Japanese Enchephalitis Vaccines

Sayenna Uduman*, M I Sahadulla**, Raja Lakshmi***
*MD, FAAP
Visiting Professor, Infection Control Committee & ID Division of the KIMS
Thiruvananthapuram, Kerala, India

**CMD, ID Division- KIMS.
***Consultant ID, ICC Chair – KIMS

First Created: 03/25/2016  Last Updated: 03/25/2016

Introduction

Preamble:

This review outlines briefly on epidemiological features and clinical background of Japanese encephalitis (JE) virus infection. Although symptomatic infection is rare, the vaccine prevention aspect of this deadly virus infection is discussed in detail.

Japanese encephalitis (JE), previously known as Japanese B encephalitis, is caused by the mosquito-borne JE virus; a member of the genus flavivirus (of the Flaviviridae family). This is related antigenically to the West Nile virus and St. Louis encephalitis virus and has similar ecologic and clinical features. Dengue virus and tick-borne encephalitis virus are less closely related flaviviruses. JE virus was first discovered and originally restricted to Japan. Now, the JE is one of the most important forms of the epidemic and sporadic encephalitis in the tropical regions of Asia, including Japan, China, Taiwan, Korea, Philippines, all of Southeastern Asia, and India. Very rarely JE had been reported in the North American region among those returned travelers to the USA from Far East endemic regions.

The virus is transmitted to humans primarily by Culex mosquitoes, which breed in flooded rice fields and pools of stagnant water. The virus is maintained in an enzootic cycle involving mosquitoes and amplifying vertebrate hosts, mainly pigs and splashing birds providing links to the human population through their close proximity to residential locations. The current epidemiologic trend suggests the disease incidence in Northern (Uttar Pradesh) & central India is escalating, and larger epidemics may occur in the future. Almost, half of the human population now lives in countries where the disease has been endemic. Most human JE infections are predominantly subclinical & in apparent; life-threatening encephalitis occur <1% of the infected persons. The annual incidence of clinical disease varies both across and within endemic countries. This has been estimated nearly 68 000 clinical cases of JE globally each year, with approximately 13 600 to 20 400 deaths. JE primarily affects children below 15 years of age and individuals of any age could be affected.

Case fatality averages 30% if clinically unrecognized and a high percentage of the survivors are left with permanent neurological sequelae. Cases of deadly JE have risen nearly five-fold in the last five years in India's northeast Assam state as a result of climatic changes, warming weather, and changing rainfall. JE virus is the most common vaccine-preventable cause of encephalitis occurring throughout Asia and parts of the western Pacific.

Clinical Description, Diagnosis & Control

Because the virus, the mosquito vectors, and hosts are ubiquitous in rural Asia, most of the population is exposed during childhood as shown by serologic studies, though disease develops in only a small proportion of infected persons. The effects range from a nonspecific febrile illness to severe meningoencephalitis, manifested by an altered level of consciousness, seizures, and acute flaccid paralysis. The incubation period is 6 to 16 days.

Laboratory confirmation for the precise diagnosis of JE is important because many etiologic agents are responsible to cause acute onset encephalitic syndrome. The disease is usually diagnosed by CSF analysis by viral culture, antigen, and antibody detection by serology testing.

There is no established antiviral treatment for the disease, but an understanding of the pathogenesis may point the way toward supportive care and vector control efforts. Since culex mosquitos have a flight range of 20 km, all local control measures will fail but should avoid further mosquito bites because the virus is maintained in nature in a transmission cycle involving mosquitoes, birds, and pigs. Apart from measures to reduce the risk of being bitten by infected mosquitos; still, the best hope for controlling Japanese encephalitis lies in vaccination.

JE Vaccine Prevention

There is little evidence to support a reduction in JE disease burden from interventions other than the vaccination of humans. WHO recommends strong JE prevention and control activities, including immunization in all regions where the disease is a recognized public health priority. Even if the number of JE-confirmed cases is low, vaccination should be considered where there is a suitable environment for JE virus transmission.

An ideal vaccine should be safe, cheap, and easy to administer and should generate neutralizing antibodies capable of protecting against JE virus infection. There are 4 main types of JE vaccines currently in use: inactivated mouse brain-derived vaccines inactivated Vero cell-derived vaccines, live attenuated vaccines, and recombinant vaccines.

The IAP Advisory Committee on Vaccines and Immunization Practices (ACVIP, 2013) recommends considering JE Vaccine for high-risk children under special circumstances indicating JE is a major pediatric health problem, in India.

The CDC recommends the vaccine for travelers who plan to spend a month or longer in areas with endemic infection during the virus transmission season. The risk of infection for most travelers to Asia is low but varies on the basis of destination, duration, season, and activities. For some travelers who will be in high-risk settings, vaccination can further reduce the risk of infection. Information on the location of JE virus transmission and detailed information on vaccine recommendations and adverse events can be obtained from the CDC (wwwnc.cdc.gov/travel/).

  • Only one JE vaccine is available commercially for use in the United States. An inactivated Vero cell culture-derived vaccine (IXIARO [JE-VC], distributed in the US by Novartis Vaccines and Diagnostics Inc., Cambridge, MA) is licensed for people 2 months of age or older in a 2-dose administered 28 days apart as primary vaccination series.

  • Children 2 months through 24 months of age receive 0.25 ml. Adults and children beyond 2 years of age receive 0.5 ml. Adults may require a booster dose at 1 year or longer after the primary dose vaccination and before traveling to potential JE virus exposure.

  • No efficacy data exist for JE-VC. No safety concerns have been identified

  • The vaccine confers no herd immunity because humans are not the primary hosts.

    Several groups of vaccines are available currently, in India. The formalin-inactivated vaccines have been safe and effective against the JE virus for at least 30 years. Of these, the most widely produced and internationally distributed is the mouse-brain derived inactivated vaccine. The efficacy and the strain from which these are produced are given in Table 1.

Table 1 - Vaccines that are in use against Japanese encephalitis.

Vaccine type JE virus strain Comments
Inactivated    
1. Inactivated mouse brain
Hamster kidney cells derived
Vero-cell culture derived formalin inactivated
Nakayama and Beijing-1, grown in suckling mouse brain
based on the Beijing-3 strain
using P20778 (Indian isolate)
WHO approved vaccine; a seroconversion rate of 80 to 90% with an efficacy rate of 91%.
Has relatively fewer side effects and is easy to manufacture. In an extensive randomized field trial in China, its efficacy was found to range between 76% and 90%.
Has induced high titers of neutralizing antibodies in mice after two injections.
Attenuated    
Live attenuated primary hamster kidney cells SA 14-14-2 In large-scale case–control studies in China has shown >90% protection after two doses with an interval of one year. The IAP ACVIP reviewed the performance of SA-14-14-2 JE vaccine in India since its launch in 2006. According to a recent case control study this vaccine efficacy has been around 60% in Uttar Pradesh and around 70% in Assam.

Formalin Inactivated mouse brain vaccine: has been in use over many years. Children required 3 primary doses followed by booster dose annually. Lasting immunity and adverse allergic reactions are a major concern and that has led to the development of newer and improved vaccines.

Hamster kidney cell-culture-derived inactivated vaccine: This vaccine is based on the Beijing-3 strain of JEV and has been in use in China since 1967 with a clinical efficacy rate ranged between 76% and 90%. Recently, Vero-cell culture-derived formaldehyde inactivated vaccine using P20778 (Indian isolate) have produced high titers of anti-JEV antibodies in animal models, and these findings needed further confirmation in clinical trials.

In recent years a Vero cell-derived purified inactivated JE vaccine-JENVAC is the first vaccine to be manufactured in the public-private partnership mode between the Indian Council of Medical Research and Bharat Biotech. The clinical trials, showed superior safety and immunogenicity, in comparison to living attenuated vaccine The most significant benefit of the JENVAC is that it can be administered during an epidemic as it is a highly purified and inactivated vaccine. A phase III clinical trials showed 98.7 percent seroprotection 28 days after the first dose and 99.8 percent seroprotection 28 days after the second dose.

Live attenuated vaccine based on cell culture-based: Studies on the 2-dose administration of the attenuated vaccine in the primary immunization schedule appeared to be highly immunogenic and safe. A case-control study in Nepal had shown an efficacy rate of 98% with a single vaccine dose administration and the long term efficacy of this observation is required.

Other JE vaccines that include a live, attenuated “chimeric” vaccine which uses a yellow fever vaccine virus strain as its backbone (ChimeriVax-JE, manufactured by Acambis); recombinant protein-based vaccines, and DNA vaccines. These vaccines have better immunogenicity and lesser vaccine adverse reactions.

Conclusions:

Approved vaccines are available to prevent serious encephalitis infection for children 2 months of age and older JE vaccine is recommended for travelers to Asia who plan to spend at least a month in areas where the infection is highly prevalent WHO recommends that JE vaccination be integrated into national immunization schedules in areas where the encephalitis disease is recognized as a major public health concern. Apart from mosquito bite control, JE disease control may be possible by well-planned immunization policies supported by the regional disease surveillance systems, especially for India.

Adverse reactions:

Usually mild and are similar that can happen after any vaccine. Pain, tenderness, redness, or swelling at the injected site associated with fever of transient nature can occur. Studies have shown that severe reactions to the JE vaccine are extremely rare; if one were to occur, it would usually be within a few minutes to a few hours after the vaccination. Vaccine providers should always be aware and familiar with the vaccine-related adverse reactions.


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2. WHO. Japanese encephalitis .December 2015 http://www.who.int/mediacentre/factsheets/fs386/en/
3. Indian Academy of Pediatrics (IAP) Recommended Immunization Schedule for Children Aged 0 through 18 years – India, 2013 and Updates on Immunization. Indian Pediatr 2013; 50: 1095-1108.
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5. Risk of Japanese Encephalitis by country, region and season – CDC 2010. http://www.itg.be/itg/Uploads/MedServ/NJAPENC%20bijlage.pdf


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