Safety and immunogenicity of a freeze-dried, Vero cell culture-derived, inactivated Japanese encephalitis vaccine (KD-287, ENCEVAC®) versus a mouse brain-derived inactivated Japanese encephalitis vaccine in children: a phase III, multicenter, double-blinded, randomized trial

Ki Wook Yun, Hoan Jong Lee, Jin Han Kang, Byung Wook Eun, Yae-Jean Kim, Kyung-Hyo Kim, Nam Hee Kim, Young Jin Hong, Dong Ho Kim, Hwang Min Kim, Sung-Ho Cha, Ki Wook Yun, Hoan Jong Lee, Jin Han Kang, Byung Wook Eun, Yae-Jean Kim, Kyung-Hyo Kim, Nam Hee Kim, Young Jin Hong, Dong Ho Kim, Hwang Min Kim, Sung-Ho Cha

Abstract

Background: Although mouse brain-derived, inactivated Japanese encephalitis vaccines (JE-MBs) have been successfully used for a long time, potential rare neurological complications have prompted the development of a Vero cell culture-derived inactivated vaccine (JE-VC). In a phase III clinical study, we aimed to compare the safety and immunogenicity of a JE-VC, KD-287 with a JE-MB, JEV-GCC, in children.

Methods: In this multicenter, double-blinded, randomized controlled trial, the study population consisted of 205 healthy Korean children aged 12-23 months. Each subject was subcutaneously vaccinated with either KD-287 or JEV-GCC twice at an interval of 2 weeks and then vaccinated once 12 months after the second vaccination. Neutralizing antibodies were measured by the plaque reduction neutralization test using the homologous and heterologous, as a post hoc analysis, challenge virus strains.

Results: The three-dose regimen of KD-287 showed a comparable safety profile with JEV-GCC except higher incidence of fever after the first dose (30.4% and 14.7%, respectively). Most of the fever was mild degree (61.3% and 66.7%, respectively). KD-287 fulfilled the non-inferiority criteria for seroconversion rate (SCR) and geometric mean titer (GMT) of the neutralizing antibody, which were the primary endpoints, at 4 weeks after the third vaccination (95% CI: -1.00, 3.10 for the SCR difference and 10.8, 17.6 for the GMT ratio). The SCRs of KD-287 were all 100% and the GMTs were higher in the KD-287 group than in the JEV-GCC group after the second vaccination and before and after the third vaccination (GMT ratio: 5.59, 20.13, and 13.79, respectively, p < 0.001 in all). GMTs were higher in the KD-287 group in the heterologous analysis also (GMT ratio: 4.05, 5.15, and 4.19, respectively, p < 0.001 in all).

Conclusions: This study suggests that the KD-287, a JE-VC is as safe as and may be more effective than the licensed MB-derived vaccine. KD-287 could thus be useful as a second-generation vaccine and substitute for the current JE-MB vaccine in Korean children.

Trial registration: ClinicalTrials.gov: NCT01150942.

Figures

Figure 1
Figure 1
Analysis populations and excluded subjects.
Figure 2
Figure 2
Changes of mean neutralizing antibody titers before and after vaccination. Satisfactory geometric mean titers (GMTs) were obtained after the second vaccination and before and after the third vaccinations in both vaccine groups, in both homologous and heterologous analyses. The GMTs before the third vaccination in the KD-287 group were higher than those after the second vaccination for both tested strains. After the third vaccination, the neutralizing antibody titer increased in all children, and the GMTs in both groups were higher than the respective GMTs after the second vaccination.

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