in collaboration with international partners, both in Asia and elsewhere.