Ixiaro

Immunogenicity of Ixiaro in Children and Adolescents

Immunogenicity of Ixiaro Days 0 and 28 Primary Series in Children and Adolescents from a JEV-Endemic Country:

• In a randomized, controlled, open-label clinical trial (Study 1) conducted in the Philippines, the immunogenicity of Ixiaro was evaluated in a subgroup of healthy children. Ixiaro was compared to the control vaccines: Havrix (Hepatitis A vaccine, pediatric 720 EL.U./0.5 mL formulation) and Prevnar (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 protein]). 

• Patients received Ixiaro intramuscularly (0.25mL for infants and children 2 months to <3 years of age or 0.5 mL for individuals 3 to <18 years of age) on Day 0 and Day 28. The immunogenicity evaluation included the proportion of subjects with PRNT₅₀ titer ≥1:10 and PRNT₅₀ geometric mean titer (GMT) at Day 56 and Month 7.

• The proportion of patients who received Ixiaro with PRNT₅₀ Titer ≥1:10 (n/N) are as followed:

• Day 56 (28 days after dose 2): 

• 2 months – <6 months: 100% (9/9)

• 6 months – <12 months: 100% (19/19)

• 1 year – <3 years: 99.2% (119/120)

• 3 years – <12 years: 100% (100/100)

• 12 years – <18 years: 100% (137/137)

• Month 7 (6 months after dose 2):

• 2 months – <6 months: 100% (10/10)

• 6 months – <12 months: 100% (18/18)

• 1 year – <3 years: 85.5% (106/124)

• 3 years – <12 years: 91.0% (91/100)

• 12 years – <18 years: 97.1% (133/137)

• Geometric Mean Titers (N):

• Day 56 (28 days after dose 2): 

• 2 months – <6 months: 687.4 (9)

• 6 months – <12 months: 377.8 (19)

• 1 year – <3 years: 258.9 (121)

• 3 years – <12 years: 213.7 (100)

• 12 years – <18 years: 175.6 (137)

• Month 7 (6 months after dose 2):

• 2 months – <6 months: 159.3 (10)

• 6 months – <12 months: 64.0 (18)

• 1 year – <3 years: 38.9 (125)

• 3 years – <12 years: 43.6 (100)

• 12 years – <18 years: 86.6 (137)

Antibody Persistence Following Ixiaro Days 0 and 28 Primary Series and Immunogenicity of Ixiaro Booster Dose in Children and Adolescents from a JEV-Endemic Country:

• 300 patients who completed primary immunization of Ixiaro in Study 1 were enrolled in an open label follow-on trial (Study 3). Patients were randomly assigned 1:1 to receive a single booster dose of Ixiaro (0.25 ml for ages 14 months to <3 years or 0.5 ml for ages 3 to <18 years) or no booster dose at 11 months after primary series.

• The proportion of patients with PRNT₅₀ Titer ≥1:10 (n/N) are as followed:

• Month 12 (11 months after completion of primary series): 

• No booster dose: 89.9% 

• 0.25mL booster dose: 97.5%

• 0.5mL booster dose: 89.6%

• Month 13 (12 months after completion of primary series): 

• No booster dose: N/A 

• 0.25mL booster dose: 100%

• 0.5mL booster dose: 100%

• Month 24 (23 months after completion of primary series): 

• No booster dose: 89% 

• 0.25mL booster dose: 100%

• 0.5mL booster dose: 100%

• Month 36 (35 months after completion of primary series): 

• No booster dose: 90.1% 

• 0.25mL booster dose: 100%

• 0.5mL booster dose: 100%

• Geometric Mean Titers:

• Month 12 (11 months after completion of primary series): 

• No booster dose: 45.5

• 0.25mL booster dose: 67.3

• 0.5mL booster dose: 40.4

• Month 13 (12 months after completion of primary series): 

• No booster dose: N/A 

• 0.25mL booster dose: 2910.8

• 0.5mL booster dose: 1365.9

• Month 24 (23 months after completion of primary series): 

• No booster dose: 49.8

• 0.25mL booster dose: 572.3

• 0.5mL booster dose: 302.1

• Month 36 (35 months after completion of primary series): 

• No booster dose: 59.4

• 0.25mL booster dose: 427.5

• 0.5mL booster dose: 279.6

Immunogenicity of Ixiaro Days 0 and 28 Primary Series in Children 2 Months to < 18 Years of Age Traveling from Non-Endemic Areas:

• In an uncontrolled, open-label clinical trial conducted in the United States, Europe and Australia, the immunogenicity of Ixiaro was evaluated as a primary series administered on Day 0 and Day 28 in healthy male and female patients with planned travel to JEV-endemic areas (Study 2).

• Patients received an intramuscular injection of Ixiaro on Day 0 and Day 28 (0.25 mL dose for infants and children 2 months to <3 years of age, 0.5 mL dose for children and adolescents 3 to <18 years of age).

• All patients were seronegative for JEV-neutralizing antibodies pre-vaccination.

• 100% of patients (n=62/62) had PRNT50 Titer ≥1:10 at 1 month after completing the primary series. 91.2% of patients (n=31/34) had PRNT₅₀ Titer ≥1:10 at 6 months after completing the primary series.

• 23 patients from Study 2 were enrolled in a follow-on study to evaluate antibody persistence. The proportions of subjects with PRNT₅₀ Titer ≥1:10 at 11 months, 23 months, and 35 months after completion of the primary series were 89.5% (17/19), 91.3% (21/23) and 89.5% (17/19) respectively.

Immunogenicity of Ixiaro in Adults

Immunogenicity of Ixiaro Days 0 and 28 Primary Series in Adults:

• The randomized, active-controlled, observer-blinded clinical trial conducted in the US, Germany and Austria (Study 5) evaluated the immunogenicity of Ixiaro in 867 healthy adults 18 years of age and older. Patients were randomly assigned to receive Ixiaro on Day 0, Day 7, PBS + Al(OH)3 (0.5 mL phosphate buffered saline with 0.1% aluminum hydroxide), and on Day 28, or the comparator arm (US-licensed JEV vaccine, JE-VAX, 1.0mL SC on DAys 0, 7,  and 28.

• The neutralizing antibody responses elicited by Ixiaro met predefined statistical criteria for non-inferiority compared to those induced by JE-VAX.

Temporal Evaluation of Immunogenicity of Ixiaro During the Days 0 and 28 Primary Vaccination Series in Adults: 

• The randomized, observer-blinded clinical study (Study 10) evaluated the immunogenicity of Ixiaro in 374 healthy adults 18 years of age and older. Ixiaro was administered 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 patients randomized to the standard dosing regimen (Ixiaro on days 0 and 28) are as followed:

• Day 10 (10 days after vaccine dose 1): 21.1% (n=24/114)

• Day 28 (28 days after vaccine dose 1): 39.8% (n=45/113)

• Day 35 (7 days after vaccine dose 2): 97.3% (n=110/113)

• Day 56 (28 days after vaccine dose 2): 97.3% (n=110/113)

Persistence of Neutralizing Antibody Response Following the Days 0 and 28 Primary Vaccination Series in Adults: 

• A subgroup of adult patients were recruited for follow-up after participation in 1 of 2 clinical trials (Study 4 and Study 5) and were evaluated for the persistence of JEV-neutralizing antibody.

• 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.

• Study 11 also evaluated the persistence of JEV-neutralizing antibody in 116 adults who completed the Days 0 and 28 Ixiaro primary immunization series.

• 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 (Days 0 and 7 Primary Series and Days 0 and 28 Primary Series) with Concomitant Rabies Vaccine in Adults 18 through 65 Years of Age: 

• The randomized, observer-blind, controlled clinical trial (Study 6) evaluated the immunogenicity of Ixiaro (Days 0 and 7 primary series and Days 0 and 28 primary series) concomitantly administered with an inactivated rabies vaccine (Rapipur; marketed in the US as RabAvert) in 661 patients 18 to 65 years of age.

• Comparing the Ixiaro Days 0 and 7 primary series administered concomitantly with rabies vaccine to the Ixiaro Days 0 and 28 primary series administered alone, the difference in proportion of subjects with JEV-neutralizing PRNT₅₀ Titer ≥1:10 at 28 days after the last Ixiaro dose was -1% (97.5% CI: -4.8%, 7.9%), which met the pre-specified non-inferiority criterion that the lower bound of the 2-sided 97.5% CI be greater than -10%.

• Comparing the Ixiaro Days 0 and 28 primary series administered concomitantly with rabies vaccine to the Ixiaro Days 0 and 28 primary series administered alone, the JEV-neutralizing PRNT50 GMT ratio at 28 days after the last IXIARO dose was 0.88 (95% CI: 0.68, 1.13), which met the pre-specfied non-inferiority criterion that the lower bound of the 2-sided 95% CI be greater than 0.5.

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 10). 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]).

Immunogenicity of Ixiaro Booster Dose 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 Days 0 and 28 primary series (Study 7). 

• The proportion of subjects with PRNT₅₀ titer ≥1:10 at pre-booster (Day 0), Day 28, Month 6 and 12 were 69.2%, 100%, 98.5% and 98.5%, respectively. 

• Geometric mean titers (GMT) at pre-booster (Day 0), Day 28, Month 6 and 12 were 22.5, 900.1 , 487.4 and 361.4, respectively.