JE

JE-VAX®

Connaught

Japanese Encephalitis Virus Vaccine Inactivated

Active Immunizing Agent

Action And Clinical Pharmacology: Japanese encephalitis (JE), a mosquito-borne arboviral Flavivirus infection is the leading cause of viral encephalitis in Asia.

Infection leads to overt encephalitis in only 1 of 20 to 1 000 cases. Encephalitis usually is severe, resulting in a fatal outcome in 25% of cases and residual neuropsychiatric sequelae in 50% of cases. JE acquired during the first or second trimesters of pregnancy may cause intrauterine infection and miscarriage. Infections that occur during the third trimester of pregnancy have not been associated with adverse outcomes in newborns.

The virus is transmitted in an enzootic cycle among mosquitoes and vertebrate amplifying hosts, chiefly domestic pigs and, in some areas, wild Ardeid (wading) birds.

JE virus is transmitted seasonally in most areas of Asia. The seasonal patterns of viral transmission are correlated with the abundance of vector mosquitoes and of vertebrate amplifying hosts. Although the abundance of vector mosquitoes fluctuates with rainfall and with the impact of the rainy season in some tropical locations, irrigation associated with agricultural practices is a more important factor affecting vector abundance, and transmission may occur year round. Thus the periods of greatest risk for JE viral transmission vary regionally and within countries, and from year to year.

In areas where JE is endemic, annual incidence ranges from 1 to 10 per 10 000 people. Cases occur primarily in children under 10 years of age. Seroprevalence studies in these endemic areas indicate nearly universal exposure by adulthood (calculating from a ratio of asymptomatic to symptomatic infection of 200 to 1, approximately 10% of the susceptible population is infected per year).

Challenge experiments in passively protected mice have defined the levels of neutralizing antibody that may be considered protective for humans. Mice passively immunized to achieve a neutralizing antibody titre of ³1:10 were protected from a JE virus challenge of 10D50, a viral dose thought to be transmitted by an infected mosquito.

The efficacy of the BIKEN Nakayama-NIH strain Japanese Encephalitis Virus Vaccine Inactivated was demonstrated in a placebo-controlled, randomized clinical trial in Thai children, sponsored by the U.S. Army. In this trial, children between 1 and 14 years of age received BIKEN monovalent Nakayama-NIH strain (n=21 628) or a bivalent vaccine containing the Nakayama-NIH and Beijing JE virus strains (n=22 080) or tetanus toxoid as a placebo (n=21 516). Immunization consisted of 2 s.c. 1 mL doses of vaccine, except in children under 3 years of age who receive two 0.5 mL doses. One case (5 cases/100 000) of JE occurred in the monovalent vaccine group, 11 cases (51 cases/100 000) in the placebo group. The observed efficacy of both monovalent and bivalent vaccines was 91% (95% confidence interval, 54 to 98%). Side effects of vaccination, including headache, sore arm, rash and swelling were reported at rates similar to those in the placebo group, usually less than 1%. Symptoms did not increase after the second dose. It should be noted that a schedule of 2 doses, separated by 7 days, as employed in this trial, may be appropriate for use in residents of endemic or epidemic areas, where pre-existing exposure to Flaviviruses may contribute to the immune response.

Experience from the Centers for Disease Control and Prevention, and a controlled immunogenicity trial performed in U.S. military personnel demonstrated the need for a 3-dose vaccination schedule for persons not native to JE virus endemic areas. The CDC experience demonstrated that neutralizing antibody was produced in fewer than 80% of vaccinees following 2 doses of vaccine in U.S. travelers and antibody levels declined substantially in most vaccinees within 6 months. The U.S. Army studied the immunogenicity of Je-Vax in 538 volunteers. Two 3-dose regimens were evaluated (Day 0, 7 and 14 or Day 0, 7 and 30). All vaccine recipients demonstrated neutralizing antibodies at 2 months and 6 months after initiation of vaccination. The schedule of Day 0, 7 and 30 produced higher antibody responses than the Day 0, 7 and 14 schedule. Two hundred and seventy-three of the original study participants were tested at 12 months post-vaccination and there was no longer a statistical difference in antibody titres between the 2 vaccination regimens.

The full duration of protection is unknown. Of U.S. Army volunteers completing a 3-dose regimen, 252 agreed to receive a booster dose of vaccine 1 year after the primary series. All boosted participants still had antibody 12 months after the booster. Protective levels of neutralizing antibody persisted for 24 months (2 years) in all 21 persons who had not received a booster. Definitive recommendations cannot be given on the timing of booster doses at this time.

Indications And Clinical Uses: Provides active immunization against JE for persons 1 year of age and older. For the recommended primary immunization series see Dosage.

Je-Vax should be considered for use in persons who plan to reside in or travel to areas where JE is endemic or epidemic during a transmission season. The incidence of JE in the location of intended stay, the conditions of housing, nature of activities, duration of stay, and the possibility of unexpected travel to high-risk areas are factors that should be considered in the decision to administer vaccine. Vaccination should generally be considered for travelers of any age who will spend 3 weeks or more in rural areas during the seasons of transmission of endemic or epidemic JE; proximity to areas of rice culture or of pig farming increases the risk of acquiring JE. Depending on the epidemic circumstances, vaccine should be considered for persons spending less than 3 weeks whose activities, such as extensive outdoor activities in rural areas, place them at particularly high risk for exposure.

In all instances, travelers are advised to take personal precautions to reduce exposure to mosquito bites.

The decision to use Je-Vax should balance the risks for exposure to the virus and for developing illness; the availability and acceptability of repellents and other alternative measures; and the side effects of vaccination. Assessments should be interpreted cautiously because risk can vary within areas and from year to year and available data are incomplete. Although Je-Vax is reactogenic, rates of serious allergic reactions (generalized urticaria and/or angioedema) are low (approximately 1 to 104 per 10 000).

Advanced age may be a risk factor for developing symptomatic illness after infection. JE acquired during pregnancy carries the potential for intrauterine infection and fetal death. These factors should be considered when advising the elderly or pregnant women who plan to visit JE endemic areas.

There are no data on the safety and efficacy of Je-Vax in infants under 1 year of age. Whenever possible, immunization of infants should be deferred until they are 1 year of age or older.

Research Laboratory Workers: Laboratory acquired JE has been reported in 22 cases. JE virus may be transmitted in a laboratory setting through needle sticks and other accidental exposures. Vaccine-derived immunity presumably protects against exposure through these percutaneous routes. Exposure to aerosolized JE virus, and particularly to high concentrations of virus, such as may occur during viral purification, potentially could lead to infection through mucous membranes and possibly directly into the CNS through the olfactory epithelium. It is unknown whether vaccine derived immunity protects against such exposures, but immunization is recommended for all laboratory workers with a potential for exposure to infectious JE virus.

As with any vaccine, vaccination with Je-Vax may not result in protection in all individuals. Long-term protection, as demonstrated by persistence of neutralizing antibody for more than 2 years, has not yet been shown.

Contra-Indications: Adverse reactions to a prior dose of JE vaccine manifesting as generalized urticaria and angioedema are considered to be contraindications to further vaccination.

JE vaccine is produced in mouse brains and should not be administered to persons with a proven or suspected hypersensitivity to proteins of rodent or neural origin. Hypersensitivity to thimerosal is a contraindication to vaccination.

Manufacturers’ Warnings In Clinical States: Adverse reactions to JE vaccine manifesting generalized urticaria or angioedema may occur within minutes following vaccination. A possibly related reaction has occurred as late as 17 days after vaccination. Most reactions occur within 10 days with the majority occurring within 48 hours (see Adverse Effects).

Vaccinees should be observed for 30 minutes after vaccination and warned about the possibility of delayed generalized urticaria, often in a generalized distribution or angioedema of the extremities, face and oropharynx, especially of the lips.

Vaccinees should be advised to remain in areas where they have ready access to medical care for 10 days after receiving a dose of JE vaccine.

Persons should not embark on international travel within 10 days of Je-Vax Japanese Encephalitis Virus Vaccine Inactivated immunization because of the possibility of delayed allergic reactions. However, if departure is imminent and will occur in less than 10 days, an assessment to use Je-Vax must balance i) the risk of exposure the traveller will have to JE virus infection (if unvaccinated, or if an incomplete vaccine series given), and ii) the risk of having a delayed allergic reaction in the absence of accessible medical care.

Vaccinees should be instructed to seek medical attention immediately upon symptoms of any serious or unusual reaction, particularly, angioedema of the extremities, face and oropharynx, especially of the lips.

Persons with a past history of urticaria after hymenoptera envenomation, drugs, physical or other provocations, or of idiopathic cause appear to have a greater risk of developing reactions to JE vaccine (relative risk 9.1, 95% confidence interval 1.8 to 50.9). This history should be considered when weighing risks and benefits of the vaccine for an individual patient. When patients with such a history are offered JE vaccine, they should be alerted to their increased risk for reaction and monitored appropriately. There are no data supporting the efficacy of prophylactic antihistamines or steroids in preventing JE vaccine-related allergic reactions.

Precautions: General: Epinephrine Injection (1:1 000) must be immediately available should an acute anaphylactic reaction occur due to any component of the vaccine.

Prior to injection of any vaccine, all known precautions should be taken to prevent adverse reactions. This includes a review of the patient’s history with respect to possible sensitivity to this vaccine, a similar vaccine or allergic disorder in general (see Contraindications).

A separate, sterile syringe and needle or a disposable unit should be used for each patient to prevent transmission of infectious agents from person to person. Needles should not be recapped and should be disposed of properly.

Although substantial neutralizing antibody titres are elicited by Japanese Encephalitis Virus Vaccine Inactivated in more than 90% of U.S. travelers without history of prior JE immunization or of prior exposure to JE, the precise relationship between antibody level and efficacy has not been established even though these titres persisted for at least 2 years after immunization.

The decision to administer Je-Vax should balance the risks for exposure to the virus and for developing illness, the availability and acceptability of repellents and other alternative protective measures, and the side effects of vaccination.

Drug Interactions: There are no data on the effect of concurrent administration of other vaccines, drugs (e.g., chloroquine, mefloquine) or biologicals on the safety and immunogenicity of Je-Vax.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been performed to evaluate carcinogenicity, mutagenic potential, or impact on fertility.

Pregnancy: Animal reproduction studies have not been conducted with Japanese Encephalitis Virus Vaccine. It is not known whether Japanese Encephalitis Virus Vaccine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pregnant women who must travel to an area where risk of JE is high should be immunized when the theoretical risks of immunization are outweighed by the risk of infection to the mother and developing fetus. Japanese Encephalitis Virus Vaccine should be given to a pregnant woman only if clearly needed.

Lactation: It is not known whether Je-Vax is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Je-Vax is administered to a nursing woman.

Children: Safety and efficacy of JE vaccine in infants under 1 year of age have not been established.

Adverse Reactions: JE vaccine is associated with a moderate frequency of local and mild systemic adverse effects.

In a study conducted by the CDC less than 5% of the 1 756 U.S. travelers immunized with a 3-dose regimen of the vaccine reported headache, flu-like symptoms, fever, and other systemic complaints. Hives and facial swelling were reported in 0.2 and 0.1% of vaccinees, respectively. Local soreness occurred in 5.9% and local redness in 2.9%. There was no increase in the number or severity of reactions with increasing numbers of doses.

The U.S. Army studied 4 034 personnel from 1987 to 1989. Using a 2- or 3-dose regimen of JE vaccine, arm soreness was described in 22.7%, local redness in 4.8%, headache in 15.2%, and a febrile episode in 5.5%. In another trial evaluating the safety and immunogenicity of a 3-dose immunizing series (Day 0, 7 and 30 or Day 0, 7 and 14), performed in 538 adult volunteers in 1990, the Army determined that local soreness and redness occurred in 21% of vaccinees after the first dose.

Since 1989, an apparently new pattern of adverse reactions has been reported among vaccinees in Europe, North America and Australia. The reactions have been characterized by urticaria, often in a generalized distribution, or angioedema of the extremities, face, especially of the lips and oropharynx. Three vaccine recipients developed respiratory distress. Distress or collapse due to hypotension or other causes led to hospitalization in several cases. Most reactions were treated successfully with antihistamines or oral steroids; however, some patients were hospitalized for parenteral steroid therapy. Three patients developed an erythema multiforme or erythema nodosum and some patients had joint swelling. Some vaccinees complained of generalized itching without objective evidence of a rash.

An important feature of the reactions has been the interval between vaccination and onset of symptoms. Reactions after a first vaccine dose occurred after a median of 12 hours after immunization (88% of reactions occurred within 3 days). The interval between administration of a second dose and onset of symptoms generally was longer, (median 3 days and possibly as long as 2 weeks). Reactions have occurred after a second or third dose, when preceding doses were received uneventfully.

Between November 1991 and May 1992, the U.S. Navy immunized 35 253 U.S. personnel (marines, other military and dependents) with Japanese Encephalitis Virus Vaccine Inactivated on Okinawa. The overall reaction rate, 62.4 per 10 000 vaccinees (95% confidence interval 54.2 to 70.6) includes persons reporting urticaria, angioedema, generalized itching and wheezing. The reaction rate per 10 000 vaccinees was 26.7 (95% confidence interval 21.3 to 32.1), 30.8 (95% confidence interval 24.6 to 37.0) or 12.2 (95% confidence interval 7.9 to 16.5) after the first, second or third dose, respectively. These reactions were generally mild to moderate in severity. Nine out of 35 253 persons immunized were hospitalized (2.6 per 10 000 vaccinees) primarily to allow administration of i.v. steroids for refractory urticaria. None of these reactions were considered life-threatening.

A case-control study conducted as part of the JE immunization campaign in Okinawa found that persons developing these reactions after JE vaccination were more likely to have had a past history of urticaria after hymenoptera envenomation, drugs, physical or other provocations of idiopathic origins (relative risk 9.1, 95% confidence interval 1.8 to 50.9). The vaccine constituents responsible for these adverse reactions have not been identified.

Other serious adverse events reported following vaccination include (1) one case of Guillain-Barre syndrome after JE vaccination has been reported in the United States since 1984, however, this patient was diagnosed as having mononucleosis 3 weeks before the onset of weakness; (2) one case of urticaria, hepatitis and respiratory failure 1 week after dose 2 (this person showed effusion and infiltrate on chest x-ray and eosinophilia), and (3) one case of respiratory and renal failure 1 week after a dose (this 26-month-old male had infiltrate on chest x-ray and acid fast bacilli in sputum); and (4) one case of newly diagnosed hypertension in a young adult male presenting with a headache several hours after receiving dose one. The etiology of these adverse events is unknown.

Sudden death occurred approximately 60 hours after receiving the first dose of JE vaccine in a 21-year-old U.S. military person with a history of recurrent hypersensitivity and an episode of possible anaphylaxis. This person also received the third dose of plague vaccine approximately 12 to 15 hours prior to the death. There was no evidence of urticaria or angioedema. Cause of death was not established at autopsy.

Surveillance of JE vaccine-related complication in Japan from 1965 to 1973 disclosed neurologic events (primarily encephalitis, encephalopathy, seizures, and peripheral neuropathy) in 1 to 2.3 per million vaccinees. Very rarely, deaths occurred with vaccine-associated encephalitis. Between 1987 and 1989, 2 cases of neurologic dysfunction were reported from Japan; one of these was a transverse myelitis, while the second included seizures, cranial nerve paresis, cerebellar ataxia, and behavior disorder. In 1992, 2 cases of acute disseminated encephalomyelitis were reported from Japan; one occurred 14 days after the second dose and the second occurred 17 days after a booster dose of JE vaccine. Both cases recovered. One case of Bell’s Palsy was reported from Thailand.

Reporting of Adverse Events: Reporting by parents and patients of all adverse events occurring after antigen administration should be encouraged. Health care providers should report any occurrences temporally related to the administration of the product in accordance with provincial and federal statutory requirements.

Health care providers also should report these events to the Department of Medical Affairs, Connaught Laboratories Limited.

Dosage And Administration: Parenteral drug products should be inspected visually for extraneous particulate matter and/or discoloration prior to administration whenever solution and container permit. If either of these conditions exist, the vaccine should not be administered.

For persons 3 years of age and older, a single dose is 1 mL of vaccine. For children 1 year to 3 years of age, a single dose is 0.5 mL of vaccine. (see Primary Immunization Schedule).

Single-Dose Vial of Lyophilized Vaccine: Remove plastic tab of flip-off cap. Do not remove rubber stopper. Cleanse stopper with a suitable disinfectant. Reconstitute only with the supplied 1.3 mL of Sterile Diluent (water for injection). Shake vial thoroughly.

Primary Immunization Schedule: The recommended primary immunization series is 3 doses of 1 mL each for individuals>3 years of age given s.c. on days 0, 7 and 30. For children 1 to 3 years of age a series of 3 doses of 0.5 mL each should be given s.c. on days 0, 7 and 30. An abbreviated schedule of days 0, 7 and 14 can be used when the longer schedule is impractical because of time constraints. (When it is impossible to follow one of the above recommended schedules, 2 doses given a week apart will induce antibodies in approximately 80% of vaccinees; however, this 2-dose regimen should not be used except under unusual circumstances.) The last dose should be given at least 10 days before the commencement of international travel to ensure an adequate immune response and access to medical care in the event of delayed adverse reactions.

A booster dose of 1 mL (0.5 mL for children from 1 to 3 years of age) may be given after 2 years. In the absence of firm data on the persistence of antibody after primary immunization, a definite recommendation cannot be made on the spacing of boosters beyond 2 years.

There are no data on the safety and efficacy of JE vaccine in infants under 1 year of age. Whenever possible, immunization of infants should be deferred until they are 1 year of age or older.

The skin at the site of injection first should be cleansed and disinfected. Shake the vial well to uniformly distribute the suspension before withdrawing the dose.

When Japanese Encephalitis Virus Vaccine Inactivated and any other vaccines are given concurrently, separate syringes and separate sites should be used.

Each person who is immunized should be given a permanent personal immunization record. In addition, it is essential that the health care provider also maintain a permanent record of the immunization history of each individual. This office record should contain the name of the vaccine, date given, manufacturer and lot number.

Availability And Storage: Japanese Encephalitis Virus Vaccine Inactivated is a sterile, lyophilized vaccine for s.c. use, prepared by inoculating mice intracerebrally with Japanese encephalitis (JE) virus, “Nakayama-NIH” strain, manufactured by The Research Foundation for Microbial Diseases of Osaka University (“BIKEN”). Infected brains are harvested and homogenized in phosphate buffered saline, pH 8.0. The homogenate is centrifuged and the supernatant inactivated with formaldehyde, then processed to yield a partially purified, inactivated virus suspension. This is further purified by ultra-centrifugation through 40% w/v sucrose. Thimerosal (mercury derivative) is added as a preservative to a final concentration of 0.007%. The suspension is then lyophilized in final containers and sealed under dry nitrogen atmosphere. The Sterile Diluent (water for injection), contains no preservative. Each 1 mL dose contains approximately gelatin 500 g, less than 100 g of formaldehyde, and less than 50 ng of mouse serum protein. No myelin basic protein can be detected at the detection threshold of the assay.

Boxes of 5 single dose vials with 5´1.3 mL vials of Sterile Diluent (water for injection). Boxes of 3 single dose vials with 3´1.3 mL vials of Sterile Diluent (water for injection). Store between 2 and 8°C. Do not freeze. After reconstitution the vaccine should be stored between 2 and 8°C and used within 8 hours. Do not freeze reconstituted vaccine.

JE-VAX® Connaught Japanese Encephalitis Virus Vaccine Inactivated Active Immunizing Agent

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