Ixiaro

Ixiaro Mechanism of Action

vaccine, japanese encephalitis

Manufacturer:

Valneva

Distributor:

Pharmaforte
Full Prescribing Info
Action
Pharmacotherapeutic group: Encephalitis vaccines. ATC code: J07BA02.
Pharmacology: Pharmacodynamics: 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 (JEV) 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 IXIAROwas studied in approximately 2,480 healthy adult subjects included in six randomized, controlled and three uncontrolled Phase 3 trials and in approximately 550 children included in one randomized, controlled and one uncontrolled Phase 3 clinical trial.
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 SC 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 (see Table 1).

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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 over 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 <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 2 for the ITT population. (See Table 2.)

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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 immunization (adults): In an uncontrolled, open-label phase 3 study a single 6 mcg 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 summarized in Table 3. (See Table 3.)

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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, 1x12 mcg: N=116 or 1x6 mcg: N=117). A single 6 mcg 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 4. (See Table 4.)

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Concomitant use (adults): 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 (see Table 5).

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Paediatric population: In a phase 2 study in healthy Indian toddlers ≥1 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 6. (See Table 6.)

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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.
Immunogenicity and Safety in Children and adolescents from non-endemic countries: The safety and immunogenicity of IXIARO was evaluated in an interim analysis of an ongoing, 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 ≥3 to <18 years received two vaccine doses of 0.5 ml and children ≥2 months to <3 years received two vaccine doses of 0.25 ml on Day 0 and Day 28 by IM injection. An interim analysis was carried out on immunogenicity data for 54 subjects. The SCRs and GMTs are displayed in Table 7. (See Table 7.)

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Pharmacokinetics: Evaluation of pharmacokinetic properties is not required for vaccines.
Toxicology: Preclinical safety data: Nonclinical toxicity data are limited.
In a reproductive and pre-/post-natal toxicity study, no vaccine-related effects were detected on reproduction, foetal weight, survival and development of the offspring. However, incomplete ossification of parts of the skeleton was observed in the group receiving 2 doses, but not in the group receiving 3 doses. It is currently difficult to explain if this phenomenon is treatment related or not.
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