Clinical proof of principle for ChimeriVax™: recombinant live, attenuated vaccines against flavivirus infections
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.
Section snippets
Vaccines
Two vaccines were used in the study: the experimental ChimeriVax™-JE vaccine and a licensed YF 17D vaccine (YF-VAX®, Aventis Pasteur, Swiftwater, PA).
ChimeriVax™-JE was constructed from a full-length cDNA of YF 17D cloned in bacterial plasmids, as previously described [3], [6]. Briefly, genes encoding the premembrane (prM) and envelope (E) proteins of YF 17D vaccine virus were replaced with the corresponding genes of JE (strain SA14-14-2) virus. The chimeric cDNA was then transcribed to RNA,
Demographics
The treatment groups were comparable for age (mean age range 35.3–44.5 years) and gender, with the exception of a greater proportion of females in the ChimeriVax™-JE (4.0 log10) and YF-VAX® groups within the YF non-immune subset. All participants were Caucasian, with the except for one Hispanic subject in the YF-VAX® (YF immune) group and two Afro-American subjects in the ChimeriVax™-JE (5.0 log10) group (YF non-immune).
AEs
There were no serious AEs, and no AE led to withdrawal of a subject from the
Discussion
There are a number of advantages of live vaccines over inactivated, subunit, and DNA approaches. Live viral vaccines actively replicate in the host, expand an array of antigens similar to the wild-type virus and provoke cytokine and immune responses similar to those following natural infection. Intracellular replication elicits strong cytotoxic T cell responses and long-term memory T cells. Immunity is exceptionally durable, and complete immunization is often achieved with a single dose.
Acknowledgements
The authors are grateful to many individuals who participated in the research and development of ChimeriVax™-JE vaccine, including Z.-X. Zhang, R. Weltzin, Ph.D., C. Miller, J. Catalan, S. Fenner, K. Georgakopoulos, S. Pougacheva, D. Pathak, and P. Papasthakis at Acambis Inc., and all study site personnel at Pharmaceutical Research Associates, particularly, D. Mathis and C. Johnson for their hard work and dedication to the study. The authors thank the staff at Syne qua non Ltd., Norfolk, UK,
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