Japanese Encephalitis Vaccine (Monograph)

Brand name: Ixiaro
Drug class: Vaccines
ATC class: J07BA01
VA class: IM100

Introduction

Inactivated virus vaccine. Commercially available in US as Japanese encephalitis vaccine inactivated adsorbed, an inactivated Vero cell culture-derived vaccine (JE-VC; Ixiaro). Other inactivated Japanese encephalitis vaccines (e.g., inactivated mouse brain-derived vaccine; JE-MB) and live, attenuated or live, chimeric Japanese encephalitis vaccines may be available in Asia or elsewhere.

Uses for Japanese Encephalitis Vaccine

Prevention of Disease Caused by Japanese Encephalitis Virus

Prevention of disease caused by Japanese encephalitis virus in adults, adolescents, and children 2 months of age or older. Used to stimulate active immunity against Japanese encephalitis virus in travelers and other individuals (e.g., laboratory personnel) at risk of exposure to the virus.

Japanese encephalitis virus, a Flavivirus closely related to West Nile virus (WNV), St. Louis and Murray Valley encephalitis viruses, yellow fever virus, and dengue virus, is transmitted to humans through the bite of infected mosquitoes that acquired the virus by biting infected vertebrate hosts (usually pigs or wading birds). Humans are incidental or dead-end hosts for Japanese encephalitis virus since level or duration of viremia usually insufficient to infect mosquitoes. Direct person-to-person transmission of the virus does not occur; however, intrauterine transmission from mother to child during pregnancy can occur and transmission through blood products or transplanted organs theoretically could occur.

Endemic transmission of Japanese encephalitis virus reported in ≥24 countries in Southeast Asia and Western Pacific. Although infection with the virus usually results in asymptomatic or mild disease (fever, headache, aseptic meningitis), 1 out of every 200–250 infections results in severe disease (rapid onset of high fever, headache, vomiting, generalized weakness, neck stiffness, disorientation, seizures, spastic paralysis, coma, death). In areas where the virus is endemic, approximately 30,000–68,000 cases of Japanese encephalitis reported annually; case fatality rate is approximately 20–30% and 30–50% of survivors have permanent neurologic or psychiatric sequelae.

For most travelers to Asia, risk of acquiring Japanese encephalitis virus is very low, but varies depending on location and duration of travel, season, and traveler's expected activities. Overall incidence of Japanese encephalitis among individuals from nonendemic countries traveling in Asia is estimated to be <1 case per 1 million travelers. Although risk considered minimal for most short-term travelers (traveling for <1 month) who only visit urban areas in Asia, risk for travelers who stay for prolonged periods in rural areas where active transmission of Japanese encephalitis virus is occurring and short-term or recurrent travelers who have extensive outdoor or nighttime exposure in rural areas during periods of active transmission of the virus is probably similar to risk in susceptible resident populations.

Risk of transmission of Japanese encephalitis virus is greatest in rural agricultural areas where the virus is endemic and often is related to rice production and flooding irrigation, which results in large numbers of vector mosquitoes breeding in close proximity to amplifying vertebrate hosts. In temperate areas of Asia, Japanese encephalitis virus is transmitted seasonally (usually peaking in the summer and fall) and large seasonal epidemics can occur. In tropical and subtropical areas, transmission of the virus can be sporadic or occur all year, but often peaks during the rainy season.

When making recommendations regarding vaccination against Japanese encephalitis virus for travelers, consider overall low risk for travel-associated Japanese encephalitis virus disease, high morbidity and mortality associated with Japanese encephalitis, low probability of serious adverse effects following vaccination, and vaccine cost. Also consider planned itinerary, including destinations, duration of travel, season, accommodations, and activities as well as possibility of unexpected travel to high-risk areas.

Travelers planning to spend ≥1 month in endemic areas during Japanese encephalitis virus transmission season: USPHS Advisory Committee on Immunization Practices (ACIP) and CDC recommend vaccination with JE-VC for all such travelers. This includes long-term travelers, recurrent travelers, or expatriates who will be based in urban areas but are likely to visit endemic rural or agricultural areas during a high-risk period of Japanese encephalitis virus transmission.

Short-term travelers (traveling for <1 month) to endemic areas during Japanese encephalitis virus transmission season if they are planning to travel outside of urban areas or do activities associated with increased exposure: ACIP and CDC state that vaccination with JE-VC should be considered for such travelers. This includes those who will spend substantial time outdoors in rural or agricultural areas (especially during the evening or nighttime), those who will participate in extensive outdoor activities (e.g., camping, hiking, trekking, biking, fishing, hunting, farming), and those staying in accommodations without air conditioning, screens, or bed nets.

Travelers to areas with an ongoing Japanese encephalitis outbreak and travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel: ACIP and CDC state that vaccination with JE-VC should be considered for such travelers.

Short-term travelers (traveling for <1 month) to Asia when visit restricted to urban areas or times outside a well-defined Japanese encephalitis virus transmission season: Vaccination with JE-VC not recommended.

All individuals considering travel to areas where Japanese encephalitis has been reported: Because risk of infection with Japanese encephalitis virus is highly variable within endemic regions and varies from year to year within a given region, consult current CDC recommendations for international travel for information concerning geographic areas where transmission of the virus is being reported. Information on risk of Japanese encephalitis in specific countries, information on mosquito avoidance and protective measures against mosquito bites, and additional information regarding benefits and risks of JE-VC vaccination in travelers is available from CDC at [Web] and [Web].

Laboratory personnel at risk of exposure to infectious Japanese encephalitis virus: ACIP recommends vaccination with JE-VC for all such workers. Laboratory-acquired cases of Japanese encephalitis reported; the virus may be transmitted in laboratory settings through needlestick injuries or, theoretically, through mucosal or inhalational exposures.

Japanese Encephalitis Vaccine Dosage and Administration

General

When decision made to administer JE-VC to travelers or other individuals (e.g., laboratory personnel) at risk of exposure to Japanese encephalitis virus, consider that the primary vaccination series includes 2 doses given 28 days apart and the series should be completed at least 1 week prior to potential exposure to the virus. (See Dosage under Dosage and Administration.)
Regardless of JE-VC vaccination or circumstances and timing of travel, advise all travelers to Asia to take precautions to avoid mosquito bites to reduce risk of exposure to Japanese encephalitis virus and other vector-borne infectious diseases. Such precautions include use of insect repellant and protective clothing; staying in accommodations with air conditioning, screens, or bed nets; and avoiding extensive outdoor activities, especially during the evening and nighttime.

Administration

Administer by IM injection. Do not give IV, intradermally, or sub-Q.

Commercially available in prefilled single-dose glass syringes containing 0.5 mL of the vaccine.

During storage, appears as clear liquid with white precipitate. Immediately prior to administration, shake syringe to obtain white, opaque, homogeneous suspension. Do not use if discolored or contains particulates.

After shaking prefilled syringe, attach sterile needle. To provide appropriate dose for children 2 months through 2 years of age (0.25 mL), expel indicated portion of syringe contents through the needle into a medical waste container according to manufacturer's directions; then, replace the needle with a new sterile needle and administer the remaining 0.25 mL of vaccine in the syringe IM. For adults, adolescents, and children ≥3 years of age, administer entire syringe contents (0.5 mL) IM.

Do not mix with any other vaccine.

Syncope (vasovagal or vasodepressor reaction; fainting) may occur following vaccination; such reactions occur most frequently in adolescents and young adults. Syncope and secondary injuries may be averted if vaccinees sit or lie down during and for 15 minutes after vaccination. If syncope occurs, observe patient until symptoms resolve.

May be given simultaneously with other age-appropriate vaccines. When multiple parenteral vaccines are administered during a single health-care visit, give each vaccine using different syringe and different injection site. Separate injection sites by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.

IM Administration

Depending on patient age, administer IM into deltoid muscle or anterolateral thigh. In infants and children 2 months through 2 years of age, anterolateral thigh is preferred; alternatively, deltoid muscle can be used in those 1 through 2 years of age if muscle mass is adequate. In adults, adolescents, and children ≥3 years of age, deltoid muscle is preferred.

To ensure delivery into muscle, make IM injections at a 90° angle to the skin using a needle length appropriate for the individual’s age and body mass, thickness of adipose tissue and muscle at injection site, and injection technique.

Avoid injection into gluteal area or into or near blood vessels or nerves. Generally do not administer vaccines into gluteal area or any area where there may be a major nerve trunk. If gluteal muscle is chosen for infants <12 months of age because of special circumstances (e.g., physical obstruction of other sites), it is essential that clinician identify anatomic landmarks prior to injection.

Dosage

Pediatric Patients

Prevention of Disease Caused by Japanese Encephalitis Virus

Children 2 Months through 2 Years of Age

Each dose is 0.25 mL from prefilled syringe (see Administration under Dosage and Administration).

Primary immunization: 2 doses given 28 days apart. Complete 2-dose primary series at least 1 week prior to potential exposure to Japanese encephalitis virus.

Booster dose: Safety and immunogenicity not evaluated in children 2 months through 2 years of age.

Children and Adolescents 3 through 16 Years of Age

Each dose is entire contents (0.5 mL) of prefilled syringe.

Primary immunization: 2 doses given 28 days apart. Complete 2-dose primary series at least 1 week prior to potential exposure to Japanese encephalitis virus.

Booster dose: Safety and immunogenicity not evaluated in children and adolescents 3 through 16 years of age.

Adults

Prevention of Disease Caused by Japanese Encephalitis Virus

Adults 17 Years of Age or Older

Each dose is entire contents (0.5 mL) of prefilled syringe.

Primary immunization: 2 doses given 28 days apart. Complete 2-dose primary series at least 1 week prior to potential exposure to Japanese encephalitis virus.

Incomplete primary immunization: If second primary dose delayed, there is some evidence that high seroconversion rates are attained in adults if second dose administered within 11 months after initial dose.

Booster dose in adults who previously received 2-dose primary series and have ongoing risk of exposure or expect reexposure to the virus: Give single 0.5-mL dose, provided it has been ≥1 year since completion of 2-dose primary series. Data not available regarding immune response in adults who receive booster dose >2 years after completion of 2-dose primary series. Data not available regarding need for and timing of additional booster doses.

Previously received JE-MB (no longer available in US but may be available in other countries) and have ongoing risk of exposure or expect reexposure to the virus: Revaccinate with usually recommended 2-dose primary series of JE-VC.

Special Populations

No special population recommendations.

Cautions for Japanese Encephalitis Vaccine

Contraindications

Severe allergic reaction (e.g., anaphylaxis) to a previous dose of JE-VC or any component of the vaccine (e.g., protamine sulfate).
Severe allergic reaction to any other Japanese encephalitis vaccine. Alternatively, because of uncertainty regarding what component of the other vaccine may have been responsible for allergic reaction, refer such individuals to an allergist for evaluation to determine whether JE-VC should be considered.

Warnings/Precautions

Sensitivity Reactions

Contains protamine sulfate, a compound known to cause hypersensitivity reactions in some individuals.

Ensure that appropriate medical care is readily available in case an anaphylactic reaction occurs.

Individuals with Altered Immunocompetence

Although specific data not available regarding use of JE-VC in individuals immunosuppressed as the result of disease or immunosuppressive therapy, inactivated vaccines usually may be administered to individuals with altered immunocompetence. Consider possibility that immune response to vaccines may be diminished or suboptimal in these individuals.

If possible, complete vaccination at least 2 weeks prior to initiation of immunosuppressive therapy or defer until at least 3 months after immunosuppressive therapy discontinued. (See Specific Drugs under Interactions.)

Concomitant Illness

A decision to administer or delay vaccination in an individual with a current or recent acute illness depends on the severity of symptoms and etiology of the illness.

ACIP states defer vaccination in individuals with a moderate or severe acute illness until they have recovered to avoid superimposing adverse effects of the vaccine on the underlying illness or to avoid mistakenly concluding that a manifestation of the underlying illness resulted from vaccination.

Limitations of Vaccine Effectiveness

JE-VC may not protect all vaccine recipients against Japanese encephalitis.

Individuals who receive only a single dose of JE-VC may not be protected against Japanese encephalitis virus; protection is unreliable until 7 days after second primary dose. (See Dosage under Dosage and Administration.)

Will not provide protection against encephalitis caused by other viruses or other pathogens; will not provide protection against other diseases transmitted by mosquitoes.

Duration of Immunity

Duration of immunity following vaccination with 2-dose primary series of JE-VC not fully determined.

Although there is some evidence from one study in adults that protective immunity persists for 6, 12, 24, and 36 months in 95, 83, 82, and 85%, respectively, of those who receive the 2-dose primary series of JE-VC, another study in adults indicated that only 83, 58, and 48% of vaccinees had protective immunity 6, 12, and 24 months, respectively, after initiation of the primary series.

Following an age-appropriate 2-dose primary series of JE-VC in children 2 months through 17 years of age, all had protective immunity 7 months later.

Improper Storage and Handling

Improper storage or handling of vaccines may reduce vaccine potency resulting in reduced or inadequate immune responses in vaccinees.

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained. (See Storage under Stability.)

Do not administer vaccine that has been mishandled or has not been stored at the recommended temperature. If there are concerns about mishandling, contact the manufacturer or state or local immunization or health departments for guidance on whether the vaccine is usable.

Specific Populations

Pregnancy

Category B.

Use during pregnancy only if clearly needed.

No adequate and well-controlled studies in pregnant women; in animal studies (female rats), no evidence of impaired fertility or harm to fetus.

Consider that Japanese encephalitis virus acquired during first or second trimester of pregnancy may cause intrauterine infection and spontaneous abortion; there is some evidence that intrauterine transmission of the virus can occur.

Report cases of inadvertent administration of JE-VC during pregnancy to 877-683-4732.

Lactation

Not known whether distributed into human milk.

Use with caution in nursing women.

Pediatric Use

Safety and efficacy not established in infants <2 months of age.

Geriatric Use

Data insufficient to determine whether adults ≥65 years of age respond differently than younger adults.

Common Adverse Effects

Infants and children 2 months through 11 years of age: Fever, irritability, flu-like symptoms, diarrhea, vomiting, loss of appetite, rash, injection site reactions (pain, tenderness, erythema).

Adults and adolescents ≥12 years of age: Headache, myalgia, fatigue, influenza-like illness, nausea, injection site reactions (pain, tenderness, erythema, induration).

Drug Interactions

Vaccines

Although specific studies may not be available evaluating concurrent administration with each antigen, simultaneous administration with other age-appropriate vaccines, including live virus vaccines, toxoids, or inactivated or recombinant vaccines, during the same health-care visit generally not expected to affect immunologic responses or adverse reactions to any of the preparations. However, each parenteral vaccine should be administered using a different syringe and different injection site.

Specific Drugs

Drug

Interaction

Comments

Hepatitis A (HepA) vaccine

Has been administered concomitantly with HepA vaccine in healthy adults; no effect on immune response to either vaccine

May be administered concurrently (using different syringes and different injection sites)

Immunosuppressive agents (e.g., alkylating agents, antimetabolites, corticosteroids, radiation)

Potential for diminished or suboptimal antibody response to JE-VC

If possible, complete vaccination ≥2 weeks prior to initiation of immunosuppressive therapy or defer vaccination until ≥3 months after such therapy discontinued

If administered during chemotherapy, revaccinate after immune competence is regained

Stability

Storage

Parenteral

Suspension for IM Use

2–8°C; do not freeze.

Store in original packaging; protect from light.

Actions

JE-VC is a sterile suspension containing purified, inactivated Japanese encephalitis virus proteins adsorbed onto aluminum hydroxide and is used to stimulate active immunity to Japanese encephalitis virus.
Promotes production of antibodies that neutralize live Japanese encephalitis virus. Data from animal studies, clinical trials of other Japanese encephalitis vaccines, and epidemiologic studies in humans suggest that a Japanese encephalitis virus-specific neutralizing antibody titer (as measured in vitro in a 50% plaque reduction neutralization test [PRNT₅₀]) of 1:10 correlates with protective immunity against Japanese encephalitis virus infection in humans.
Following vaccination with a 2-dose primary series of JE-VC in adults ≥18 years of age residing in countries where Japanese encephalitis virus is not endemic, only 21% of vaccinees had protective levels of antibody 10 days after first dose, but 97% had protective antibody levels 7 days after second vaccine dose and still had protective antibody levels 28 days after second dose. Data from a study in adults residing in nonendemic countries indicate that protective levels of antibody persist for 6, 12, 24, and 36 months in 95, 83, 82, and 85%, respectively, of those who receive a 2-dose primary series of JE-VC.
Following vaccination with an age-appropriate 2-dose primary series of JE-VC in infants and children 2 months through 17 years of age residing in nonendemic countries, 100% had protective antibody levels when evaluated 56 days and 7 months later.
A single booster dose of JE-VC given 14–24 months after completion of 2-dose primary series elicits a booster response in adults. Data from a study in adults residing in nonendemic countries who received a single booster dose of JE-VC 14 months after completion of the 2-dose primary series indicate that the proportion of these adults with protective antibody levels increased from 69% immediately prior to the booster dose to 100% at 28 days after the booster dose; 99% still had protective antibody levels 12 months after the booster dose.
Although further study needed, administration of JE-VC in adults who previously received primary vaccination with inactivated mouse brain-derived Japanese encephalitis vaccine (JE-MB; no longer available in the US but may be available in other countries) results in a booster response.

Advice to Patients

Prior to administration of each dose of JE-VC, provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient’s legal representative (VISs are available at [Web]).
Advise patient and/or patient’s parent or guardian of the risks and benefits of vaccination against Japanese encephalitis virus.
Importance of consulting current US and international advisories regarding the prevalence of Japanese encephalitis in specific locations prior to travel. Information is available from CDC at [Web] and [Web].
Importance of completing the 2-dose primary vaccination series of JE-VC at least 1 week prior to potential exposure to Japanese encephalitis virus.
Advise patient and/or patient's parent or guardian that JE-VC may not fully protect everyone who receives the vaccine, and that travelers to areas with Japanese encephalitis virus should take precautions to avoid mosquito bites (e.g., use insect repellant, wear protective clothing, stay in accommodations with air conditioning, screens, or bed nets).
Importance of informing clinicians of any reactions to a previous dose of JE-VC or to any other vaccines.
Importance of informing clinicians of any signs and/or symptoms of severe adverse reactions or anaphylaxis (e.g., difficulty breathing, wheezing, weakness or fast heart beat, hives) that occur after administration of JE-VC. Clinicians or individuals can report any adverse reactions that occur following vaccination to Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.