New Vaccine Design Based on Defective Genomes That Combines Features of Attenuated and Inactivated Vaccines

Abstract

[Background] New vaccine designs are needed to control diseases associated with antigenically variable RNA viruses. Foot-and-mouth disease (FMD) is a highly contagious disease of livestock that inflicts severe economic losses. Although the current whole-virus chemically inactivated vaccine has proven effective, it has led to new outbreaks of FMD because of incomplete inactivation of the virus or the escape of infectious virus from vaccine production premises. We have previously shown that serial passages of FMD virus (FMDV) C-S8c1 at high multiplicity of infection in cell culture resulted in virus populations consisting of defective genomes that are infectious by complementation (termed C-S8p260).[Principal Finding] Here we evaluate the immunogenicity of C-S8p260, first in a mouse model system to establish a proof of principle, and second, in swine, the natural host of FMDV C-S8c1. Mice were completely protected against a lethal challenge with FMDV C-S8c1, after vaccination with a single dose of C-S8p260. Pigs immunized with different C-S8p260 doses and challenged with FMDV C-S8c1 either did not develop any clinical signs or showed delayed and mild disease symptoms. C-S8p260 induced high titers of both FMDV-specific, neutralizing antibodies and activated FMDV-specific T cells in swine, that correlated with solid protection against FMDV.[Conclusions] The defective virus-based vaccine did not produce detectable levels of transmissible FMDV. Therefore, a segmented, replication-competent form of a virus, such as FMDV C-S8p260, can provide the basis of a new generation of attenuated antiviral vaccines with two safety barriers. The design can be extended to any viral pathogen that encodes trans-acting gene products, allowing complementation between replication-competent, defective forms.This research was supported by grants AGL2004-0049, AGL2007-61374, CSD2006-07 and BFU2008-02816/BMC from Ministerio de Ciencia e Innovación, Spain, and European Union, Network of Excellence, EPIZONE (Contract # FOOD-CT-2006-016236). CIBERehd (Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestivas) is funded by Instituto de Salud Carlos III. Work at Centro de Biologı´a Molecular ‘‘Severo Ochoa’’ (CISC-UAM) was supported by an institutional grant from Fundacio´n Ramo´n Areces. T.R-C. was supported by a contract from Comunidad Auto´noma de Madrid; S.O. and M.S-R were supported by a predoctoral fellowship from the Ministerio de Educacio´n y Ciencia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe