Concomitant or sequential administration of live attenuated Japanese encephalitis chimeric virus vaccine and yellow fever 17D vaccine: randomized double-blind phase II evaluation of safety and immunogenicity

Abstract

A randomized, double-blind, study was conducted to evaluate the safety, tolerability and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) co-administered with live attenuated yellow fever vaccine (YF-17D strain; Stamaril®, Sanofi Pasteur) or administered successively. Participants (n = 108) were randomized to receive: YF followed by JE-CV 30 days later, JE followed by YF 30 days later, or the co-administration of JE and YF followed or preceded by placebo 30 days later or earlier. Placebo was used in a double-dummy fashion to ensure masking. Neutralizing antibody titers against JE-CV, YF-17D and selected wild-type JE strains was determined using a 50% serum-dilution plaque reduction neutralization test. Seroconversion was defined as the appearance of a neutralizing antibody titer above the assay cut-off post-immunization when not present pre-injection at day 0, or a least a four-fold rise in neutralizing antibody titer measured before the pre-injection day 0 and later post vaccination samples. There were no serious adverse events. Most adverse events (AEs) after JE vaccination were mild to moderate in intensity, and similar to those reported following YF vaccination. Seroconversion to JE-CV was 100% and 91% in the JE/YF and YF/JE sequential vaccination groups, respectively, compared with 96% in the co-administration group. All participants seroconverted to YF vaccine and retained neutralizing titers above the assay cut-off at month six. Neutralizing antibodies against JE vaccine were detected in 82-100% of participants at month six. These results suggest that both vaccines may be successfully co-administered simultaneously or 30 days apart.

Figures

Figure 1

Study disposition.

Figure 2

Geometric mean anti-JE-CV neutralizing antibody titer in the PP vaccinees following immunization with either JE, YF or both JE and YF co-administered together at day 0. Ratio of means for Group 3 (Co-ad total)/Group 1 (JE followed by YF) at day 30 = 0.2 (95% CI 0.1, 0.7). Ratio of means for Group 2 (YF followed by JE)/Group 1 (JE followed by YF) at day 30 = 0.3 (95% CI 0.1, 0.9). A significant difference between treatment groups (p

Figure 3

Percent of participants in the PP population seroconverting (PRNT50 ≥ 1:20 or 4-fold rise from baseline) to JE-CV and wild-type JEV strains, 30 days after last immunization with either JE, YF or both JE and YF co-administered together at day 0.

Figure 4

Geometric mean anti-YF-17D neutralizing antibody titer in the PP vaccinees following immunization with either JE, YF or both JE and YF coadministered together at day 0. Ratio of means for Group 3 (Co-ad total)/Group 1 (JE followed by YF) at day 30 = 0.6 (95% CI 0.3, 1.2). Ratio of means for Group 2 (YF followed by JE)/Group 1 (JE followed by YF) at day 30 = 1.1 (95% CI 0.5, 2.6). A significant difference between treatment groups (p