Foot-and-mouth disease vaccines: recent updates and future perspectives

DNA vaccines were introduced less than a decade ago but have already been applied to a wide range of infectious and malignant diseases. Here we review the current understanding of the mechanisms underlying the activities of these new vaccines. We focus on recent strategies designed to enhance their function including the use of immunostimulatory (CpG) sequences, dendritic cells (DC), co-stimulatory molecules and cytokine- and chemokine-adjuvants. Although genetic vaccines have been significantly improved, they may not be sufficiently immunogenic for the therapeutic vaccination of patients with infectious diseases or cancer in clinical trials. One promising approach aimed at dramatically increasing the immunogenicity of genetic vaccines involves making them 'self-replicating'. This can be accomplished by using a gene encoding RNA replicase, a polyprotein derived from alphaviruses, such as Sindbis virus. Replicase-containing RNA vectors are significantly more immunogenic than conventional plasmids, immunizing mice at doses as low as 0.1 microg of nucleic acid injected once intramuscularly. Cells transfected with 'self-replicating' vectors briefly produce large amounts of antigen before undergoing apoptotic death. This death is a likely result of requisite double-stranded (ds) RNA intermediates, which also have been shown to super-activate DC. Thus, the enhanced immunogenicity of 'self-replicating' genetic vaccines may be a result of the production of pro-inflammatory dsRNA, which mimics an RNA-virus infection of host cells.

Although present conventional foot-and-mouth disease (FMD) vaccines can prevent clinical disease, protection is short lived ( approximately 6 months), often requiring frequent revaccination for prophylactic control, and vaccination does not induce rapid protection against challenge or prevent the development of the carrier state. Furthermore, it is clear that the clinical protection depends upon the length of immunization and the duration of exposure/challenge methods. This review summarizes the present and future strategies for FMD control in endemic and FMD-free countries, the effectiveness of FMD vaccines in cattle, sheep and pigs, new methods for selecting vaccine strains, suggestions for alternative methods of vaccine testing, suggestions for the development of new-generation efficacious vaccines and their companion tests to differentiate infection in vaccinated animals.

The pathogenesis of foot-and-mouth disease (FMD) is reviewed, taking account of knowledge gained from field and experimental studies and embracing investigations at the level of the virus, the cell, the organ, the whole animal and the herd or flock. The review also addresses the immune response and the carrier state in FMD. Progress made in understanding the pathogenesis of the disease is highlighted in relation to developments in diagnosis and methods of control.