Available Vaccines

Japanese Encephalitis

Introduction

Japanese encephalitis (JE), is a mosquito-borne viral infection of the central nervous system. Numerically it is the most important cause of viral encephalitis across Asia with an estimated 70,000 cases and 10,000 to 15,000 deaths annually. The causative agent, JE virus (genus Flavivirus, family Flaviviridae) is transmitted primarily among birds, pigs, and other vertebrate hosts by Culex species mosquitoes that breed in flooded rice fields and stagnant water and bites largely at dusk and night. While pigs and water birds serve as the main amplifying hosts, humans are merely incidental dead-end hosts that become infected when they encroach on the enzoonotic cycle. The viraemia that occurs during the prodromal period of JE virus infection in humans is too low to permit further transmission.

The virus is found in South East Asia, India, Nepal, China, Korea peninsula, Japan, Pacific islands Rim and northern Australia. There are two transmission patterns of JEV in three climatic zones: in temperate climate zones such as Japan, Korea and mainland China and Taiwan, and sub-tropical climate zones such as Nepal, and northerly areas of India, Thailand and Vietnam, JEV exhibits an epidemic or outbreak transmission pattern, characterised by a well-defined seasonal peak during the summer months. In tropical climate zones such as Malaysia, Indonesia, southerly areas of Vietnam and Thailand, JEV exhibits an endemic transmission characterised by sporadic human cases throughout the year with seasonal peaks that coincides with high rainfall during the monsoon season.

In parts of Asia where JE is endemic, it is primarily a disease of children living in rural areas. Whilst most people living in endemic areas are infected by the age of 15 years, JE virus can infect all age groups, particularly when it is newly introduced into geographical areas where the general population has no pre-existing immunity. Only 1 in 300 infections result in symptomatic illness. These may range from a non-specific flu-like illness, febrile seizures, aseptic meningitis, encephalitis and poliomyelitis-like acute flaccid paralysis.

In endemic areas most cases of encephalitis occur in children, but travelers from non-JE endemic region are also at risk. There is no specific antiviral treatment for severe JE apart from supportive care. The acute case fatality rate of encephalitis is approximately 30%, and up to 50% of the survivors develop severe neurological sequelae. Although the clinical condition of many JE survivors improves during the first 3–6 months after hospital discharge, less than 50% make a full recovery, and about 20% experienced subsequent deterioration on long term follow-up.

In Malaysia, the great majority of laboratory-confirmed JE cases are found in Sarawak. There is a paucity of data on JE in other parts of Malaysia although 2 outbreaks have been recorded in peninsular Malaysia – Pulau Langkawi in 1974 (Fang et al. 1980) and Penang in 1988 (Cardosa et al. 1995).

Vaccines Available in Malaysia

 

1. IMOJEV®
(Live attenuated recombinant chimeric JE vaccine, prM and E protein are derived from SA-14-14-2 vaccine strain)
Sanofi-Aventis (M) Sdn Bhd/Government Pharmaceutical Organisation-Merieux Biological Product Company Limited, Thailand

2. Japanese Encephalitis Vaccine®
(Inactivated mouse brain derived JE vaccine, Nakayama strain)
Propharm (M) Sdn Bhd/Green Cross Corporation, South Korea

3. CD.JEVAX®
(Live attenuated JE vaccine, SA-14-14-2 vaccine strain)
Farmaco Healthcare Sdn Bhd/Chengdu Institute of Biological Products, China

Mode of Administration

  • Live-attenuated recombinant chimeric JE vaccine (IMOJEV®)
        1. Administration route: subcutaneous injection
            • Children aged 9 months and above: a single injection. A booster dose should be given preferably 1-2 year after the first vaccination for those aged <18 years. No booster is recommended for adults.

  • Inactivated mouse brain-derived vaccine (Japanese Encephalitis Vaccine®)
      1. Administration route: subcutaneous injection
          • Individuals living in endemic areas: 2 primary doses (1.0 ml for those aged >3 years to adults, 0.5ml for those 1-3 years) at 4 weeks apart, followed by a booster 1 year after the primary series. Subsequent boosters are recommended at 3-year intervals up to the age of 15 years.
          • For travelers aged >1 year visiting rural areas of endemic countries for >2 weeks: 3 primary doses at days 0, 7 and 28. When continual protection is required, boosters should be given after 1 year, subsequently every 3 years.

  • Live attenuated JE vaccine (CD.JEVAX®)
      1. Administration route: subcutaneous injection
          • Children aged 8 months and above: a single injection. No booster is required.

Co-administration with Other Vaccines

  • JE vaccine is frequently co-administered with other vaccines on the immunisation schedule. Simultaneous administration of inactivated JE vaccine with measles, mumps, rubella vaccine did not result in reduced immunogenicity or increased side effects. JE vaccine can be given concurrently with the 4th dose of diphtheria, tetanus toxoids and pertussis (DTP) and, oral poliovirus vaccine at 18 months.

Contraindications and Adverse Effects

  1. IMOJEV® should not be administered to anyone with a history of severe allergic reaction to any component of the vaccines, after previous administration of the vaccine or any vaccine containing the same components or constituents. In adults, adverse effects following IMOJEV® were similar to those in placebo recipients, but occurred less often than in recipients of the mouse brain-derived JE vaccine. The most common adverse effects in two key studies were injection site pain, headache, fatigue and malaise. Most symptoms resolved within 3 days.

  2. Mouse brain-derived Japanese Encephalitis Vaccine® is contraindicated in people who have had an allergic reaction to the vaccine, gelatin or other rodent-derived products, including previous doses of JE vaccine. The most common adverse effects include local redness, pain, or swelling at the injection site.

  3. CD.JEVAX® should not be administered to persons with/on:

      • a proven or suspected history of hypersensitivity/ anaphylactic reaction to any component of the vaccine, including gelatin.

      • fever, acute infectious disease, tympanitis or active untreated tuberculosis.

      • malnutrition, general allergy and convulsion.

      • cardiac, liver or renal impairment.

      • any type of immunosuppressive therapy.

      • immune systems that are weak or not functioning properly.

As is the case with all medications, the administration of CD.JEVAX® can cause adverse reactions. Adverse reactions are observed in a small percentage of the vaccinees after administration of CD.JEVAX®. Some minor adverse effects, such as fever, rash, and nausea have been reported after injection but normally do not last longer than 2 days. Most are relieved spontaneously without requiring any particular treatment.

Target Groups in Malaysia

  1. Workers, travelers and other individuals on an extended stay in Sarawak.

  2. Research laboratory personnel who may potentially be exposed to field or virulent strains of the virus, as well as those who have contact with live swine (pig farmers and abattoir workers).

Note:
Children in Sarawak receive live-attenuated recombinant chimeric JE vaccine (IMOJEV®) at 9 and 21 months under the Expanded Programme of Immunisation (EPI).

Evidence for Effectiveness

Human vaccination is the most effective measure in reducing the disease burden of JE in endemic areas. When a high rate of immunisation coverage is sustained in populations at risk, the incidence of JE could be reduced significantly despite the fact that the virus remains in circulation.

Studies have shown the use of inactivated mouse brain derived and live attenuated vaccines have reduced considerably the incidence of JE in Japan, Thailand, Nepal and Sarawak. The average annual incidence of JE in Sarawak prior to introduction of inactivated mouse brain derived vaccine into the EPI in 2001 was 9.8 cases per 100 000 population aged 12 years and below. By the end of 2006, the average annual incidence had dropped to 4.3 cases per 100 000 population aged 12 years and below. There is still no data on the population impact for live-attenuated recombinant chimeric JE vaccine yet.

It is pertinent to note that JEV is a zoonotic virus and humans are incidental dead-end hosts. Vaccination has no impact on the zoonotic transmission of the virus, hence susceptible individuals will continue to be at risk of disease even when few cases are observed. Thus any vaccination programme would have to target all susceptible individuals without expecting herd immunity to contribute to a reduction in incidence.

References

  1. Bista, M. B., Banerjee, M., Shin, S. H., Tandan, J., Kim, M. H., Sohn, Y. M., . . . Halstead, S. B. (2001). Efficacy of single-dose SA 14–14–2 vaccine against Japanese encephalitis: A case control study. The Lancet, 358(9284), 791-795. doi:10.1016/s0140-6736(01)05967-0
  2. Campbell, G., Hills, S., Fischer, M., Jacobson, J., Hoke, C., Hombach, J., Ginsburg, A. (2011). Estimated global incidence of Japanese encephalitis:. Bulletin of the World Health Organization, 89(10), 766-774. doi:10.2471/blt.10.085233
  3. Gatchalian S, Yao Y, Zhou B, et al. (2006). Measles vaccine immunogenicity after coadministration with live attenuated
  4. Halstead, S. B., Hills, S. L., & Dubischar, K. (2018). Japanese encephalitis vaccine. In 979245011 758798570 P. A. Offit, 979245012 758798570 W. A. Orenstein, & 979245013 758798570 S. A. Plotkin (Authors), Plotkin’s vaccines (7th ed.). Philadelphia, PA: Elsevier.
  5. Hennessy, S., Strom, B., Bilker, W., Zhengle, L., Chao-Min, W., Hui-Lian, L., . . . Halstead, S. (1996). Effectiveness of live-attenuated Japanese encephalitis vaccine (SA14-14-2): A case-control study. The Lancet, 347(9015), 1583-1586. doi:10.1016/s0140-6736(96)91075-2
  6. Impoinvil, D. E., Ooi, M. H., Diggle, P. J., Caminade, C., Cardosa, M. J., Morse, A. P., Solomon, T. (2013). The Effect of Vaccination Coverage and Climate on Japanese Encephalitis in Sarawak, Malaysia. PLoS Neglected Tropical Diseases, 7(8). doi:10.1371/journal.pntd.0002334 Japanese encephalitis vaccine shows equivalence to that of measles vaccine given alone [abstract]. In: American Society of Tropical and Medicine and Hygiene 54th Annual Meeting. Atlanta (GA). 2605
  7. Japanese Encephalitis Vaccines: WHO position paper (2006). (34/35), 81, 331-340.
  8. Japanese Encephalitis Vaccines: WHO position paper. (2015). (9), 69-88, 90.
  9. Monath, T., Guirakhoo, F., Nichols, R., Yoksan, S., Schrader, R., Murphy, C., . . . Bedford, P. (2003). Chimeric Live, Attenuated Vaccine against Japanese Encephalitis (ChimeriVax‐JE): Phase 2 Clinical Trials for Safety and Immunogenicity, Effect of Vaccine Dose and Schedule, and Memory Response to Challenge with Inactivated Japanese Encephalitis Antigen. The Journal of Infectious Diseases, 188(8), 1213-1230. doi:10.1086/378356
  10. Nasveld, P. E., Ebringer, A., Elmes, N., Bennett, S., Yoksan, S., Aaskov, J., . . . Reid, M. (2010). Long term immunity to live attenuated Japanese encephalitis chimeric virus vaccine. Human Vaccines, 6(12), 1038-1046. doi:10.4161/hv.6.12.13057The Malaysian National Centre of Adverse Drug Reactions Database. Accessed: October 10, 2019
  11. National Pharmaceutical Regulatory Agency (NPRA), Ministry of Health Malaysia. Senarai Produk Vaksin Berdaftar Dengan Pihak Berkuasa Kawalan Dadah. Received September 5, 2019.
  12. Ohrr, H., Tandan, J., Sohn, Y. M., Shin, S. H., Pradhan, D. P., & Halstead, S. B. (2005). Effect of single dose of SA 14-14-2 vaccine 1 year after immunisation in Nepalese children with Japanese encephalitis: A case-control study. The Lancet, 366(9494), 1375-1378. doi:10.1016/s0140-6736(05)67567-8
  13. Ooi, M., Lewthwaite, P., Lai, B., Mohan, A., Clear, D., Lim, L., . . . Solomon, T. (2008). The Epidemiology, Clinical Features, and Long‐Term Prognosis of Japanese Encephalitis in Central Sarawak, Malaysia, 1997–2005. Clinical Infectious Diseases, 47(4), 458-468. doi:10.1086/590008
  14. Sohn, Y. M., Park, M. S., Rho, H. O., Chandler, L. J., Shope, R. E., & Tsai, T. F. (1999). Primary and booster immune responses to SA14-14-2 Japanese encephalitis vaccine in Korean infants. Vaccine, 17(18), 2259-2264. doi:10.1016/s0264-410x(99)00006-7
  15. The Malaysian National Centre of Adverse Drug Reactions Database. Accessed: October 10, 2019.
  16. Torresi, J., Mccarthy, K., Feroldi, E., & Méric, C. (2010). Immunogenicity, safety and tolerability in adults of a new single-dose, live-attenuated vaccine against Japanese encephalitis: Randomised controlled phase 3 trials. Vaccine, 28(50), 7993-8000. doi:10.1016/j.vaccine.2010.09.035
  17. Wong, S. C., Ooi, M. H., Abdullah, A. R., Wong, S. Y., Krishnan, S., Tio, P. H., Cardosa, M. J. (2008). A decade of Japanese encephalitis surveillance in Sarawak, Malaysia: 1997-2006. Tropical Medicine & International Health, 13(1), 52-55. doi:10.1111/j.1365-3156.2007.01967.x
  18. Xin, Y. Y., Jian, A., Peng, G. Y., Min, L. H., & Ming, Z. G. (1988). Safety of a Live-Attenuated Japanese Encephalitis Virus Vaccine (SA14-14-2) for Children. The American Journal of Tropical Medicine and Hygiene, 39(2), 214-217. doi:10.4269/ajtmh.1988.39.214