Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Encephalitis vaccines. ATC code: J07BA02

Mechanism of action
The 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 safety
No 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.

Seroconversion rate
Time point                              IXIARO                            JE-VAX N=365                             N=370
% (n)                             % (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                            JE-VAX N=365                             N=370
GMT (n)                           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) 
The effect of age on the immune response to IXIARO and JE VAX was assessed as a secondary endpoint in this active controlled study, comparing subjects aged ≥50 years of age (N=262, mean age 59.8) with those below 50 years of age (N=605, mean age 33.9).
There was no significant difference between seroconversion rates of IXIARO and JE VAX in subjects aged
<50 years compared to those aged ≥50 years at Day 28 or Day 56 following vaccination.
Geometric mean titers were significantly higher at Day 28 in subjects aged <50 years than those aged ≥50 years in the JE VAX group (80.9 vs. 45.9, p=0.0236) but there was no significant difference at Day 56 for this treatment group. There were no significant effects of age on geometric mean titer in the group receiving IXIARO. There was no significant difference between seroconversion rates in subjects aged <50 years compared to those aged ≥50 years at Day 28 or Day 56 for either treatment group.
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          GMT (N)               95% Confidence Interval                                      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] 
The observed decline in GMT is as expected and compares well with data from other inactivated JE vaccines.

In another open-label, follow-up Phase 3 study, the persistence of antibodies up to 24 months after primary vaccination was assessed. A total of 116 subjects who had received the recommended primary schedule of IXIARO were included in this follow-up study. Rates of subjects with PRNT50≥1:10 were 82.8% (95% CI: 74.9, 88.6, N=116) at Month 6 and 58.3% at Month 12 (95% CI: 49.1, 66.9, N=115). At Month 24, 48.3% (95% CI: 39.4, 57.3, N=116) of subjects who completed the recommended primary immunization still had PRNT50 titers of ≥1:10. GMT in these subjects was 16.2 (95% CI: 13.8, 19.0) at Month 24.

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            69.2%               [62.4%, 75.2%]            22.5            [19.0, 26.7] (n=198)
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                     GMT
(Rate of subjects with PRNT50≥1:10)     (plaque reduction neutralization test) Rapid Schedule Conventional             Rapid Schedule Conventional
% (n/N)            Schedule              (N)               Schedule
% (n/N)                                  (N)
Vaccination scheme     IXIARO Day 0,7 IXIARO Day 0,28          IXIARO Day 0,7 IXIARO Day 0, 28 Rabipur Day 0,3,7 -                     Rabipur Day 0,3,7 -
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) NA= not applicable

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 (PRNT 50 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                                      299 [254-352] (157/157)                                (157)
IXIARO                            100                                      337 [252-451] (49/49)                                  (49)
Vaccination schedules: IXIARO: Day 0/28, Rabipur: Day 0/7/28.

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 - <75 years                     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 population
In 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 country The 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 2 months –         6 months –           1 year –           3 years -               12 years - Age Group
<6 months          <12 months           < 3 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) 
100.0%
Day 56             100% (9/9)        100% (19/19)      99.2% (119/120)                           100% (137/137) (100/100)
Month 7                                                       85.5%                                      97.1% 100% (10/10)       100% (18/18)                           91.0% (91/100) (106/124)                                  (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                                83.3 (15/18)       75.8 (94/124)      71.0 (71/100)            65.0 (89/137) 90.0 (9/10)

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) 
◊Negative Pre-Vaccination titers were imputed to 5.

Safety and tolerability was evaluated in the entire study population. Parents or subjects recorded adverse events on a diary card for the first seven days after each vaccination. Parents or subjects were asked for any unsolicited AEs on the day of the second vaccination and at in-person visits including a medical exam 28 days (Day 56) and 6 months (Month 7) after the second dose. The safety profile of IXIARO was comparable to that of Havrix or Prevenar.

Antibody persistence and booster dose in children and adolescents from a JEV-endemic country The 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
Booster dose 12 months after primary
Without Booster immunization
N = 150
N = 149
Time point after primary                          0.25 mL Booster Dose 0.5 mL Booster Dose immunization                                           N=81                   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
Month 12                    46                          67                     40 
Month 13                    n.a.                    2911                      1366 
Month 24                    50                      572                        302 Month 36                    59                      427                        280 n.a. = not available


Immunogenicity and safety in children and adolescents from non-endemic countries The safety and immunogenicity of IXIARO was evaluated in 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         Time           SCR               GMT       95% CI
Dose         Point          n/N
100%              216.2   106.0; 441.0
Age Group ≥2 months to <3 years          0.25 ml        Day 56
5/5
100%               48.0      0.0;
Month 7                                   3214485.7
2/2
100%              340.7   269.8; 430.3
Age Group ≥3 to <18 years                 0.5 ml        Day 56
57/57
38.4;
57.1        84.9
Month 7           90.6%
29/32

Antibody persistence in children and adolescents from non-endemic countries Antibody 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                  Geometric Mean Titer
(Rate of subjects with PRNT50≥1:10) (plaque reduction neutralization test) % (n/N)                            GMT [95%CI]
After 0.25 mL Dose After 0.5 mL Dose After 0.25 mL Dose After 0.5 mL Dose Primary           Primary            Primary           Primary
Immunization      Immunization       Immunization      Immunization
0% (0/0)       89.5% (17/19)            -             48 [28; 80]
Month 12

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]  n.a. 95% Confidence Interval could not be established (single-subject data) 

Pharmacokinetic Properties

5.2        Pharmacokinetic properties

Evaluation of pharmacokinetic properties is not required for vaccines.