Flavivirus immunization with capsid-deletion mutants: basics, benefits, and barriers

The flaviviruses comprise a number of arthropod-transmitted human disease agents that cause significant and increasing health threats in major parts of the world. The development of new vaccines is of vital importance, but the stringent need for safety, efficacy and cost-effectiveness together with the problems associated with the specific immune pathogenesis of some flavivirus infections impose significant challenges to innovative vaccine research. Using tick-borne encephalitis virus (TBEV) as a model, the viral capsid protein gene was recently identified as a novel target for generating flavivirus vaccines. This approach can be applied to produce either attenuated strains that can serve as live vaccines or to make a new type of a genetic vaccine consisting of non-infectious RNA replicons from which subviral particles are synthesized in vivo. Flaviviruses are small, enveloped viruses with an unsegmented positive-stranded RNA genome encoding a single polyprotein that is cleaved into the individual viral proteins. The specific introduction of various deletions and other mutations into the genomic segment coding for the capsid protein C and the biochemical and immunological characterization of the resulting mutants in cell culture and an animal model have revealed remarkable properties of this building block of the nucleocapsid and yielded information that opened the way for new vaccine approaches. In this review the in vitro and in vivo findings with various capsid deletion mutants of TBEV are summarized and discussed in the context of recent structural and biochemical data obtained for protein C of various flaviviruses. Potential benefits of this new strategy for generating flavivirus vaccines as well as hurdles that still have to be overcome are discussed in comparison to conventional or other experimental approaches. Capsid-deletion mutants can be used to rationally design safe and effective vaccine strains or to create new vaccines that combine advantages of genetic vaccination, conventional inactivated, and live vaccines.