IXIARO Japanese Encephalitis Vaccine Ref.[10105] Active ingredients: Japanese encephalitis, live attenuated

IXIARO has not been evaluated for carcinogenic or mutagenic potential. IXIARO was found to have no effect on fertility of female rats at intramuscular doses of up to 300‑fold excess relative to the projected human dose (on a mg/kg basis) administered prior to and after mating [See Use in Specific Populations (8.1)]. The effect of IXIARO on male fertility has not been evaluated.

Immunogenicity of IXIARO in a Pediatric Clinical Trial in the Philippines

The immunogenicity of IXIARO was evaluated in a subgroup of children included in a randomized, controlled, open-label clinical trial in healthy children conducted in the Philippines (Study 1)¹ in which the safety of IXIARO was compared to control vaccines: HAVRIX (Hepatitis A vaccine, pediatric 720 EL.U./0.5 mL formulation) and Prevnar (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM₁₉₇ protein]). Subjects in the IXIARO treatment arm received intramuscular doses on Day 0 and Day 28. A total of 396 subjects from the group receiving an age-appropriate dosage of IXIARO (0.25 mL for infants and children 2 months to <3 years of age or 0.5 mL for individuals 3 to <18 years of age) were randomized in an age-stratified scheme into the immunogenicity subgroup (mean age: 7.7 years; 49.6% female; ethnicity: 100% Asian) [See Adverse Reactions (6.1)].

The immunogenicity evaluation included the proportion of subjects with PRNT₅₀ titer ≥1:10 and geometric mean titer (GMT) at Day 56 and Month 7. The JEV-neutralizing antibody responses elicited by IXIARO in the Intent-to-Treat population (defined as all subjects who received at least one dose of IXIARO) are presented in Table 9.

Table 9. JEV-Neutralizing Antibody Response After IXIARO* Among Children 2 Months to <18 Years of Age Residing in the Philippines, Intent-To-Treat Population**, Study 1^§:

^§ NCT01041573
* Infants and children ≥2 months to <3 years of age received two 0.25 mL doses administered on Days 0 and 28. Individuals 3 years of age and older received two 0.5 mL doses administered on Days 0 and 28.
** The Intent to Treat population consisted of all subjects who received at least one dose of IXIARO.
N=number of subjects with data available
n=number of subjects with a PRNT₅₀ titer ≥1:10
^◊ Reciprocal titers <10 were imputed to 5.

Immunogenicity of IXIARO in a Pediatric Clinical Study in Children 2 Months to <18 Years of Age Traveling from Non-Endemic Countries

The immunogenicity of IXIARO was evaluated in an uncontrolled, open-label clinical study conducted in the United States, Europe and Australia in healthy male and female children with planned travel to JEV-endemic areas (Study 2)². IXIARO (0.25 mL dose for children 2 months to <3 years of age, 0.5 mL dose for children and adolescents 3 to <18 years of age) was administered by intramuscular injection on Day 0 and Day 28. An analysis was carried out on immunogenicity data for the first 54 subjects enrolled (median age: 15.2 years, range 10 months to 17 years; 59.3% female; ethnicity: White: 81.5%, Asian: 14.8%, Black: 3.7%) [See Adverse Reactions (6.1)].

JEV neutralizing antibody titers were available for 51 subjects at Day 56 (5 subjects 2 months to <3 years of age and 46 subjects 3 to <18 years of age) and for 18 subjects at Month 7 (2 subjects 2 months to <3 years of age and 16 subjects 3 to <18 years of age). All subjects had PRNT₅₀ titers ≥1:10 at Day 56 and Month 7, and GMTs were similar to those among children vaccinated with IXIARO in a study conducted in the Philippines, where JEV is endemic (see Table 9).

Immunogenicity of IXIARO in a Clinical Trial in Adults

Immunogenicity of the vaccine was evaluated in a randomized, active‑controlled, observer‑blinded clinical trial conducted in the U.S., Germany and Austria (Study 4)⁴ in 867 healthy adults 18 years of age and older (mean age: 41.3 years; 60.8% female; ethnicity: White 80.8%, Asian 0.8%, Black 13.1%, Other 5.3%). Subjects in the IXIARO treatment arm received the following schedule of three intramuscular doses: Day 0, IXIARO, Day 7, PBS + Al(OH)₃(0.5 mL phosphate buffered saline with 0.1% aluminum hydroxide), and on Day 28, IXIARO. Subjects in the comparator arm received a subcutaneous dose of 1.0 mL of the US‑licensed JEV vaccine, JE-VAX, on Days 0, 7 and 28 [See Adverse Reactions (6.1)].

The proportion of subjects with, PRNT₅₀ titer ≥1:10, and GMT were evaluated at Day 56 in the per protocol population which included all subjects who had no major protocol deviations and who had a PRNT₅₀ titer <1:10 at baseline. The neutralizing antibody responses elicited by IXIARO met predefined statistical criteria for non-inferiority compared to those induced by JE‑VAX, and are presented in Table 10. All subjects were seronegative at baseline (PRNT₅₀ titer <1:10).

Table 10. JEV-Neutralizing Antibody Response After IXIARO or JE‑VAX Among Adults Residing in Non-Endemic Areas, Per Protocol Population*, Study 4^§:

^§ NCT00604708
* The Per Protocol population consisted of subjects with no major protocol deviations and a PRNT₅₀ titer <1:10 at baseline
^† Non-inferiority was demonstrated if the lower bound of the 2-sided 95% confidence interval (CI) for the difference in proportion of subjects with PRNT₅₀ titer ≥1:10 (IXIARO minus JE‑VAX) was >‑10% at Day 56.
^‡ Non-inferiority was demonstrated if the lower bound of the 2-sided 95% CI for the GMT ratio (IXIARO /JE‑VAX) was >1/1.5 at Day 56.
n=number of subjects with a PRNT₅₀ titer ≥1:10
N=number of subjects in the Per Protocol Population
** N=Number of subjects with immunogenicity data
^◊ Reciprocal titers <10 were imputed to 5.

Temporal Evaluation of Immunogenicity of IXIARO During Vaccination Series in Adults

In a randomized, observer-blinded clinical study in 374 healthy adults 18 years of age and older (Study 5)⁵, the immunogenicity of IXIARO was evaluated on days 10, 28, 35, and 56 during the vaccination period. The proportion of subjects with PRNT₅₀ titer ≥1:10 at each time point for the subjects randomized to the standard dosing regimen (IXIARO on days 0 and 28) are displayed in Table 11.

Table 11. JEV-Neutralizing Antibody Response During the Vaccination Series (IXIARO on Days 0 and 28) Among Adults Residing in Non-Endemic Areas, Per Protocol Population*, Study 5^§:

^§ NCT00505790
* The Per Protocol population consisted of all subjects with no major protocol deviations
n=number of subjects with a PRNT₅₀ titer ≥1:10
N=number of subjects with immunogenicity data

Persistence of Neutralizing Antibody Response in Adults

The persistence of JEV-neutralizing antibody was evaluated in a subgroup of adult subjects recruited for follow-up after participation in one of two clinical trials (Study 4 and Study 5) ^{4, 5}. In the Intent-to-Treat population of subjects randomized to vaccination with IXIARO (N=181) and in the population of subjects who intended to stay in the study until month 36 (ITT36, N=152), the proportion of subjects with PRNT₅₀ titer ≥1:10 at 6, 12, 24 and 36 months after initiation of the two-dose series were 95% [95% CI 90.8, 97.4], 83.4% [95% CI 77.3, 88.1] , 81.8% [95% CI 75.5, 86.7] and 84.9% [95% CI 78.3, 89.7], respectively. Geometric mean titers (GMT) at 6, 12, 24 and 36 months after initiation of the two-dose series were 83.5 [95% CI 70.9, 98.4], 41.2 [95% CI 34.4, 49.3], 44.3; [95% CI 36.7, 53.4] and 43.8 [95% CI 36.5, 52.6], respectively.

In another study with 116 adults who completed the IXIARO primary immunization series (Study 9) ⁹, the proportions of subjects with PRNT₅₀ titers ≥1:10 at 11 and 23 months after completion of the primary series were 58.3% [95% CI 49.1, 66.9] and 48.3% [95% CI 39.4, 57.3], respectively, and GMTs were 18.0 [95% CI 14.3, 22.6] and 16.2 [95% CI 12.6, 20.8].

Immunogenicity of IXIARO Booster Doses in Adults

A single booster dose of IXIARO was evaluated in 198 adult subjects enrolled in an uncontrolled, open-label phase 3 study. IXIARO was administered 14 months after completion of the primary series (Study 8) ⁸. The JEV neutralizing antibody responses from this study are presented in Table 12.

Table 12. JEV-Neutralizing Antibody ResponseFollowing a Booster Dose of IXIARO Administered 14 Months After Completion of the Primary Series Among Adults Residing in Non-Endemic Areas, Intent to Treat Population*, Study 8^§:

^§ NCT00595309
* The Intent to Treat population consisted of all subjects who received the booster vaccination
n=number of subjects with a PRNT₅₀ titer ≥1:10
N=number of subjects with immunogenicity data

The immunogenicity of booster doses was assessed in adult subjectsin another study investigating persistence of immunity following vaccination with the primary series of IXIARO (Study 5)⁵. Subjects with PRNT₅₀ titers <1:10 at 11 months after completion of the primary series received a booster dose of IXIARO 11 months later (22 months after completion of the primary series). Among 27 subjects with available immunogenicity data at 4 weeks after the booster dose, the proportion of subjects with PRNT₅₀ titer ≥1:10 was 100% [95% CI 87.5, 100.0], and the GMT was 2536.7 [95% CI 1467.7, 4384.4].

Concomitant Administration of IXIARO and Hepatitis A Vaccine, HAVRIX in Adults

The concomitant use of IXIARO with inactivated Hepatitis A Virus vaccine (HAVRIX) was evaluated in a randomized, controlled, single‑blind clinical trial including 192 healthy adults 18 to 61 years of age (Study 7)⁷. Subjects were divided into three treatment groups: Group A (N=62) received IXIARO (Day 0 and 28) + HAVRIX (Day 0); Group B (N=65) received IXIARO (Day 0 and 28) + control (0.5 mL phosphate buffered saline with 0.1% aluminum hydroxide by intramuscular injection on Day 0); Group C (N=65) received HAVRIX (Day 0) + control (Day 0 and 28). Anti-JEV GMT at Day 56 in Group A met non-inferiority criteria compared to anti-JEV GMT at Day 56 in Group B. In addition, anti-HAV GMT at Day 28 in Group A met non-inferiority criteria compared to anti-HAV GMT at Day 28 in Group C. Therefore, concomitant administration of IXIARO and HAVRIX did not adversely affect immunogenicity compared to administration of either vaccine individually. Safety results regarding co-administration of IXIARO with HAVRIX are summarized in Adverse Reactions (6.1).

Delayed Completion of Primary Immunization in Adults

The immunogenicity of a second dose of the primary series administered 11 months after dose 1 was assessed in 100 adults in a study investigating persistence of immunity following vaccination with different dose-schedules of IXIARO (Study 5)⁵. Four weeks after this delayed second dose, 99.0% of subjects (99/100) had a PRNT₅₀ titer ≥1:10 (GMT 504.3 [95% CI: 367.3, 692.3]). One year later, 88.5% of subjects (85/96) had a PRNT₅₀ titer ≥1:10 (GMT 121.0 [95% CI: 87.4, 167.6]).