Japanese encephalitis virus (JEV)

ATAGI clinical guidance on Japanese encephalitis virus vaccines

The Australian Technical Advisory Group on Immunisation (ATAGI) have made recommendations for healthcare providers administering Japanese encephalitis virus (JEV) vaccines.

The Therapeutic Goods Administration of Australia (TGA) has approved the supply of Ixiaro, an alternative brand product of the inactivated Japanese encephalitis vaccine, until March 2023 under Section 19A of the Therapeutic Goods Act 1989. This vaccine is also registered as JEspect in Australia. It is registered as Ixiaro by certain overseas regulators, including the Food and Drug Administration (FDA) of the USA, and the European Medicines Agency (EMA). Registration conditions of Ixiaro with the FDA and EMA include its use in children aged 2 months or older. Recommendations by ATAGI on the use of Ixiaro are equivalent to those for JEspect.

Japanese encephalitis virus (JEV) vaccines are used in a number of countries internationally as part of the routine immunisation schedule, but are not on the Australian National Immunisation Program (NIP). More information on JE and vaccines is available in the Australian Immunisation Handbook.1

Clinical recommendations

There are 2 JEV vaccines available in Australia:

  1. Imojev
  2. JEspect

Both are safe and effective for preventing JEV in those at risk of disease.

Imojev

Imojev is a live attenuated JEV vaccine that is a combination of the yellow fever and JE viral components, and is given as a single dose. It is suitable for people aged ≥9 months where there are no contraindications to its use.

Imojev is contraindicated in pregnant women and immunocompromised people and is not licensed for use in children <9 months of age.

A broad use of this vaccine is appropriate because of the advantage that it is given as a single dose, and if there is constrained supply of the alternative vaccine which is suitable for those who are contraindicated for Imojev.

JEspect

JEspect is an inactivated vaccine given in a 2-dose schedule, and is recommended for pregnant women, children aged 2 months to <9 months, and immunocompromised individuals. 

The interval between the 2 doses of JEspect for the primary course should be 7 days for adults who are at a high risk of immediate exposure (e.g. residents of or farm workers on affected piggeries).

The interval between the 2 doses of JEspect for the primary course should be 28 days for adults at lower risk of exposure and for all children (aged 2 months to <18 years). Ixario is an equivalent brand product of the JEspect vaccine.

The recommended doses of JEspect vary with age.

For those at risk of Japanese encephalitis virus infection (as advised by the local public health authority) who are previously vaccinated with a JEV vaccine, a booster dose is recommended if more than 1 year has passed since the last primary course dose, regardless of which vaccine (including for people who cannot identify the vaccine brand that they received). The exception is people who have evidence that they received a dose of Imojev when they were aged ≥18 years, for whom a booster dose of a JE vaccine is not required.

The intradermal route for JEV vaccine administration is not currently recommended. ATAGI will review this advice if there is a requirement to consider increasing vaccine utilisation in the setting of constrained supply.

Background

Japanese encephalitis (JE) is an infection of the brain caused by the Japanese encephalitis virus (JEV). The disease is serious, but rare and less than 1 in 200 people who get infected will develop encephalitis. JEV can be spread by some types of mosquitoes. Pigs and certain water birds are amplifying hosts for the JEV.

Cases of JE have been reported in pigs in multiple states in southeast Australia in early 2022. JEV occurs in many parts of Southeast Asia and China, and is now considered endemic in the Torres Strait region and Papua New Guinea. Apart from 2 incursions to Cape York in 1998 and 2004, there has been no previously documented transmission on the Australian mainland. One human case of JE was acquired on the Tiwi Islands in 2021.

Current efforts are focused at better understanding the risk to humans in affected areas. In these areas, vaccination of people at risk of JEV infection is the most important measure to prevent severe disease.

Target populations

JE vaccination is suitable for people likely to be at greatest risk of JEV infection. In addition to routine recommendations for travellers to endemic areas and residents of the Torres Strait Islands, ATAGI now recommends vaccination of people ≥2 months of age in high risk settings in Australia.

The risk of JEV transmission and human disease in various settings and occupations is still being evaluated. State and territory health departments will provide more detailed risk assessment information to guide who should be vaccinated. Guidance will be updated as more information becomes available

A broad use of Imojev is appropriate, as it has the benefit of requiring only a single dose, and if there are constraints on supply of JEspect, which is the only vaccine available for those who are contraindicated for Imojev. JEspect is acceptable for use if Imojev is not available.

Both vaccines have similar immunogenicity after completing the primary course.

Recommended dosages

Vaccine

Age group

Dose

Contraindications

Imojev 

≥9 months

Single dose schedule

0.5 mL subcutaneously (SC)

Pregnancy; immunocompromised (live attenuated vaccine)

Recent receipt of immunoglobulin or immunoglobulin containing blood products (within last 6-12 weeks)

Anaphylaxis to vaccine or component

JEspect

 

2 months – <3 years

2-dose schedule

0.25 mL IM 28 days apart 

Anaphylaxis to vaccine or component, including a serious hypersensitivity reaction to protamine sulphate (for JEspect only)

≥3 years

2-dose schedule

0.5 mL IM 28 days apart (7 days apart for adults aged ≥18 years if imminent exposure)

For people at risk of JEV infection (as advised by the local ) who have previously been vaccinated against JE, they may be suitable for a booster dose if it has been more than 1 year since their primary schedule.

Women who are pregnant or breastfeeding

Pregnant women at risk of acquiring JE are recommended to receive JEspect. JEV infection during the first and second trimesters have been associated with miscarriage. 

No adverse outcomes of pregnancy have been attributed to vaccination with JEspect.

For breastfeeding women who are at increased risk of acquiring JE, JEspect is recommended in preference to Imojev. Imojev is not contraindicated in breastfeeding.

Booster doses

Booster doses are recommended for certain individuals if there is ongoing risk of JEV infection. The need for a booster dose of JE vaccine depends on the person’s age when they received their primary vaccination course, and the vaccine used for this primary course.

A booster dose (of either Imojev or JEspect) is recommended for people who are at risk of JEV infection (as advised by the local public health authority) and more than 1 year has passed since their primary JE vaccine course in childhood or as an adult.

This includes people who cannot identify the JE vaccine brand that they received, or those who have received the JE vaccine previously used in Australia (JEvax), or JE vaccines that are registered overseas that are used for JE vaccination program in endemic countries. The exception is people who have evidence that they received a dose of Imojev when they were aged ≥18 years, for whom a booster dose of a JE vaccine is not required.

Further information on booster doses is in the Australian Immunisation Handbook1

Co-administration with other vaccines

ATAGI advises that either Imojev or JEspect can be co-administered with other vaccines if required. For more information see the Australian Immunisation Handbook1.

Protective benefits after vaccination

Imojev and JEspect were registered based on immunologic correlate rather than efficacy trials.2 After vaccination with the primary schedule, for both vaccines and among both adults and children, a very high proportion (>95%) of subjects in the studies achieved the antibody level that were protective against the same viral strain as the vaccine, and at least 70% achieved that against related viral strains.3-12 Refer to the Australian Immunisation Handbook for more details.

Protection following vaccination has also been observed in studies in JE endemic areas. It is still possible that someone who is vaccinated may get infected with the JEV. All people in areas with JEV activity should use other measures to reduce the chance of infection through mosquito bites, such as the use of insect repellents and protective clothing, even if vaccinated.

Vaccine safety

Adverse events following JE vaccination are generally minor and short-lived, with most symptoms resolving within a few days.

Imojev

In adults, reported adverse events include injection site pain (4%-12%), headache (6%-26%), fatigue (2%-23%) and malaise (18%).5 In children aged 12-24 months adverse events occurred slightly more commonly, including pain (32%), redness (23%) and swelling (9%) at the injection site, fever (21%), appetite loss (26%), irritability (28%) and abnormal crying (23%).6

JEspect

Pain (33%), tenderness (33%), redness (9%), headache (20%) and myalgia (13%) occur commonly in adults. The frequency of reported systemic and local symptoms was lower after the second vaccination dose.13-17

In children aged 2 months to 17 years who received JEspect, adverse events included redness (25%), induration (8%), tenderness (8%), diarrhoea (17%) and loss of appetite (8%) with 0.25 mL and tenderness (50%), pain (25%), muscle aches (31%) and excessive fatigue (11%) with 0.5 mL.18 Fever (≥37.7°C) was more commonly reported in infants (24% after first dose) and young children (20% after the first dose in children aged 1 to <3 years) compared with older children, adolescents and adults.11

Adverse events reported following a booster dose of JEspect were similar to those reported following the primary course.14,19

Variation from product information

The Australian Product Information for JEspect currently states that this vaccine is for use in people aged ≥18 years. ATAGI recommends that children and adolescents aged ≥2 months to <18 years can receive this vaccine. This is based on paediatric studies.10-12 It should also be noted that numerous other regions and countries (e.g. the USA, UK, Europe) have registered and recommended the use of Ixario (the equivalent vaccine to JESpect with a different registered brand name) from 2 months of age.20-22

Note JESpect is also known as Ixiaro in some other countries (manufactured by Valneva and distributed in Australia by Seqirus/CSL).

Further reading

  1. Australian Immunisation Handbook. Japanese encephalitis. 2018. Available from: Japanese encephalitis
  2. World Health Organisation. Japanese Encephalitis Vaccines: WHO position paper – February 2015. Geneva, Switzerland: 2015. 
  3. Nasveld PE, Ebringer A, Elmes N, et al. Long term immunity to live attenuated Japanese encephalitis chimeric virus vaccine: randomized, double-blind, 5-year phase II study in healthy adults. Hum Vaccin 2010;6:1038-46.
  4. Erra EO, Askling HH, Rombo L, et al. A single dose of vero cell-derived Japanese encephalitis (JE) vaccine (Ixiaro) effectively boosts immunity in travelers primed with mouse brain-derived JE vaccines. Clin Infect Dis 2012;55:825-34.
  5. Torresi J, McCarthy K, Feroldi E, Méric C. Immunogenicity, safety and tolerability in adults of a new single-dose, live-attenuated vaccine against Japanese encephalitis: Randomised controlled phase 3 trials. Vaccine 2010;28:7993-8000.
  6. Chokephaibulkit K, Sirivichayakul C, Thisyakorn U, et al. Safety and immunogenicity of a single administration of live-attenuated Japanese encephalitis vaccine in previously primed 2- to 5-year-olds and naive 12- to 24-month-olds: multicenter randomized controlled trial. Pediatr Infect Dis J 2010;29:1111-7.
  7. Monath TP, Guirakhoo F, Nichols R, et al. 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. J Infect Dis 2003;188:1213-30.
  8. Monath TP, McCarthy K, Bedford P, et al. Clinical proof of principle for ChimeriVax: recombinant live, attenuated vaccines against flavivirus infections. Vaccine 2002;20:1004-18.
  9. Tauber E, Kollaritsch H, Korinek M, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet 2007;370:1847-53.
  10. Centers for Disease Control and Prevention. Use of Japanese Encephalitis Vaccine in Children: Recommendations of the Advisory Committee on Immunization Practices, 2013. Morbidity and Mortality Weekly Report 2013;62:898-900.
  11. Food and Drug Adminstration. Clinical review: IXIARO. 2013. 
  12. Dubischar-Kastner K, Ayad, A, Cramer, JP. Safety and immunogenicity data for inactivated Japanese encephalitis vaccine (JE-VC), IC51, in children from JE non-endemic countries [poster 2.7]. 5th Northern European Conference on Travel Medicine; June 2014; Bergen, Norway.
  13. Schuller E, Klingler A, Dubischar-Kastner K, Dewasthaly S, Müller Z. Safety profile of the Vero cell-derived Japanese encephalitis virus (JEV) vaccine IXIARO(®). Vaccine 2011;29:8669-76.
  14. Dubischar-Kastner K, Eder S, Buerger V, et al. Long-term immunity and immune response to a booster dose following vaccination with the inactivated Japanese encephalitis vaccine IXIARO, IC51. Vaccine 2010;28:5197-202.
  15. Kaltenböck A, Dubischar-Kastner K, Schuller E, et al. Immunogenicity and safety of IXIARO (IC51) in a Phase II study in healthy Indian children between 1 and 3 years of age. Vaccine 2010;28:834-9.
  16. Dubischar-Kastner K, Eder S, Buerger V, et al. Long-term immunity and immune response to a booster dose following vaccination with the inactivated Japanese encephalitis vaccine IXIARO, IC51. Vaccine 2010;28:5197-202.
  17. Appaiahgari MB, Vrati S. IMOJEV(®): a Yellow fever virus-based novel Japanese encephalitis vaccine. Expert Rev Vaccines 2010;9:1371-84.
  18. Jelinek T, Cromer MA, Cramer JP, et al. Safety and immunogenicity of an inactivated Vero cell_derived Japanese encephalitis vaccine (IXIARO(®), JESPECT(®)) in a pediatric population in JE non-endemic countries: An uncontrolled, open-label phase 3 study. Travel Med Infect Dis 2018;22:18-24.
  19. Eder S, Dubischar-Kastner K, Firbas C, et al. Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIARO®, IC51. Vaccine 2011;29:2607-12.
  20. European Medicines Agency. Ixiaro: Japanese encephalitis vaccine (inactivated, adsorbed). 2009.
  21. Centers for Disease Control and Prevention. Japanese Encephalitis Vaccine. 2019. 
  22. UK Health Security Agency. Chapter 20: Japanese encephalitis. 2018.
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