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

Abstract

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.

Figure 1

Participant disposition and reason for withdrawal at the end of the treatment phase (day 56) and at month 6, 7, 12, 24, 36, 48 and 60 for participants treated with a single 3.8 log₁₀ dose of JE-CV and placebo with or without a booster dose of 3.8 log₁₀ JE-CV at month 6. Treatment period withdrawals (to day 56): Group A: One Treated related adverse event (TRAE) (mild glomerulonephritis and anemia). Two military deployments/training. All three participants received JE-CV but not placebo. Group B: Two instances of protocol non-compliance. One participant with a protocol deviation received both JE-CV and placebo while one participant withdrawn for a reason in the “Other” category received only placebo. Second dose group withdrawals (to month 7): Five withdrawals—lost to follow-up. All participants received vaccine. Long term follow-up withdrawals: (1) One participant was withdrawn due to mouse brain derived, inactivated JE immunization administered between month 48 and month 60. This was required because the participant had no detectable JEV antibodies and was required to deploy to a JE endemic area. (2) A total of 125 participants did not attend the annual follow-up visit over 5 years, principally due to military deployments, leaving the service or posting outside the visitation range of the single center study site.

Figure 2

Kaplan-Meier survival analysis showing seroprotection (PRNT50 > 10) over time for 1-dose (Group C) and 2-dose (Group D) JE-CV groups from month 6 to 60. Kaplan-Meier survival analysis was used to determine the proportion of participants maintaining seroconversion to JE-CV from month 6 to 60 with separate analyses undertaken for participants given a single dose of vaccine and those given two doses of vaccine (log-rank test). Participant numbers “at risk”, “failed” and “censored” reflect those who attended each visit and a particular study population (i.e. safety or ITT populations) (Table 3). Month 7 was not performed for the single dose participant with a serology value at month 7. PRNT50 values reported at < 10 were converted to a PRNT50 = 5. If a PRNT50 value was missing for a visit and the participant returned for the next visit and was seroprotected at that time; the participant was assumed to have remained seroprotected at the time of the missing visit. If a PRNT50 value was missing for a visit and the participant returned for the next visit and was not seroprotected (i.e. PRNT50 < 10) at that time, the participant was assumed to have not been seroprotected at the time of the missing visit. For participants who missed two consecutive visits, only the data up to the missing visits was used for the Kaplan-Meier estimate.

Figure 3

GMT and GMT ratio for 1-dose (Group C) and 2-dose (Group D) from month 6 to 60. The geometric mean ratio was calculated by ANOVA and was considered significant if the 95% CI did not contain the value one. Significant differences (p < 0.05) in the anti-JE-CV GMT from month 12 through month 48 are indicated by an asterisks.