Japanese encephalitis primary prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anthony Gallo, B.S. [2]

Overview

Effective measures for the primary prevention of Japanese encephalitis include mosquito population control, avoidance of mosquitos, and immunization. Mosquito control has been difficult to achieve in rural settings. Avoidance of exposure is also difficult, as Culex mosquitos are active during day hours. Immunization is the only effective method for sustainable control. Routine immunization of school-age children is currently in use in Korea, Japan, China, Thailand, and Taiwan. The introduction of the Japanese encephalitis vaccine into the Expanded Program of Immunization has helped curb the disease in countries like Thailand, Vietnam, Sri Lanka, and China.

Primary Prevention

Primary prevention strategies for Japanese encephalitis include:

• Removal of standing water
• Screens on doors and windows
• When outdoors, wearing:
  • Insect repellent containing DEET
  • Long sleeves, pants; tucking in pants into high socks
• Vaccination

Vaccine

Infection with Japanese encephalitis virus confers life-long immunity. All current vaccines are based on the genotype III virus. Among the currently available vaccines is a formalin-inactivated vaccine derived from mouse brain-grown Japanese encephalitis virus strain Nakayama, which still is produced by manufacturers in Korea, Thailand, and Vietnam. It was first produced in Japan in the 1930s and was validated for use in Taiwan in the 1960s and in Thailand in the 1980s. The widespread use of vaccine and urbanization has led to control of the disease in Japan, Korea, Taiwan, and Singapore. The high cost of the vaccine, which is grown in live mice, means that poorer countries have struggled to administer it as part of a routine immunization program. The vaccine requires three doses on days 0, 7, and 30, a booster at 1 year, and thereafter at intervals of 3 years. The vaccine can often generate neurological adverse reactions. In addition to local and systemic side effects, individual cases of generalized urticaria and angioedema were reported in about 1 per 1000 vaccinees after vaccination of travelers from western countries.

Inactivated Vaccines

Another formalin-inactivated Japanese encephalitis vaccine is prepared in China using the Japanese encephalitis virus-P3 strain propagated in primary hamster kidney cell cultures. The vaccine appears to be more immunogenic than that based on the Nakayama strain and can be integrated into the routine childhood immunization schedule, but is not distributed outside of China. It is now largely being replaced by the live attenuated vaccine.

Several attempts are in progress to prepare inactivated Japanese encephalitis virus vaccines starting from virus grown in controlled cell line cultures. Several manufacturers are developing Vero cell-derived purified inactivated Japanese encephalitis vaccines, either using the virulent Nakayama strain, or starting from the attenuated SA14-14-2 JEV strain. Phase I and Phase II clinical trials have shown that the vaccine was safe and immunogenic; Phase III trials were recently completed. The most common adverse effects are redness and pain at the injection site. Uncommonly, an urticarial reaction can develop about four days after injection. Because the vaccine is produced from mouse brain, there is a risk of autoimmune neurological complications of around 1 per million vaccinations.

Live Attenuated Vaccines

The live attenuated Japanese encephalitis vaccine strain, SA14-14-2, which was obtained after 11 passages in weaning mice followed by 100 passages in primary hamster kidney cells, has been developed and used in China since 1988. The vaccine, which is produced by the Chengdu Institute of Biological Products in China, was licensed in recent years in several Asian countries and was extensively used from 2006 to 2008 in mass immunization campaigns in India. The vaccine is administered to children at one year of age and again at two years, in annual spring campaigns. Initial observational studies in southern China involving more than 200,000 children had demonstrated the vaccine safety, immunogenicity (99-100% seroconversion rate in nonimmune subjects), and protective efficacy over 5 years. The short-term effectiveness of a single dose of SA14-2-14 was demonstrated in 2001 in a case control study on Nepalese children, where an efficacy of 99.3% was reported. A five year follow-up study found the single-dose efficacy was maintained at 96.2%. Another five-year follow up study showed that neutralizing antibody persistence was close to 90% at 4 years and 64% at 5 years after a single-dose of the vaccine in adult volunteers. Recent studies in the Philippines have demonstrated the safety and efficacy of the vaccine even when co-administered with measles vaccine at 9 months of age.

Currently, more than 30 million doses of the live SA14-2-14 vaccine are distributed annually in southern and western China, and are exported to Nepal, India, and Korea. Starting in May 2006, the SA14-2-14 live attenuated vaccine was used in India to vaccinate 9.3 million children in 11 districts scattered among 4 states where Japanese encephalitis was considered as highly endemic. More than 500 adverse events were reported during the campaign, including 66 severe adverse events, of which 22 were fatal. These cases were reviewed by an expert committee which concluded that none of the deaths were attributable to the vaccine. The severe adverse events and critical press coverage nevertheless had a deep negative impact on vaccine acceptance in the rest of the country, highlighting the need for proper safety monitoring and case investigations.

Chimeric Vaccines

A promising approach for a future Japanese encephalitis vaccine has been the construction of a YF-JE chimera based on the attenuated 17D YF virus genome, in which the YFV sequences encoding viral structural proteins prM and E were replaced by the corresponding prM and E sequences from JEV strain SA14-2-14. The vaccine was tested in human adult volunteers in the United States, demonstrating good safety and immunogenicity, with 94% of the vaccinees in the Phase II trial developing protective neutralizing antibody levels after a single dose. The chimeric virus was shown not to replicate in mosquitos which were fed the Chimerivax-JE vaccine, a further proof of attenuation.

Live Recombinant JEV Vaccines

Replication-defective canarypox (ALVAC) and the highly attenuated vaccinia virus strain NYVAC were used as vectors to express the pr-M, E, NS1 and NS2a gene from Japanese encephalitis virus. The vaccine candidates were found to be well tolerated but their immunogenicity was too weak, especially in non-vaccinia immune volunteers, to warrant further development.

Vaccination in Population at Risk

Neutralizing antibody persists in the circulation for at least two to three years, and perhaps longer. The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are recommended every two years for people who remain at risk.

For US expatriates, Japanese encephalitis vaccine is recommended for persons who plan to reside in areas where Japanese encephalitis is endemic or epidemic (residence during a transmission season). Risk for acquiring Japanese encephalitis is highly variable within the endemic regions. The incidence of Japanese encephalitis in the location of intended residence, the conditions of housing, nature of activities, and the possibility of unexpected travel to high-risk areas are factors that should be considered in the decision to seek vaccination.

For travelers, Japanese encephalitis is recommended for those who plan to spend at least 1 month in endemic areas during the Japanese encephalitis virus transmission season, or if high-risk activities are being performed during shorter periods of travel.

Risk for travellers

The risk of japanese encephalitis is very low for most travellers to Asia, particularly for short-term visitors to urban areas. However, the risk varies according to season, destination, duration of travel and activities.

• Vaccination is recommended for travellers with extensive outdoor exposure (such as camping, hiking and working) during the transmission season, particularly in endemic countries or areas where farming involves flooding irrigation.
• Prevention is by avoidance of mosquito bites and by vaccination.

Vaccine

Inactivated Vero cell-derived, live attenuated and live recombinant vaccines are available. Vaccination against japanese encephalitis is recommended for travellers to endemic areas who will have extensive outdoor exposure during the transmission season.

Summary of vaccine data

Considerations
Type of vaccine and schedules	Japanese encephalitis vaccines fall into 3 classes:
	Inactivated Vero cell-derived vaccines: It requires 2 intramuscular doses administered 4 weeks apart. The recommended age for the first dose varies. The dose for children aged <3 years is 0.25 ml, and for those aged ≥3 years 0.5 ml. Travellers aged ≥17 years who have received primary immunization more than one year previously may be given a booster dose if continued or repeated exposure to Japanese encephalitis virus is expected.
	Live attenuated vaccines: In China, the first dose is given subcutaneously at age 8 months, followed by a booster dose at 2 years of age. In Australia, the first dose is administered to persons aged ≥ 9 months, and no booster is required for persons aged ≥18 years when receiving the primary dose. In some areas and countries, an additional booster is offered at 6–7 years of age.
	Live recombinant (chimeric) vaccines: Primary immunization is with 1 dose given subcutaneously at 9 months of age or older. A booster dose is recommended 12–24 months later for those <18 years of age. Currently, there is no booster recommendation for adults.
Adverse reactions	Occasional mild local or systemic reactions.
Contraindications and precautions	A hypersensitivity reaction to a previous dose is a contraindication. In principle, the live attenuated vaccine should not be given to pregnant women unless there is a high risk of exposure to the infection.

References

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