Immunization, Vaccines and Biologicals

Japanese encephalitis

Introduction and information

Japanese encephalitis (JE) is the main cause of viral encephalitis in many countries of Asia. The infection is mosquito-borne and caused by the JE virus, a flavivirus related to dengue, yellow fever and West Nile viruses. The virus exists in a transmission cycle between mosquitoes, pigs and/or water birds (enzootic cycle). Humans get infected when bitten by an infected mosquito. The disease is predominantly found in rural and periurban settings.

Burden of disease

Annual mortality is estimated to range from 10-15 000 deaths. A recent literature review estimates that, of the 68 000 clinical cases of JE, at least 30% result in permanent neuropsychiatric sequelae. The disease is endemic with seasonal distribution in temperate climate zones of Asia as well as South and South-East Asia. All year transmission is observed in tropical climate zones. Currently, JE is considered hyperendemic in parts of India and Nepal, where authorities have responded with immunization campaigns.

Japanese encephalitis vaccination

WHO recommends JE immunization in all regions where the disease is a recognized public health problem, and for travellers to endemic regions. Several vaccines have been available for decades with proven ability to control the disease. However, vaccine use has been limited due to its price, cumbersome immunization schedules, and lack of recognition of the burden of disease. Investment into disease surveillance and the availability of new vaccines have given momentum to the control of JE through vaccination. In addition, the GAVI Alliance has committed to support JE vaccination in eligible countries once a WHO-prequalified vaccine is available.

Licensed vaccines

The traditional mouse-brain derived inactivated vaccines are still being produced by several manufacturers. Grown on mouse neural tissue, virulent strains of Nakayama or Beijing 1 type are then inactivated and purified. Vaccines require 3 doses for primary immunization and boosters. Due to the complex production, the vaccines are relatively expensive.

More recently, JE viruses have been adapted to Vero cells for vaccine production. Several Japanese manufacturers produce Vero-derived Beijing 1 inactivated vaccine for paediatric indication. A similar product is registered in China. Another cell-culture derived inactivated JE vaccine, using the attenuated SA 14-14-2 strain, has been developed by an Austrian biotech company and is currently commercialized as a traveller’s vaccine. An equivalent product has been developed by an Indian manufacturer and has received marketing authorization. These vaccines require 2–3 doses for primary immunization and boosters. Research into a paediatric indication is ongoing.

A live attenuated vaccine using the SA 14-14-2 strain has recently become the most widely used JE vaccine in endemic countries. Manufactured by a Chinese company and grown on primary hamster kidney cells, this vaccine only requires 1–2 doses to confer long-lasting immunity. The vaccine is made available at a highly competitive price to low-income countries.

Another live attenuated, chimeric vaccine has obtained marketing authorization in some JE endemic countries. The vaccine, grown on Vero cells, uses the yellow fever vaccine as vector, combined with the E protein encoding gene from the SA 14-14-2 virus. It has an indication as a 1dose vaccine, and booster requirements remain to be determined.

Pipeline vaccines

Several candidate JE vaccines are under development, including adjuvanted inactivated vaccines, candidates using different virus strains, and other genetically engineered constructs.

IVR focus on research

IVR monitors and advises on research related to the design of optimal strategies for immunization, including the selection of age groups for catch-up and the definition of at-risk populations, and the impact of vaccination. The duration of protection and booster needs, and well as immunization of special target groups, also require further analysis. Regulatory guidelines for production, quality control and evaluation of novel live, chimeric vaccines are in preparation.