Concomitant or sequential administration of live attenuated Japanese encephalitis chimeric virus vaccine and yellow fever 17D vaccine

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.

Acknowledgements

The authors gratefully acknowledge the assistance of Dr. Thomas Monath, Dr. Scott Kitchener and the former staff of Acambis Inc, as study Sponsors. Corporal Andrew Baron, Corporal Natalie Lehmann and staff of the Australian Army Malaria Institute for flavivirus serology. Associate Professor Sutee Yoksan and staff at the Center for Vaccine Development, Institute for Molecular Biosciences, Mahidol University at Salaya, Thailand for Japanese encephalitis virus serology. Dr. Simon Coggins and staff at Pharmaceutical Product Development Inc., for full service, contract research support as well as staff at Sanofi Pasteur for critically reviewing the manuscript.

Conflict of Interest

Mark Reid has acted as a paid consultant to Acambis Inc., in relation to JE vaccine trials. Karen McCarthy and Niranjan Kanesa-thasan are former employees of Acambis Inc., Emmanuel Feroldi is a current employee of Sanofi Pasteur. These statements are made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reflect those of the Australian Defence Health Services or any extant policy.

Financial Disclosure

The study was supported by Acambis Inc., (Cambridge, UK).

Figures and Tables

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 < 0.05) occurs when the geometric means does not contain the value 1.

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 < 0.05) occurs when the geometric means does not contain the value 1.

Table 1 Treatment-related adverse events reported by two or more participants during the thirty days following first administration, on Day 0 of JE-CV or YF-17D alone, or the co administration of JE-CV and YF-17D, or placebo

Table 2 Percent of participants in the PP population seroconverting (PRNT₅₀ ≥1:20 or 4-fold rise from baseline) to JE-CV or YF-17D at day 30 or day 60 after first immunization