Phase III Clinical Trials Comparing the Immunogenicity and Safety of the Vero Cell-Derived Japanese Encephalitis Vaccine Encevac with Those of Mouse Brain-Derived Vaccine by Using the Beijing-1 Strain

Abstract

The immunogenicity and safety of an inactivated cell culture Japanese encephalitis vaccine (CC-JEV) were compared with those of an inactivated mouse brain-derived Japanese encephalitis vaccine (MB-JEV) in phase III clinical multicenter trials conducted in children. The vaccines contain the same Japanese encephalitis virus strain, the Beijing-1 strain. Two independent clinical trials (trials 1 and 2) were conducted. Trial 1 was conducted in 468 healthy children. Each subject was injected with 17 g per dose of either CC-JEV or MB-JEV, and the immunogenicity and safety of the vaccines were investigated. Trial 1 showed that CC-JEV was more immunogenic and reactive than MB-JEV at the same dose. Therefore, to adjust the immunogenicity of CC-JEV to that of MB-JEV, a vaccine that has had a good track record regarding its efficacy for a long time, trial 2 was conducted in 484 healthy children. To improve the stability, CC-JEV was converted from a liquid type to a freeze-dried type of vaccine. Each subject was injected subcutaneously with either 4 g per dose of CC-JEV, 8 g per dose of CC-JEV, or 17 g per dose of MB-JEV twice, at an interval of 2 to 4 weeks, followed by an additional booster immunization 1 to 15 months after the primary immunization. Based on the results of trial 2, 4 g per dose of the freeze-dried CC-JEV (under the label Encevac) was selected as a substitute for the MB-JEV. Encevac was approved and launched in 2011 and has since been in use as a 2nd-generation Japanese encephalitis vaccine in Japan. (These studies have been registered at the JapicCTI under registration no. JapicCTI-132063 and JapicCTI-080586 for trials 1 and 2, respectively.) J apanese encephalitis (JE) is an infectious disease caused by the JE virus (JEV), which is mediated by mosquitoes, such as Culex tritaeniorhynchus (1, 2). JE occurs not only in Japan but also in many other Asian countries, including Korea, Taiwan, China, Vietnam, Thailand, Malaysia, Myanmar, and India (3). The number of cases and fatalities due to JE are reported to be about 20,000 and 600 per year, respectively (1). To prevent this infectious disease, a JE vaccine derived from infected mouse brain tissue has been in use for a long time in Japan and other countries. Concurrently, a live-attenuated vaccine developed from a passaged culture of the JEV SA14 strain in primary hamster kidney cells and animals (mice and hamsters) with successive plaque purifications in primary chicken embryo cells, SA14-14-2, has been in use since 1989 in China and other countries (4). Moreover, an inactivated vaccine produced using the SA14-14-2 vaccine strain has been licensed in the United States, Europe, Canada, and Australia (5).In Japan, mouse brain-derived JE vaccine (MB-JEV) was initially produced using mouse brains inoculated with JEV Nakayama-NIH as a vaccine virus strain. At that time, MB-JEV was produced by adding formalin to the centrifugal supernatant of a 5% emulsion of mouse brain to inactivate the JE virus (6). Later, the quality of MB-JEV was improved through purificatio...

Polysaccharide-based chromatographic adsorbents for virus purification and viral clearance

“…The commercial product Cellufine™ Sulfate (JNC Corporation) which is produced by the functionalization of CEL beads [109] with a low concentration of sulfate esters [80], has been shown to be effective for virus purification with a view to improving production processes of vaccines, in particular against flavivirus infections [110]. Thus, cellufine sulfate chromatography is the polishing step of Vero cell-derived Japanese encephalitis virus in the production scheme of inactivated Japanese encephalitis vaccine [111], commercialized as Encevac® (Kaketsuken, Kumamoto, Japan) and tested in recent years in phase III clinical trial [112,113]. A final cellufine sulfate chromatographic step was also applied in the purification of XRX-001, a whole-virus, inactivated yellow fever vaccine candidate produced in Vero cell cultures and adjuvanted by alum (aluminum hydroxide) [114].…”

Immunogenicity and safety of currently available Japanese encephalitis vaccines: A systematic review

“…13,14,[56][57][58] The pooled OR was 0.07 (95%CI, 0.02-0.31) with a moderate heterogeneity (I 2 D 21.84%) (Figure 2). The funnel plot was not symmetric (data not shown) and the Egger's test was significant (P D 0.02), which indicated a high probability of publication bias.…”

“…14 Efficacy of 99.3% (95%CI, 94.9-100%) was observed in a median of 2 weeks after vaccination by Bista et al 58 in Nepal. The protective effect of vaccine after 12-15 months was 98.5% (95%CI, 90.1-99.2%), 57 and maintained at 96.2% (95%CI, 73.1-99.9%) 5 years after administration of a single dose.…”

Japanese encephalitis vaccines: Immunogenicity, protective efficacy, effectiveness, and impact on the burden of disease

“…29 It has been noted that, compared to MBDI vaccines, the Vero cell-derived inactivated vaccine elicits markedly higher NAb responses, or that lower amounts of antigen are sufficient to elicit equivalent responses. 74,132,141,142,145 Although the factors responsible for this are not known, some of the suggested reasons for higher potency of CCDI vaccines are: (a) less bioprocess steps and milder down-stream processing conditions, (b) ultrastructural morphology of cell culture-derived vaccine virus being more similar than the MBDI vaccine virus to the native virus, (c) higher affinity toward several monoclonal antibodies, 141 and (d) differential glycosylation of the E protein. 146 …”