Clinical proof of principle for ChimeriVax™: recombinant live, attenuated vaccines against flavivirus infections

Abstract

ChimeriVax™ is a live, attenuated recombinant virus constructed from yellow fever (YF) 17D in which the envelope protein genes of YF 17D are replaced with the corresponding genes of another flavivirus. A ChimeriVax™ vaccine was developed against Japanese encephalitis (JE). A randomized, double-blind, outpatient study was conducted to compare the safety and immunogenicity of ChimeriVax™-JE and YF 17D. Six YF immune and six non-immune adults were randomized to receive a single SC inoculation of ChimeriVax™-JE (5 log₁₀ PFU), ChimeriVax™-JE (4 log₁₀ PFU) or YF-VAX^® (5 log₁₀ PFU). Mild, transient injection site reactions and flu-like symptoms were noted in all treatment groups, with no significant difference between the groups. Nearly all subjects inoculated with ChimeriVax™-JE at both dose levels developed a transient, low-level viremia which was similar in magnitude and duration to that following YF-VAX^®. Neutralizing antibody seroconversion rates to ChimeriVax™-JE was 100% in the high and low dose groups in both naı̈ve and YF immune subjects; seroconversion to wild-type JE strains was similar or lower than to the homologous (vaccine) virus. Mean neutralizing antibody responses were higher in the ChimeriVax™-JE high dose groups (naı̈ve subjects LNI 1.55, PRNT₅₀ 254; YF immune subjects LNI 2.23, PRNT₅₀ 327) than in the low dose groups (naı̈ve subjects 1.38, PRNT₅₀ 128; YF immune subjects LNI 1.62, PRNT₅₀ 270). JE antibody levels were higher in YF immune than in naı̈ve subjects, dispelling concerns about anti-vector immunity. The safety and immunogenicity profile of ChimeriVax™-JE vaccine appears to be similar to that of YF 17D. The new vaccine holds promise for prevention of JE in travelers and residents of endemic countries. The ChimeriVax™ technology platform is being exploited for development of new vaccines against dengue and West Nile.

Introduction

The genus Flavivirus contains approximately 70 single-strand RNA viruses, most of which are transmitted by mosquitoes or ticks. Medically important flaviviruses include yellow fever (YF), dengue (DEN), and Japanese, tick-borne, West Nile, St. Louis and Murray Valley encephalitis [1]. Vaccines have been developed against some of these diseases. The most successful vaccine is that against YF—a live, attenuated virus (the 17D strain) developed in 1936 by empirical passage and used in over 400 million persons, with an excellent record of safety and efficacy [2]. A single dose induces neutralizing antibodies in nearly 100% of vaccinated individuals. Immunity is probably life long, although revaccination is recommended every 10 years. YF 17D has been considered as an ideal live vector for development of new vaccines, because it is a highly effective and reliable vaccine [3].

Here, we report, the first clinical proof of principle that a recombinant, chimeric live vaccine incorporating genes of a heterologous flavivirus [Japanese encephalitis (JE)] in a YF 17D vector is well tolerated and highly immunogenic. JE, a mosquito-borne flavivirus, is a leading cause of life-threatening viral CNS disease in Asia [4]. The World Health Organization has placed a high priority on the development of an improved JE vaccine [5].

The clinical results reported here, together with a substantial body of preclinical data in non-human primates [3], [6], [7], [8], [9], [10], [11], indicate that chimeric YF viruses represent an important new platform for construction of new vaccines against JE, DEN, tick-borne encephalitis (TBE), West Nile and other flavivirus diseases.