- japanese encephalitis vaccine (inactivated, adsorbed)
POM: Prescription only medicine
This information is intended for use by health professionals
Adults (18-65 years of age)The primary vaccination series consists of two separate doses of 0.5 ml each, according to the following conventional schedule:First dose at Day 0.Second dose: 28 days after first dose.Rapid schedule Persons aged 18-65 years can be vaccinated in a rapid schedule as follows:First dose at Day 0.Second dose: 7 days after first dose. With both schedules, primary immunisation should be completed at least one week prior to potential exposure to Japanese encephalitis virus (JEV) (see section 4.4).It is recommended that vaccinees who received the first dose of IXIARO complete the primary 2-dose vaccination course with IXIARO.If the primary immunization of two injections is not completed, full protection against the disease might not be achieved. There is data that a second injection given up to 11 months after the first dose results in high seroconversion rates (see section 5.1).Booster dose A booster dose (third dose) should be given within the second year (i.e. 12 - 24 months) after primary immunization, prior to potential re-exposure to JEV. Persons at continuous risk for acquiring Japanese encephalitis (laboratory personnel or persons residing in endemic areas) should receive a booster dose at month 12 after primary immunization (see section 5.1). Long-term seroprotection data following a first booster dose administered 12 - 24 months after primary immunization suggest that a second booster should be given 10 years after the first booster dose, prior to potential exposure to JEV. Elderly (≥ 65 years of age)The primary vaccination series consists of two separate doses of 0.5 ml each, according to the following conventional schedule:First dose at Day 0.Second dose: 28 days after first dose.The primary immunisation should be completed at least one week prior to potential exposure to Japanese encephalitis virus (JEV) (see section 4.4).It is recommended that vaccinees who received the first dose of IXIARO complete the primary 2-dose vaccination course with IXIARO.If the primary immunization of two injections is not completed, full protection against the disease might not be achieved. There is data that a second injection given up to 11 months after the first dose results in high seroconversion rates (see section 5.1).Booster doseAs with many vaccines, the immune response in elderly persons to IXIARO is lower than in younger adults. Duration of protection is uncertain in elderly persons, therefore a booster dose (third dose) should be considered before any further exposure to JE virus. Long-term seroprotection following a booster-dose is not known.
Children and adolescents from 3 years to < 18 years of ageThe primary vaccination series consists of two separate doses of 0.5 ml according to the following schedule:First dose at Day 0.Second dose: 28 days after first dose.
Children from 2 months to < 3 years of ageThe primary vaccination series consists of two separate doses of 0.25 ml according to the following schedule:First dose at Day 0.Second dose: 28 days after first dose.See section 6.6 for instructions on preparing a 0.25 ml dose for children aged 2 months to <3 years.It is recommended that vaccinees who received the first dose of IXIARO complete the primary 2-dose vaccination course with IXIARO.Booster dose (Children and adolescents)A booster dose (third dose) should be given within the second year (i.e. 12 - 24 months) after primary immunization, prior to potential re-exposure to JEV.Children and adolescents at continuous risk for acquiring Japanese encephalitis (residing in endemic areas) should receive a booster dose at month 12 after primary immunization (see section 5.1).Children and adolescents from 3 years to < 18 years of age should receive a single 0.5 ml booster dose.Children from 14 months to < 3 years of age should receive a single 0.25 ml booster dose. See section 6.6 for instructions on preparing a 0.25 ml dose for children aged 2 months to <3 years.No long-term seroprotection data beyond two years after a first booster administered 1 year after primary immunization has been generated in children.
Children below 2 months of ageThe safety and efficacy of IXIARO in children younger than 2 months has not been established. No data are available.
Method of administrationThe vaccine should be administered by intramuscular injection into the deltoid muscle. In infants, the anterolateral aspect of the thigh may be used as injection site. IXIARO should never be injected intravascularly.When IXIARO is administered concomitantly with injectable vaccines, they should be given with separate syringes at opposite sites.Exceptionally, IXIARO can also be administered subcutaneously to patients with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration. Subcutaneous administration could lead to a suboptimal response to the vaccine (see section 4.4). However, it should be noted that there are no clinical efficacy data to support administration by the subcutaneous route.
Concomitant administration of IXIARO with other vaccines:Concomitant administration of IXIARO with inactivated hepatitis A vaccine and with inactivated rabies vaccine in two different schedules has been evaluated in clinical studies. There was no interference with the immune response to Japanese encephalitis virus (JEV) or to hepatitis A or rabies virus vaccines (see section 5.1).The safety profiles of IXIARO and the other studied vaccines were not compromised when administered concomitantly.In patients receiving immunosuppressive therapy or patients with immunodeficiency an adequate immune response may not be obtained.
Paediatric populationNo interaction studies have been performed in children and adolescents.
PregnancyThere are limited amount of data from the use of IXIARO in pregnant women.In animal studies findings of unclear clinical relevance have been identified (see section 5.3).As a precautionary measure, the use of IXIARO during pregnancy should be avoided.
Breast-feedingIt is unknown whether IXIARO is excreted in human milk.No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to IXIARO is negligible. However, in the absence of data and as a precautionary measure the use of IXIARO during lactation should be avoided.
FertilityA study in rats did not indicate vaccine-related effects on female reproduction, foetal weight, survival and development of the off-spring.
Summary of the safety profileThe safety of Ixiaro was assessed in controlled and uncontrolled clinical studies in 5,021 healthy adults (from non-endemic countries) and 1,559 children and adolescents (mostly from endemic countries).Approximately 40% of treated subjects experienced systemic adverse reactions and approximately 54% experienced injection site reactions. They usually occur within the first three days after vaccination, are usually mild and resolve within a few days. No increase in the number of adverse reactions was noted between first and second doses or following a booster dose in adults. Most commonly reported adverse reactions in adults included headache (20% of subjects), myalgia (13%), injection site pain (33%), injection site tenderness (33%) and fatigue (12.9%).Most commonly reported adverse reactions in children and adolescents included pyrexia, diarrhoea, influenza like illness, irritability, injection site pain, injection site tenderness, and injection site redness (see table 1).Adverse reactions are listed according to the following frequencies:Very common: ≥ 1/10Common: ≥ 1/100 to < 1/10Uncommon: ≥1/1,000 to < 1/100Rare: ≥1/10,000 to < 1/1,000Adult and older adults (≥65 years) population
Blood and lymphatic system disordersUncommon: lymphadenopathyRare: thrombocytopenia
Nervous system disordersVery common: headacheUncommon: migraine, dizziness Rare: paraesthesia, neuritis, dysgeusia
Ear and labyrinth disordersUncommon: vertigo
Eye disordersRare: eyelid oedema
Cardiac disordersRare: palpitations, tachycardia
Respiratory, thoracic and mediastinal disordersRare: dyspnoea
Gastrointestinal disordersCommon: nauseaUncommon: vomiting, diarrhoea, abdominal pain
Skin and subcutaneous tissue disordersUncommon: rash, pruritus, hyperhidrosis Rare: urticaria, erythema
Musculoskeletal and connective tissue disordersVery common: myalgiaUncommon: musculoskeletal stiffness, arthralgiaRare: pain in extremity
General disorders and administration site conditionsVery common: injection site pain, injection site tenderness, fatigueCommon: influenza like illness, pyrexia, other injection site reactions e.g. redness, hardening, swelling, itching Uncommon: chills, malaise, asthenia Rare: oedema peripheral
InvestigationsUncommon: hepatic enzymes increased
Paediatric population (2 months to <18 years of age)Table 1: Frequency of adverse reactions observed in children given the 0.25 ml dose (2 months to <3 years of age) and in children and adolescents given the 0.5 ml dose (3 years to <18 years of age)
|Frequency of adverse reactions(%) by dose/age|
|System Organ Class Preferred Term||0.25 ml N=783 2 months to <3 years||0.5 ml N=628 3 to <18 years|
|Blood and Lymphatic System Disorders|
|Metabolism and Nutrition Disorders|
|Nervous System Disorders|
|Respiratory, Thoracic and Medistinal Disorders|
|Skin and Subcutaneous Tissue Disorders|
|Musculoskeletal and Connective Tissue Disorders|
|General Disorders and Administration Site Conditions|
|Influenza like illness||10.9||2.9|
|Injection site redness||10.0||4.1|
|Injection site pain||6.1||14.1|
|Injection site tenderness||4.2||14.7|
|Injection site swelling||3.6||2.2|
|Injection site hardening||1.2||1.9|
|Injection site itching||0.6||1.6|
|Hepatic enzymes increased||0.5||0.2|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
Paediatric population:No case of overdose has been reported in the paediatric population. Inadvertent administration of an 0.5 ml dose of IXIARO in children aged 1 to <3 years does not pose any safety concerns (section 5.1.).
Mechanism of actionThe mechanism of action of Japanese encephalitis (JE) vaccines is not well understood. Studies in animals have shown that the vaccine triggers the immune system to produce antibodies against Japanese encephalitis virus that are most often protective. Challenge studies were performed in mice that were treated with human IXIARO antisera. These studies showed that almost all mice that had a Plaque Reduction Neutralization Test titre of at least 1:10 were protected from a lethal Japanese encephalitis virus challenge.
Clinical efficacy and safetyNo prospective efficacy trials have been performed. Immunogenicity of IXIARO was studied in approximately 3,119 healthy adult subjects included in seven randomized, controlled and five uncontrolled Phase 3 trials and in approximately 550 healthy children included in two randomized, controlled and two uncontrolled Phase 3 clinical trials.
Pivotal immunogenicity trial (adults)Immunogenicity of the vaccine was evaluated in a randomized, active controlled, observer blinded, multicenter Phase 3 clinical trial including 867 healthy male and female subjects given IXIARO or the US licensed JEV vaccine JE VAX (on a 0, 7 and 28 day schedule by subcutaneous injection). The co-primary endpoint was seroconversion rate (anti JEV antibody titer ≥1:10) and geometric mean titers (GMT) at Day 56 as assessed by a Plaque Reduction Neutralization Test (PRNT) for the entire study population.By Day 56, the proportion of subjects who had seroconverted was similar for both treatment groups (96.4% vs. 93.8% for IXIARO and JE VAX, respectively). GMT increased by Day 56 to 243.6 for IXIARO and to 102.0 for JE VAX, respectively. The immune responses elicited by IXIARO were non inferior to those induced by JE VAX (Table 2).Table 2: Seroconversion rates and geometric mean titers of IXIARO and JE VAX in the Per Protocol Population. Neutralising antibody titers against JEV were measured against the JEV strain SA14-14-2.
|Time point||IXIARO N=365 % (n)||JE-VAX N=370 % (n)|
|Visit 0 (Screening)||0||0|
|Visit 3 (Day 28)||54 (197)||86.8 (321)|
|Visit 4 (Day 56)||96.4 (352)||93.8 (347)|
|Geometric mean titer (by plaque reduction neutralization test)|
|Time point||IXIARO N=365 GMT (n)||JE-VAX N=370 GMT (n)|
|Visit 0 (Screening)||5.0 (365)||5.0 (370)|
|Visit 3 (Day 28)||17.4 (363)||76.9 (367)|
|Visit 4 (Day 56)||243.6 (361)||102.0 (364)|
Antibody persistence (adults)Antibody persistence was evaluated in an uncontrolled Phase 3 follow up clinical trial, enrolling subjects who had completed two pivotal studies, and who received at least one dose of IXIARO. Long term immunogenicity of IXIARO was assessed in a subset of 181 subjects up to month 24 (Intent-to-treat (ITT) population) and in 152 subjects up to month 36 after the first IXIARO vaccination.Rates of subjects with PRNT50≥1:10 and GMTs at Months 2, 6, 12, 24 and 36 are summarized in Table 3 for the ITT population. Table 3: Rates of subjects with PRNT50≥1:10 and geometric mean titers (GMT) at Month 2, 6, 12, 24 and 36 after vaccination with IXIARO (ITT population)
|Rate of subjects with PRNT50≥1:10||GMT|
|Time point||% (n/N)||95% Confidence Interval||GMT (N)||95% Confidence Interval|
|Month 2||98.9 (179/181)||[96.1, 99.7]||310.8 (181)||[268.8, 359.4]|
|Month 6||95.0 (172/181)||[90.8, 97.4]||83.5 (181)||[70.9, 98.4]|
|Month 12||83.4 (151/181)||[77.3, 88.1]||41.2 (181)||[34.4, 49.3]|
|Month 24||81.8 (148/181)||[75.5, 86.7]||44.3 (181)||[36.7, 53.4]|
|Month 36||84.9 (129/152)||[78.3, 89.7]||43.8 (152)||[36.5, 52.6]|
Booster immunisation (adults)In an uncontrolled, open-label phase 3 study a single 6 mcg (0.5 ml) booster dose of IXIARO was given at month 15 after primary immunization. All of the 198 subjects treated were included in the ITT and Safety Populations.Rates of subjects with PRNT50≥1:10 and GMT over time are summarised in table 4:Table 4: Rates of subjects with PRNT50≥1:10 and GMT before and at months 1, 6 and 12 after a single 6 mcg (0.5 ml) booster dose administered to subjects at 15 months after recommended primary immunization with IXIARO (ITT population)
|Rate of subjects with PRNT50≥1:10||GMT|
|95% CI||95% CI|
|Pre-booster, Day 0 (n=198)||69.2%||[62.4%, 75.2%]||22.5||[19.0, 26.7]|
|Day 28 (n=198)||100.0%||[98.1%, 100.0%]||900.1||[742.4, 1091.3]|
|Month 6 (n=197)||98.5%||[95.6%, 99.5%]||487.4||[390.7, 608.1]|
|Month 12 (n=194)||98.5%||[95.6%, 99.5%]||361.4||[294.5, 443.5]|
Antibody persistence after booster immunisation (adults)In an uncontrolled, open-label extension to the booster study described above, 67 subjects were followed up for determination of JEV neutralizing antibody titres at approximately 6 years after a booster dose. 96% of subjects (64/67) still had protective antibody levels (PRNT50≥1:10), with a GMT of 148 (95%CI: 107; 207). Mathematical modelling was applied to project the average duration of protection. Based on this model, it is estimated that average duration of protection will be 14 years and 75% of vaccinees will retain protective antibody levels (PRNT50≥1:10) for 10 years. A second booster should therefore be given 10 years after the first booster dose, administered 1 year after the primary immunization, prior to potential exposure to JEV.
Rapid immunisation schedule (adults)The immunogenicity of IXIARO administered in a rapid vaccination schedule was evaluated in a randomized, observer-blind, phase 3 study. A total of 217 subjects aged 18-65 years received IXIARO together with inactivated rabies vaccine (Rabipur) in a rapid immunisation schedule on Day 0 and Day 7 and 56 subjects received IXIARO alone in the conventional immunisation schedule on Day 0 and Day 28. The proportion of subjects that seroconverted by 7 and by 28 days after the last immunisation was similar for both schedules. Seroconversion rates and antibody titers also remained comparably high up to 12 months after the first immunisation in both schedules (Table 5).The rapid schedule was tested for concomitant administration of IXIARO and Rabipur but it can also be used for administration of IXIARO alone, as no immune interference of the two vaccines has been observed (see section 4.5).Table 5: Seroconversion rates and GMTs for anti-JEV neutralizing antibodies on Day 0, 14, 21, 35, 56 and 365 after immunisation with IXIARO and inactivated rabies vaccine in a rapid schedule and IXIARO alone in a conventional schedule (Per Protocol population)
|Seroconversion Rate (Rate of subjects with PRNT50≥1:10)||GMT (plaque reduction neutralization test)|
|Rapid Schedule % (n/N)||Conventional Schedule % (n/N)||Rapid Schedule (N)||Conventional Schedule (N)|
|Vaccination scheme||IXIARO Day 0,7 Rabipur Day 0,3,7||IXIARO Day 0,28 -||IXIARO Day 0,7 Rabipur Day 0,3,7||IXIARO Day 0, 28 -|
|Day 0||6 (13/215)||9 (5/55)||5.63 (215)||5.73 (55)|
|Day 14||99 (206/209)||NA||715 (209)||NA|
|Day 21||100 (207/208)||NA||1255 (208)||NA|
|Day 35||99 (203/206)||100 (47/47)||690 (206)||376 (47)|
|Day 56||98 (200/204)||100 (49/49)||372 (204)||337 (49)|
|Day 365||94 (188/199)||88 (42/48)||117 (199)||39 (48)|
Incomplete primary immunization (adults)The immunogenicity of booster doses was also assessed in the study investigating persistence of immunity following different primary immunization regimens (2x6 mcg: N=116, 1x12mcg: N=116 or 1x6 mcg: N=117). A single 6 mcg (0.5 ml) booster dose was administered at 11 or 23 months after the first dose to subjects, which were determined to be seronegative (PRNT50 titers < 1:10) at month 6 and/or month 12 after the primary immunization. Results indicate that the second injection of the primary immunization series can be given up to 11 months after the first dose. The immune responses to further doses at different time points after complete or incomplete primary immunization are shown in table 6.Table 6: SCR and GMT at four weeks after a single 6 mcg booster dose administered to subjects with a PRNT50 <1:10 (PRNT50<1:10 means a subject is no longer seroprotected) at month 11 or month 23 after recommended primary immunization (2x 6 mcg) or incomplete (1x6 mcg) primary immunization with IXIARO (ITT population)
|(n / N)||SCR||GMT||[95% CI]|
|Booster following recommended primary immunization (2x6 mcg)|
|Booster at Month 11||(17 / 17)||100 %||673.6||[378.7, 1198.2]|
|Booster at Month 23||(27 / 27)||100 %||2536.7||[1467.7, 4384.4]|
|Second dose following incomplete primary immunization (1x6 mcg)|
|Second dose at Month 11||(99 / 100)||99 %||504.3||[367.3, 692.3]|
|Second dose at Month 23||(5 / 5)||100 %||571.4||[88.2, 3702.9]|
Concomitant use (adults)
Concomitant administration of IXIARO with inactivated hepatitis A virus (HAV) vaccine (HAVRIX 1440)The concomitant use of IXIARO with inactivated hepatitis A virus (HAV) vaccine (HAVRIX 1440) has been explored in one clinical trial. There was no interference with the immune response to the JE virus and HAV, respectively. Concomitant administration of IXIARO and inactivated hepatitis A vaccine was shown to be non-inferior to single vaccinations with regard to GMT of anti-JE virus neutralizing antibody and HAV antibody, and for seroconversion rates of both antibody types (Table 7).Table 7: Seroconversion rates and geometric mean titer of anti JEV neutralizing antibody at Day 56 and seroconversion rates and geometric mean titer for HAV antibody at Day 28 in the Per Protocol Population
|Seroconversion rates and geometric mean titer for anti-JEV neutralizing antibody at Day 56|
|% with SCR||GMT||95% CI|
|Group C: IXIARO + HAVRIX1440||100.0||202.7||[153.7, 261.2]|
|Group A: IXIARO + Placebo||98.2||192.2||[147.9, 249.8]|
|Seroconversion rates and geometric mean titer for HAV antibody at Day 28|
|% with SCR||GMT||95% CI|
|Group C: IXIARO + HAVRIX 1440||100.0||150.0||[111.7, 202.3]|
|Group B: HAVRIX + Placebo||96.2||124.0||[91.4, 168.2]|
Concomitant administration of IXIARO with inactivated rabies vaccine (Rabipur):In an observer-blind Phase 3 study, concomitant administration of IXIARO and Rabipur has been studied in adults aged 18 to 65 years of age in comparison to respective single vaccinations in conventional schedule. No interference was observed with regards to geometric mean titer (GMT) and seroconversion rates for anti JEV neutralizing antibodies (Table 8). There was also no interference with the immune response to Rabipur.Table 8: Seroconversion rates (rate of subjects with PRNT50≥1:10) and GMTs (plaque reduction neutralization test) for anti-JEV neutralizing antibodies after administration of IXIARO and Rabipur in conventional schedule, Per Protocol population
|Seroconversion rates and geometric mean titer for JEV neutralizing antibody at Day 56|
|SCR [%] (n/N)||GMT [95% CI] (N)|
|IXIARO + Rabipur||100 (157/157)||299 [254-352] (157)|
|IXIARO||100 (49/49)||337 [252-451] (49)|
Immunogenicity in elderly persons (≥65 years)The immunogenicity of IXIARO was evaluated in an open-label, uncontrolled trial in 200 healthy elderly persons aged 65 to 83 years, including subjects with stable underlying conditions like hypercholesterolemia, hypertension, cardiovascular disease or non insulin-dependent diabetes mellitus. JEV neutralizing antibodies were determined 42 days after the second dose of the primary series (Day 70). Elderly persons have a lower immune response to vaccination compared to younger adults or children, in terms of seroconversion rates (percentage of subjects with PRNT50 titer ≥1:10) and geometric mean titers (Table 9). Table 9: Seroconversion rates and geometric mean titer of JEV neutralizing antibody at Day 70 in the Intent-to-treat Population, for the entire study population and stratified by age
|Seroconversion rates and geometric mean titer for JEV neutralizing antibody at Day 70|
|n / N||SCR||GMT||95% CI|
|Total Study Population||128/197||65%||37||29.2, 47.8|
|Age group 65 - <75years||113/173||65.3%||37.2||28.6, 48.3|
|Age group ≥75 years||15/23||65.2%||42.2||19.2, 92.7|
Paediatric populationIn a phase 2 study in healthy Indian toddlers aged ≥1 year to <3 years, 24 children were vaccinated with 0.25 ml of IXIARO (the licensed dose for this age group) and 24 children received the adult 0.5 ml dose. Data are limited but there were no differences in the safety profile between the 0.25 ml and the 0.5 ml dose in this age group.
Immunogenicity and safety of IXIARO in children and adolescents from a JEV-endemic countryThe safety and immunogenicity of IXIARO were evaluated in a randomized, controlled, open-label clinical trial conducted in the Philippines, where JEV is endemic. The safety profile of IXIARO was compared to control vaccines Havrix (Hepatitis A vaccine, paediatric 720 EL.U./0.5 mL formulation) and Prevenar (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 protein]). The immunogenicity evaluation was performed in a subset of the study population and included the determination of the seroconversion rate (SCR), defined as JEV neutralizing antibody titer ≥1:10, the proportion of subjects achieving an at least four-fold increase in antibody titers and the geometric mean titer (GMT) at Day 56 and Month 7, by dose and by age group. The immune responses elicited by IXIARO are presented in Table 10.Table 10: Seroconversion rates, rates of subjects with at least 4-fold increase in JEV neutralizing antibody titers and Geometric Mean Titers at baseline, Day 56 and Month 7 stratified by age group, Intent To Treat Population
|Vaccine Dose||0.25 ml||0.5 ml|
|Age Group||2 months <6 months||6 months <12 months||1 year < 3 years||3 years - < 12 years||12 years - < 18 years|
|Seroconversion Rates % (n/N)|
|Pre-Vaccination||30% (3/10)||0% (0/20)||3.2% (4/125)||16.8% (17/101)||45.7% (64/140)|
|Day 56||100% (9/9)||100% (19/19)||99.2% (119/120)||100.0% (100/100)||100% (137/137)|
|Month 7||100% (10/10)||100% (18/18)||85.5% (106/124)||91.0% (91/100)||97.1% (133/137)|
|Proportion of Subjects Achieving an ≥4-fold Increase in JEV Antibody Titers % (n/N)|
|Day 56||100 (9/9)||94.7 (18/19)||96.7 (116/120)||94.0 (94/100)||77.4 (106/137)|
|Month 7||90.0 (9/10)||83.3 (15/18)||75.8 (94/124)||71.0 (71/100)||65.0 (89/137)|
|Geometric Mean Titer (N)|
|Pre-Vaccination||8.42 (10 )||5 ◊ (20)||5.52 (124)||6.54 (101)||13.08 (140)|
|Day 56||687.35 (9)||377.79 (19)||258.90 (121)||213.67 (100)||175.63 (137)|
|Month 7||159.27 (10)||64.00 (18)||38.91 (125)||43.60 (100)||86.61 (137)|
Antibody persistence and booster dose in children and adolescents from a JEV-endemic countryThe persistence of JEV neutralizing antibodies after primary immunisation and safety and immunogenicity of an IXIARO booster dose 12 months after primary immunization were evaluated in a randomized, controlled, open-label clinical trial conducted in the Philippines, where JEV is endemic (300 children, mean age 5.3 years, range 1.2 - 17.3 years). 150 children were followed-up for three years without booster, additional 150 children received a booster after 1 year (0.25 ml if aged <3 years at time of the booster, 0.5 ml if aged 3 years and above) and were followed-up for further two years. Seroprotection rate (SPR) defined as neutralizing antibody titer ≥1:10 and geometric mean titers (GMT) are presented in Table 11. The booster dose led to a pronounced increase in GMTs and seroprotection rate remained at 100% two years after the booster. Table 11: Seroprotection Rates and Geometric Mean Titers with and without a booster of IXIARO at Month 12, 13, 24 and 36, Intent To Treat Population
|Without Booster N = 150||Booster dose 12 months after primary immunization N = 149|
|Time point after primary immunization||0.25 mL Booster Dose N=81||0.5 mL Booster Dose N=67|
|Seroprotection Rate % (n/N)|
|Month 12||89.9 (134/149)||97.5 (79/81)||89.6 (60/67)|
|Month 13||n.a.||100 (81/81)||100.0 (67/67)|
|Month 24||89.0 (130/146)||100 (80/80)||100.0 (67/67)|
|Month 36||90.1 (128/142)||100.0 (76/76)||100.0 (67/67)|
|Geometric Mean Titer|
n.a. = not available
Immunogenicity and safety in children and adolescents from non-endemic countriesThe safety and immunogenicity of IXIARO was evaluated in an uncontrolled, open-label clinical trial conducted in the United States, Europe and Australia in healthy male and female subjects with planned travel to JEV-endemic areas. Children and adolescents aged ≥ 3 to < 18 years received two vaccine doses of 0.5ml and children aged ≥ 2 months to < 3 years received two vaccine doses of 0.25ml on Day 0 and Day 28 by intramuscular injection. Immunogenicity data were evaluated in 64 subjects. The SCRs and GMTs are displayed in Table 12. Table 12: Seroconversion rates and geometric mean titer of JEV neutralizing antibody by vaccine dose and age group. Intent-to-treat Population
|IXIARO Dose||Time Point||SCR n / N||GMT||95% CI|
|Age Group ≥2 months to <3 years||0.25 ml||Day 56||100% 5/5||216.2||106.0; 441.0|
|Month 7||100% 2/2||48.0||0.0; 3214485.7|
|Age Group ≥3 to <18 years||0.5 ml||Day 56||100% 57/57||340.7||269.8; 430.3|
|Month 7||90.6% 29/32||57.1||38.4; 84.9|
Antibody persistence in children and adolescents from non-endemic countriesAntibody persistence was evaluated for three years after the primary vaccination with IXIARO in an uncontrolled, open-label follow-up clinical trial conducted in the United States, Europe and Australia. Long-term immunogenicity data were evaluated in 23 children, mean age 14.3 years, range 3 - 18 years). The SPRs and GMTs are displayed in Table 13. Table 13: Seroprotection rates and geometric mean titer of JEV neutralizing antibody by vaccine dose and age group. Intent-to-treat Population
|Seroprotection Rate (Rate of subjects with PRNT50≥1:10) % (n/N)||Geometric Mean Titer (plaque reduction neutralization test) GMT [95%CI]|
|After 0.25 mL Dose Primary Immunization||After 0.5 mL Dose Primary Immunization||After 0.25 mL Dose Primary Immunization||After 0.5 mL Dose Primary Immunization|
|Month 12||0% (0/0)||89.5% (17/19)||-||48 [28; 80]|
|Month 24||100% (1/1)||90.9% (20/22)||193 [n.a.]||75 [46; 124]|
|Month 36||100% (1/1)||88.9% (16/18)||136 [n.a.]||61 [35; 106]|
Information on the administration of a 0.5 ml dose of IXIARO for persons 3 years of age and aboveFor administration of the full 0.5 ml dose follow the steps below: 1. Shake the syringe to obtain a homogeneous suspension. 2. Remove the syringe tip cap by gently twisting it. Do not attempt to snap or pull the tip off as this may damage the syringe.3. Attach a needle to the pre-filled syringe.
Information on the preparation of a 0.25 ml dose of IXIARO for use in children below 3 years of ageFor administration of a 0.25 ml dose in children aged 2 months to < 3 years, follow the steps below: 1. Shake the syringe to obtain a homogeneous suspension. 2. Remove the syringe tip cap by gently twisting it. Do not attempt to snap or pull the tip off as this may damage the syringe.3. Attach a needle to the pre-filled syringe. 4. Hold the syringe in an upright position.5. Push the plunger stopper up to the edge of the red line on the syringe barrel, indicated by a red arrow (see Figure 1)*, to discard excess volume.6. Attach a new sterile needle prior to injection of the remaining volume.* If you pushed the plunger stopper beyond the red line, a 0.25 ml dose is not guaranteed and a new syringe should be used.