Safety profile of the Vero cell-derived Japanese encephalitis virus (JEV) vaccine IXIARO(®).

Japanese encephalitis (JE) is the most common cause for viral encephalitis in Asia and can be effectively prevented by vaccination. IXIARO(®) is a Vero cell-derived, inactivated JE virus vaccine which has been licensed and distributed in the US, Europe, Canada, Hongkong, Israel, and distributed in Australia under the trade name JESPECT(®). This paper reviews the safety profile of IXIARO(®) in the first 12months after licensure and discusses the observed profile in the context of clinical trial results for IXIARO(®) and post-marketing safety data for JE-VAX(®). The clinical safety profile is derived from a pooled analysis including safety data from 10 phase III trials in 4043 subjects who received at least one IXIARO(®) vaccination and were followed-up for up to 3years after the primary immunization. Local and systemic tolerability of IXIARO(®) was similar to an earlier safety analysis at the time of licensure of the vaccine. In post-marketing AE reports, the system organ classes affected following vaccination with IXIARO(®) were similar to the previously observed clinical trial profile. No serious allergic reactions were observed in the 12-month post-marketing period. This comprehensive safety review confirms the good safety profile of IXIARO(®) in clinical and post-marketing use.

Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIARO®, IC51.

INTRODUCTION: IXIARO (IC51), a recently approved inactivated Japanese Encephalitis vaccine, is immunogenic and safe in a 0/28 days primary immunization schedule. Neutralizing antibody titers decline with time and booster doses are likely needed to enhance persistence of immunity. OBJECTIVES: To assess the effect of a booster dose on neutralizing JE antibody titers for up to 12 months after boostering. METHODS: In this phase III trial, 198 subjects, who had received primary immunization in a preceding randomized trial, were boosted with IXIARO 15 months after the primary immunization. Neutralizing antibody titers were assessed by plaque-reduction neutralisation test, PRNT. RESULTS: Prior to the booster dose, 69.2% (137/198) of subjects had PRNT50 titers ≥ 1:10. One month after the booster, the rate of subjects with PRNT50 ≥ 1:10 (recognized as a protective titer) was 100%. This rate remained high at 98.5% at 6 and 12 months; GMTs were 22.5 before the booster and 900, 487 and 361 at 1, 6 and 12 months after the booster, respectively. CONCLUSION: A booster dose of IXIARO at 15 months after primary immunization was highly immunogenic with GMTs >5-fold higher than those seen immediately after primary immunization, and remained at high levels for at least 12 months after the booster.

Safety analysis of a Vero-cell culture derived Japanese encephalitis vaccine, IXIARO (IC51), in 6 months of follow-up.

Japanese encephalitis (JE) is the most common viral encephalitis in Asia. IXIARO is a Vero cell-derived, inactivated JE virus vaccine which has recently been approved in the US, Europe, Canada and Australia (trade name JESPECT). This overview of the safety and tolerability of IXIARO, for 6 months after the first vaccination in 7 Phase III trials, includes: 3558 subjects with at least one IXIARO vaccination, 435 subjects with a JE-VAX (manufactured by BIKEN, distributed by Sanofi Pasteur) vaccination, and 657 with phosphate-buffered saline solution with 0.1% Al(OH)(3) (PBS+Alum) control vaccination. The percentage of subjects reporting solicited local adverse events (AEs) with IXIARO (54%) was similar to PBS+Alum vaccination (56%) as were solicited systemic adverse events (40% IXIARO; 40% PBS+Alum vaccination). JE-VAX showed a higher frequency of subjects with solicited local adverse events (61%) but a slightly lower frequency of subjects with solicited systemic adverse events (36%). The frequency of subjects with any solicited and unsolicited AE with IXIARO (64%) was also similar to PBS+Alum vaccination (61%) and JE-VAX (64%); as for subjects with serious AEs (1% IXIARO; 2% PBS+Alum vaccination, 1% JE-VAX). No serious allergic reactions were observed in any group. This safety analysis indicates that IXIARO has a favorable safety profile, comparable to PBS+Alum control vaccination and appears to have a better local tolerability profile than JE-VAX.

Long-term immunity and immune response to a booster dose following vaccination with the inactivated Japanese encephalitis vaccine IXIARO, IC51.

IC51 (IXIARO, JESPECT) is a recently approved prophylactic Japanese encephalitis virus vaccine with a two-vaccine primary immunization regimen. In this phase 3 trial, after primary immunization with a Day 0/28 dose schedule, seroprotection rates were 83%, 58% and 48% at Month 6, Month 12 and Month 24, respectively. A booster dose at Month 11 and/or Month 23 in subjects with neutralizing antibody titers below the limit of detection (defined as a serum dilution giving a 50% reduction of plaque counts in a plaque reduction neutralization test [PRNT50]<1:10) led to 100% seroconversion. After a single-dose immunization (incomplete primary immunization), only 9% of subjects were seroprotected at Month 6; however, a booster dose at Month 11 led to seroconversion in 99% of subjects. Hence, subjects with incomplete primary immunization can complete their schedule within at least 11 months.

IC51 Japanese encephalitis vaccine.

Japanese encephalitis is the leading cause of viral encephalitis in Asia. Every year 30,000 - 50,000 cases and 10,000 deaths from Japanese encephalitis are reported, and underreporting has been suggested. No effective antiviral therapy exists to treat this mosquito-borne flavivirus infection. For active immunization vaccines are available. The manufacturing of the only vaccine that was internationally licensed, JE-VAX, was ceased in 2005. Therefore a shortage of Japanese encephalitis vaccines might occur before new generation vaccines based on cell culture technology will be available. A promising new vaccine candidate is the inactivated whole-virus vaccine IXIARO (Strain SA(14)-14-2), developed by Intercell AG. Which was licensed in Europe, the USA and Australia in spring 2009. Recently, successful Phase III immunogenicity and tolerability studies were published, indicating that this vaccine will be an acceptable approach to active immunization against Japanese encephalitis. Cell-culture-based vaccines will not only be used in the population living in endemic areas where the risk of infection is high, but also by travelers and military personnel.