Imojev

Live, attenuated, recombinant Japanese encephalitis virus (propagated in Vero cells).

After reconstitution, one dose (0.5 mL) contains: Live, attenuated, recombinant Japanese encephalitis virus^*: 4.0 - 5.8 log PFU^**.
^* Propagated in Vero cells.
^** Plaque Forming Unit.
Excipients/Inactive Ingredients: Powder: Mannitol, Lactose monohydrate, Glutamic acid, Potassium hydroxide, Histidine, Human Serum Albumin.
Diluent: Sodium chloride, Water for injections.
No adjuvant or antimicrobial preservative is added.
The powder is a white to creamy white homogeneous cake which might be retracted from the sides of the vial.
The diluent is a clear solution.
After reconstitution, IMOJEV is a colourless to amber suspension.

Pharmacology: Pharmacodynamics: Mechanism of action: The vaccine is a live attenuated virus. Following administration, the virus replicates locally and elicits neutralising antibodies and cell-mediated immune responses that are specific to the Japanese encephalitis virus. Available results indicate that protection is mainly mediated by neutralising antibodies.
In nonclinical studies, all animals that received a single dose of the vaccine developed specific neutralising antibodies against Japanese encephalitis virus and were protected against infection by a virulent Japanese encephalitis virus experimental challenge.
Immunogenicity: Passive antibody transfer results in a small animal model indicate that protection is mediated by neutralising antibodies and that the threshold for protection is a plaque reduction neutralisation titer of 1:10.
Immunogenicity data in adult population: A single dose administration of IMOJEV is as immunogenic as a three-dose regimen of an inactivated Japanese encephalitis comparator vaccine administered in adults 18 years of age and over.
A seroprotective level of antibodies is generally reached 14 days after vaccination.
In a randomised comparative phase III trial, 410 subjects over 18 years of age received a single dose of not less than 4.0 log PFU/dose of 0.5 mL of IMOJEV and 410 subjects over 18 years of age received a three-dose regimen of 1 mL of an inactivated Japanese encephalitis comparator vaccine.
Thirty days after vaccination, the seroprotection rates for the subjects who received IMOJEV were more than 99% when measured against the homologous virus strain. These results are non inferior to those observed after the three dose regimen of the inactivated Japanese encephalitis comparator vaccine.
Fourteen days after a single dose of IMOJEV, approximately 93% of the vaccinees showed seroprotective levels of neutralising antibodies.
In a long-term follow-up assessment in a randomised control phase II trial, 97.6% (95% CI, 93.3; 98.8) of subjects showed seroprotective levels six months after a single administration of IMOJEV.
Long-term immunogenicity data up month 60 are presented as Kaplan-Meier estimates the probability of being still seroprotected 60 months after vaccination for those who were seroprotected at six months is 86.8%.
Immunogenicity data in paediatric populations: Primary Vaccination: A seroprotective level of antibodies is generally reached 28 days after vaccination.
A single dose administration of IMOJEV in 2 randomised trials in 1,231 toddlers (12 to 24 months) not previously immunized with a Japanese encephalitis vaccine shows that approximately 95% of subjects seroconverted and are seroprotected (neutralizing antibody level above the threshold of protection) after 28 days. A single dose administration of IMOJEV in a randomised comparative phase III trial in infants and toddlers (9 to 18 months) (N=126) not previously immunized with a Japanese encephalitis vaccine showed that more than 99% of individuals seroconverted and were seroprotected after 28 days.
The persistence of seroprotection was assessed in a Phase II and a Phase III trials in toddlers (12 to 24 months).
In the phase II trial, approximately 65% of toddlers who did not receive any Japanese encephalitis vaccine before the single dose administration of IMOJEV were shown to still have seroprotective antibody level 5 years after the vaccination (N = 151).
Table 1 shows the immune response up to 5 years after vaccination with a single dose of IMOJEV (see Table 1).


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In the Phase III trial, approximately 75% of toddlers who did not receive any Japanese encephalitis vaccine before the single dose administration of IMOJEV were shown to still have seroprotective antibody levels 5 years after the vaccination (N=478). All the toddlers included in this trial with serological data available 28 days after vaccination were seroprotected at this time point.
Table 2 shows the immune response against the homologous virus, up to 5 years after vaccination with a single dose of IMOJEV (see Table 2).


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In another phase III trial in infants and toddlers (9 to 18 months) not previously immunized with a Japanese encephalitis vaccine, approximately 88% of individuals were still seroprotected 1 year after the single dose administration of IMOJEV.
Booster: Booster dose of IMOJEV after primary vaccination with IMOJEV: In a phase III trial, a second dose (booster dose) of IMOJEV was administered in children (36 to 42 months) (N = 340) 24 months after primary vaccination with IMOJEV. A control group of children (36 to 42 months) (N = 39) who never received a Japanese encephalitis vaccine, received IMOJEV for the first time to characterize the primary response to IMOJEV.
The Geometric Mean Titer (GMT) increased by nearly 6 fold from Day 0 to Day 7 after the administration of IMOJEV to subjects previously vaccinated. By comparison, the GMT did not increase the control group, thus demonstrating an anamnestic response in the booster group. The GMT increased by nearly 57 fold from Day 0 to Day 28 in the booster group.
100% of children previously vaccinated with IMOJEV showed seroprotective antibody levels 28 days after the administration of the booster dose 24 months after primary vaccination.
Table 3 shows the immune response against the homologous virus strain, 7 and 28 days after administration of a booster dose of IMOJEV (see Table 3).


Click on icon to see table/diagram/image


In a Phase III trial, a second dose (booster dose) of IMOJEV was administered in children (18 to 36 months of age) (N=53) between 12 and 18 months after primary vaccination with IMOJEV.
The GMT increased by nearly 62 fold from Day 0 to Day 28 in the booster group.
100% of children previously vaccinated with IMOJEV showed seroprotective antibody titers 28 days after the administration of the booster dose between 12 and 18 months after primary vaccination.
In the long-term follow-up assessment of the phase III trial, nearly all children (98.2%) who received the booster dose of IMOJEV 24 months after primary vaccination were shown to still have seroprotective antibody levels 4 years after the vaccination.
Table 4 shows the immune response up to 4 years after vaccination with a booster dose of IMOJEV (see Table 4).


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Booster vaccination with IMOJEV after the administration of an inactivated JE vaccine as a primary immunization.
In a Phase II trial, IMOJEV was administered to children (2 to 5 years) (N = 97) 6 to 38 months after a two-dose primary vaccination with an inactivated Japanese encephalitis vaccine (mouse brain-derived Japanese encephalitis vaccine).
The GMT increased by nearly 59 fold from Day 0 to Day 28. Approximately 93% of subjects seroconverted and they were all seroprotected (titer above a threshold considered as protective) 28 days after the administration of IMOJEV.
Table 5 shows the immune response 28 days after the administration of a booster dose of IMOJEV after a primary vaccination with an inactivated JE vaccine (see Table 5).


Click on icon to see table/diagram/image


In the long-term follow up assessment of the phase II trial, nearly all children (97.5%) who received the booster dose of IMOJEV 6 to 38 months after the two-dose primary vaccination with the inactivated Japanese encephalitis vaccine were shown to still have seroprotective antibody levels 3 years after the vaccination.
Table 6 shows the immune response up to 5 years after the administration of a booster dose of IMOJEV after a primary vaccination with an inactivated JE vaccine (see Table 6).


Click on icon to see table/diagram/image


Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non clinical data revealed no special hazard for humans based on animal studies.

Imojev is indicated for prophylaxis of Japanese encephalitis caused by the Japanese encephalitis virus, in subjects from 9 months of age and over.

Posology: Primary Vaccination: Subjects 9 months of age and over one 0.5 mL single injection of the reconstituted vaccine.
Booster: Paediatric population: Paediatric population (up to 18 years of age): If a long term protection^* is required, one 0.5 mL dose of IMOJEV should be given as a booster dose after primary vaccination. The booster dose should be given preferably 12 months after primary vaccination and can be given up to 24 months after primary vaccination.
One 0.5 mL dose of Imojev can also be given as a booster vaccination in children who were previously given an inactivated Japanese encephalitis vaccine for primary vaccination, in accordance with the recommended timing for the booster of the inactivated Japanese encephalitis vaccine.
^*Immunity is maintained at a high level at least 4 years after the booster dose when the vaccine used for primary vaccination is JE-CV (Imojev).
Adult population: The need for and timing of a possible booster dose have not yet been determined.
Method of administration: Once the freeze-dried vaccine has been completely reconstituted using the diluent provided (see Special precautions for disposal and other handling under Cautions for Usage), it is administered via the subcutaneous route.
In subjects 2 years of age and over, the recommended injection site is the deltoid region of the upper arm.
In subjects between 9 and 24 months of age, the recommended injection site is the anterolateral aspect of the thigh or the deltoid region.
Do not administer by intravascular injection.
IMOJEV must not be mixed with any other injectable vaccine(s) or medicinal product(s).

Not documented.

IMOJEV should not be administered to anyone with a history of severe allergic reaction to any component of the vaccine or after previous administration of the vaccine or a vaccine containing the same components or constituents.
Vaccination must be postponed in case of febrile or acute disease.
Congenital or acquired immune deficiency impairing cellular immunity, including immunosuppressive therapies such as chemotherapy, high doses of systemic corticosteroids given for 14 days or more (see Precautions and Interactions).
IMOJEV must not be administered to persons with symptomatic HIV infection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function.
Pregnancy (see Use in Pregnancy & Lactation).
Lactation (see Use in Pregnancy & Lactation).

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following administration of the vaccine.
For patients following a treatment with high doses of systemic corticosteroids given for 14 days or more, it is advisable to wait for at least one month or more following the interruption of therapy before carrying out the vaccination until immune function has recovered.
Do not administer by intravascular injection.
Effects on the ability to drive and use machines: No studies on the effects on the ability to drive or use machines have been performed.

Animal studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryo-foetal development, parturition or post-natal development (see Pharmacology: Toxicology: Preclinical safety data under Actions).
As with all live attenuated vaccines, pregnancy constitutes a contra-indication (see Dosage & Administration). Animal studies did not indicate direct or indirect harmful effects with respect to lactation (see Pharmacology: Toxicology: Preclinical safety data under Actions).
It is not known whether this vaccine is excreted in human milk.
IMOJEV vaccination is contraindicated in breastfeeding women (see Contraindications).
Animal studies did not indicate direct or indirect harmful effects with respect to female fertility.
No fertility data are available in Humans.

Data from clinical trials: Data in adult population: The safety of IMOJEV has been assessed in 8 randomised clinical trials in subjects over 18 years of age. During the development in the adult population, approximately 2,500 subjects received an injection of IMOJEV.
Safety evaluation was performed for all subjects during the first 4 weeks following vaccination and serious adverse reactions were collected during at least six months of follow-up after a single dose of IMOJEV.
The most frequently reported systemic reactions after the administration of IMOJEV were headache, fatigue, malaise and myalgia. All these reactions were as frequently reported as after the administration of the inactivated Japanese encephalitis comparator vaccine or a placebo.
The most frequently reported reaction at the injection site after the administration of IMOJEV was injection site pain. All the injection site reactions were less frequently reported than after the administration of the inactivated Japanese encephalitis comparator vaccine and as frequently reported as after the administration of a placebo.
Local and systemic reactions are ranked within each system organ class, under headings of frequency, using the following convention [Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), including isolated reports].
The following possibly related Adverse Events were reported during clinical trials within 30 days after vaccination: General disorders and administration site conditions: Very common: Fatigue, malaise, injection site pain.
Common: Feeling hot, chills, injection site erythema, injection site pruritus, injection site swelling, injection site bruising.
Uncommon: Pyrexia.
Nervous system disorders: Very common: Headache.
Common: Dizziness.
Musculoskeletal and connective tissue disorders: Very common: Myalgia.
Common: Arthralgia.
Gastrointestinal disorders: Common: Diarrhoea, nausea, abdominal pain, vomiting.
Respiratory, thoracic and mediastinal disorders: Common: Pharyngolaryngeal pain, dyspnea, rhinorrhoea, cough, wheezing, nasal congestion.
Skin and subcutaneous tissue disorders: Common: Rash.
Infections and infestations: Rare: Viral infections such as influenza-like illness.
Data in paediatric populations: Results from five Phase II and Phase III clinical trials with similar methodology for recording safety data were included in an integrated analysis of safety. During these clinical trials approximately 2200 individuals between 9 months and 5 years of age (approximately 100 children from 2 years of age, 2050 toddlers from 12 months of age and 50 infants from 9 to 12 months of age) received an injection of IMOJEV.
Safety evaluation was performed for all subjects during the first 4 weeks following vaccination and serious adverse reactions were collected during at least six months of follow-up after a single dose of IMOJEV.
The most frequently reported systemic reactions were malaise, myalgia, fever and headache in children (2 to 5 years) previously immunized with a two-dose primary vaccination with an inactivated Japanese encephalitis vaccine; and irritability, appetite loss, crying and fever in infants and toddlers (9 to 24 months) not previously immunized with a Japanese encephalitis vaccine.
The most frequently reported reactions at the injection site after the administration of IMOJEV was injection site pain/tenderness and injection site erythema.
These adverse events observed during paediatric clinical trials were generally of mild intensity and of short duration. The onset of systemic reactions was generally seen within 3 days after immunisation.
Local and systemic reactions are ranked within each system organ class, under headings of frequency, using the following convention [Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), including isolated reports].
The following related Adverse Events were reported during clinical trials within 28 days after vaccination: General disorders and administration site conditions: Very common: Pyrexia, malaise, irritability, injection site pain/ tenderness, injection site erythema.
Common: Injection site swelling.
Uncommon: Injection site reactions (induration, bruising, haematoma, haemorrhage).
Rare: Injection site pruritus.
Nervous system disorders: Very common: Headache, somnolence.
Musculoskeletal and connective tissue disorders: Very common: Myalgia.
Gastrointestinal disorders: Very common: Vomiting.
Metabolism and nutrition disorders: Very common: Appetite loss.
Infections and infestations: Uncommon: Upper respiratory tract infection.
Rare: Viral infection.
Skin and subcutaneous tissue disorders: Uncommon: Urticaria.
Rare: Rash, maculo-papular rash, post inflammatory pigmentation change.
Psychiatric disorders: Very common: Crying.
Infections and infestations: Rare: Upper respiratory tract infection, viral infections.
The safety of IMOJEV presented no clinically relevant difference with the previously described safety profile in the following phase III trials.
In 390 subjects between 36 and 42 months of age (45 out of the 390 received a single dose of IMOJEV, and 345 out of the 390 received a second dose (booster dose) of IMOJEV 2 years after the first dose).
In 119 children between 18 and 36 months of age who received a second dose (booster dose) of IMOJEV.
No additional adverse reactions were identified from the phase IV safety trial conducted in 10,000 individuals between 9 months and 5 years of age.
Data from post-marketing experience: No additional adverse reaction has been identified during post-marketing experience at this time.

Separate injection sites and separate syringes should be used when other vaccines are concomitantly administered with IMOJEV (see Dosage & Administration).
From 12 months of age, IMOJEV may be administered at the same time with MMR vaccine. No studies on concomitant administration with vaccine against measles either stand alone or combined.
For children living in areas where risk for measles is high, IMOJEV may be administered at the same time as measles vaccine, either stand alone or combined with mumps and/or rubella vaccines, from 9 months of age.
IMOJEV may be administered to adults at the same time as yellow fever vaccine.
In the case of immunosuppressive therapy or corticosteroid therapy, see Contraindications and Precautions.
Administering the vaccine in subjects who have previously received immunoglobulins: In order to avoid any neutralisation of the attenuated viruses contained in the vaccine, vaccination must generally not be performed within 6 weeks, and preferably not within 3 months of injection of immunoglobulins or blood products containing immunoglobulins, such as blood or plasma.

Incompatibilities: In the absence of compatibilities studies, this vaccine must not be mixed with any other vaccine or medicinal products.
Special precautions for disposal and other handling: The freeze-dried vaccine should appear as a white to creamy white homogeneous cake which might be retracted from the sides of the vial.
The diluent should appear as a clear solution.
After reconstitution, IMOJEV is a colourless to amber suspension.
Contact with disinfectants is to be avoided since they may inactivate the vaccine virus.
Instructions for reconstitution and administration: Imojev single dose: Using aseptic technique, IMOJEV vaccine is reconstituted by injecting all the 0.4% sodium chloride solution into the vial of freeze-dried vaccine, using the syringe and one of the needles provided in the carton. The vial is gently swirled. After complete dissolution, a 0.5 mL dose of the reconstituted suspension is withdrawn into this same syringe. For injection, the syringe is fitted with the second needle provided in the package.
The product should be used once reconstituted.
Imojev multidose: Using aseptic technique, IMOJEV MD vaccine is reconstituted by injecting all the 0.9% sodium chloride solution into the 4-dose vial of freeze-dried vaccine, using a syringe fitted with a needle. The vial is gently swirled. After complete dissolution, a 0.5 mL dose of the reconstituted suspension is withdrawn. For injection, the syringe should be fitted with a new sterile needle. A new sterile syringe and needle should be used when withdrawing each of the four doses.
After reconstitution, any remaining vaccine contained in the vial must be used within 6 hours. Partially used vials must be kept at the required temperature, i.e. between +2°C and +8°C (never place the product in a freezer).
Disposal: A partially used multidose vial must be discarded immediately if: Sterile dose withdrawal has not been fully observed; There is any suspicion that the partially used vial has been contaminated; There is visible evidence of contamination, such as change in appearance.
After use, any remaining vaccine and container must be disposed of safely, preferably by heat inactivation or incineration, according to locally agreed procedures.

Expiry Date: After reconstitution: the product should be used once reconstituted.
Store in a refrigerator (2°-8°C).
Do not freeze.
Keep the vials in the outer carton in order to protect from light.
For storage conditions of the reconstituted product, see Expiry Date as previously mentioned.

Vaccines, Antisera & Immunologicals

J07BA03 - encephalitis, Japanese, live attenuated ; Belongs to the class of encephalitis viral vaccines.

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