Primary immunization of infants and toddlers in Thailand with Japanese encephalitis chimeric virus vaccine in comparison with SA14-14-2: a randomized study of immunogenicity and safety.

BACKGROUND: The live, attenuated Japanese encephalitis (JE) chimeric virus vaccine (JE-CV) is licensed in Thailand and Australia for prophylaxis of JE in individuals at the age of 12 months. JE-CV has not yet been compared with the SA14-14-2 JE vaccine, which is also licensed in Thailand. METHODS: In this phase 3, observer-blinded trial, 300 children at the age of 9-18 months were randomized 1:1 to receive 1 dose of JE-CV or SA14-14-2. JE neutralizing antibody titers were assessed using PRNT50. The primary endpoint was the noninferiority of seroconversion against JE on Day 28 after JE-CV compared with SA14-14-2, as assessed using the 95% confidence interval of the difference between the groups. Safety and reactogenicity were described in each group using conventional methods, including the reporting of solicited and unsolicited adverse events. RESULTS: The seroconversion rate on Day 28 was 99.2% in each group. Noninferiority was demonstrated as the difference between the JE-CV and SA14-14-2 groups was -0.012 percentage points (95% confidence interval: -3.6 to 3.6), which was above the required -10%. The seroprotection rate remained very high at Month 6 and comparable between groups, but a slight decrease was observed in the JE-CV group between Months 6 and 12. Current recommendations for both vaccines call for a booster dose 12-24 months after primary immunization to maintain high seroprotection rates in the long term. Geometric mean titers (GMTs) on Day 28 after vaccination were 507 (1/dil) in the JE-CV group and 370 (1/dil) in the SA14-14-2 group, decreasing by 4.3-fold and 3.6-fold, respectively, to Month 6 before remaining stable to Month 12 and comparable between groups. Solicited reactions were all reported at lower rates after vaccination with JE-CV compared with SA14-14-2. CONCLUSIONS: A single dose of JE-CV elicited a noninferior immune response compared with SA14-14-2 and had a satisfactory safety profile.

Immune response to live-attenuated Japanese encephalitis vaccine (JE-CV) neutralizes Japanese encephalitis virus isolates from south-east Asia and India.

BACKGROUND: During clinical development of the licensed Japanese encephalitis chimeric virus vaccine (JE-CV), the neutralization capacity of vaccine-induced antibodies was assessed against the vaccine virus and against well characterized wild-type (wt) viruses isolated between 1949-1991. We assessed whether JE-CV-induced antibodies can also neutralize more recent wt Japanese encephalitis virus (JEV) isolates including a genotype 1 isolate. METHODS: Sera from 12-18 month-old children who received a single dose of JE-CV in a phase III study in Thailand and the Philippines (ClinicalTrials.gov NCT00735644) were randomly selected and pooled according to neutralization titer against JE-CV into eight samples. Neutralization was assessed by plaque reduction neutralization tests (PRNT50) against three recent isolates from JEV genotypes 1 and 3 in addition to four JEV previously tested. RESULTS: Neutralization titers against the three recent JEV strains were comparable to those observed previously against other strains and the vaccine virus. The observed differences between responses to genotype 1 and 3 viruses were within assay variability for the PRNT50. CONCLUSIONS: The results were consistent with previously generated data on the neutralization of wt JEV isolates, immune responses induced by JE-CV neutralize recently isolated virus from southeast (SE) Asia and India.

Memory immune response and safety of a booster dose of Japanese encephalitis chimeric virus vaccine (JE-CV) in JE-CV-primed children.

Japanese encephalitis chimeric virus vaccine (JE-CV) is a licensed vaccine indicated in a single dose administration for primary immunization. This controlled phase III comparative trial enrolled children aged 36-42 mo in the Philippines. 345 children who had received one dose of JE-CV in a study two years earlier, received a JE-CV booster dose. 105 JE-vaccine-naïve children in general good health were randomized to receive JE-CV (JE-vaccine naïve group; 46 children) or varicella vaccine (safety control group; 59 children). JE neutralizing antibody titers were assessed using PRNT50. Immunological memory was observed in children who had received the primary dose of JE-CV before. Seven days after the JE-CV booster dose administration, 96.2% and 66.8% of children were seroprotected and had seroconverted, respectively, and the geometric mean titer (GMT) was 231 1/dil. Twenty-eight days after the JE-CV booster dose seroprotection and seroconversion were achieved in 100% and 95.3% of children, respectively, and the GMT was 2,242 1/dil. In contrast, only 15.4% of JE-CV-vaccine naïve children who had not received any prior JE vaccine were seroprotected seven days after they received JE-CV. One year after receiving the JE-CV booster dose, 99.4% of children remained seroprotected. We conclude that JE-CV is effective and safe, both as a single dose and when administrated as a booster dose. A booster dose increases the peak GMT above the peak level reached after primary immunization and the antibody persistence is maintained at least one year after the JE-CV booster dose administration. Five year follow up is ongoing.

Long term immunity to live attenuated Japanese encephalitis chimeric virus vaccine: randomized, double-blind, 5-year phase II study in healthy adults.

In a randomized, double-blind study, 202 healthy adults were randomized to receive a live, attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and placebo 28 days apart in a cross-over design. A subgroup of 98 volunteers received a JE-CV booster at month 6. Safety, immunogenicity, and persistence of antibodies to month 60 were evaluated. There were no unexpected adverse events (AEs) and the incidence of AEs between JE-CV and placebo were similar. There were three serious adverse events (SAE) and no deaths. A moderately severe case of acute viral illness commencing 39 days after placebo administration was the only SAE considered possibly related to immunization. 99% of vaccine recipients achieved a seroprotective antibody titer ≥ 10 to JE-CV 28 days following the single dose of JE-CV, and 97% were seroprotected at month 6. Kaplan Meier analysis showed that after a single dose of JE-CV, 87% of the participants who were seroprotected at month 6 were still protected at month 60. This rate was 96% among those who received a booster immunization at month 6. 95% of subjects developed a neutralizing titer ≥ 10 against at least three of the four strains of a panel of wild-type Japanese encephalitis virus (JEV) strains on day 28 after immunization. At month 60, that proportion was 65% for participants who received a single dose of JE-CV and 75% for the booster group. These results suggest that JE-CV is safe, well tolerated and that a single dose provides long-lasting immunity to wild-type strains.

Immunogenicity, safety and tolerability in adults of a new single-dose, live-attenuated vaccine against Japanese encephalitis: Randomised controlled phase 3 trials.

Japanese encephalitis chimeric virus vaccine (JE-CV) was developed to replace licensed mouse brain-derived vaccine (MBD-JE), the production of which ceased in 2005. Two randomised controlled phase 3 studies were conducted. Immunogenicity study: 410 participants received one JE-CV injection, 410 received 3 MBD-JE injections. Safety study: 1,601 participants received JE-CV, 403 received placebo. Seroconversion after a single JE-CV vaccination (99.1%) was statistically non-inferior to that after three-dose MBD-JE (95.1%) vaccination. JE-CV elicited a rapid immune response, with 93.6% of participants seroconverting within 14 days. Adverse reaction rates were significantly lower with JE-CV (67.6%) than with MBD-JE (82.2%) (p<0.001), and the reactogenicity profile of JE-CV was comparable with that of placebo. A single dose of JE-CV elicited rapid seroconversion in a higher proportion of vaccinees than the current vaccine with fewer reactions. The safety profile of JE-CV is good.

Lack of induction of autoantibody responses following immunization with cytomegalovirus (CMV) glycoprotein B (gB) in healthy CMV-seronegative subjects.

Possible correlations have been proposed between autoimmune diseases, such as systemic lupus erythematosus (SLE), and infection with human cytomegalovirus (CMV). The recent observation that an adenovirus expressing the immunodominant envelope glycoprotein of CMV, glycoprotein B (gB), may be capable of inducing autoantibodies in certain mouse strains has prompted interest in exploring potential relationships between gB immunization and autoimmune disease. We examined whether a recombinant CMV gB vaccine, or a gB canarypox vectored vaccine (ALVAC-CMVgB), administered to a total of 76 CMV-seronegative subjects, was capable of inducing cross-reactive antibodies to Smith antigen (Sm), ribonucleoprotein complex (RNP), and the U1-70 kDa component of the RNP complex. Using immunofluorescence, EIA and immunoblot analyses, we failed to identify induction of autoantibodies following vaccination with gB, whether administered alone as a purified protein subunit with adjuvant, or in combination with expression in a vectored approach using a recombinant canarypox. These data reinforce the favorable safety profile of CMV gB vaccines.

Effect of previous or simultaneous immunization with canarypox expressing cytomegalovirus (CMV) glycoprotein B (gB) on response to subunit gB vaccine plus MF59 in healthy CMV-seronegative adults.

Development of a vaccine for prevention of congenital cytomegalovirus (CMV) disease is a priority. This study evaluated a "prime-boost" strategy by comparing the safety and immunogenicity of 3 doses of subunit CMV glycoprotein B (gB) vaccine plus MF59 (a squalene-in-water emulsion), 2 doses of a canarypox recombinant vaccine expressing CMVgB (ALVAC-CMVgB) followed by 2 doses of the subunit gB vaccine, 3 doses of both vaccines administered concomitantly, and placebo in 105 healthy, CMV-seronegative adults. Systemic adverse events were rare, but local reactions were common in all groups. After the first subunit vaccination, neutralizing antibody titers in the prime-boost group were comparable to those in subjects receiving 2 subunit vaccinations, indicating a priming effect of ALVAC-CMVgB. However, after the final dose, antibody and cell-mediated immune responses were not significantly different among the groups. All 3 vaccine regimens induced high-titer antibody and lymphoproliferative responses, but no benefit for priming or simultaneous vaccination was detected.