Towards improvements in foot-and-mouth disease vaccine performance

Abstract

Foot-and-mouth disease (FMD) remains one of the most economically important infectious diseases of production animals. Six (out of 7 that have been identified) different serotypes of the FMD virus continue to circulate in different parts of the world. Within each serotype there is also extensive diversity as the virus constantly changes. Vaccines need to be "matched" to the outbreak strain, not just to the serotype, to confer protection. Vaccination has been used successfully to assist in the eradication of the disease from Europe but is no longer employed there unless outbreaks occur. Thus the animal population in Europe, as in North America, is fully susceptible to the virus if it is accidentally (or deliberately) introduced. Almost 3 billion doses of the vaccine are made each year to control the disease elsewhere. Current vaccines are produced from chemically inactivated virus that has to be grown, on a large scale, under high containment conditions. The vaccine efficiently prevents disease but the duration of immunity is rather limited (about 6 months) and vaccination does not provide sterile immunity or block the development of carriers. Furthermore, the vaccine is quite unstable and a cold chain needs to be maintained to preserve the efficacy of the vaccine. This can be a challenge in the parts of the world where the disease is endemic. There is a significant interest in developing improved vaccines and significant progress in this direction has been made using a variety of approaches. However, no alternative vaccines are yet available commercially. Improved disease control globally is clearly beneficial to all countries as it reduces the risk of virus incursions into disease free areas.

Keywords: Capsid assembly; Duration of immunity; Persistent infection; Picornavirus.

Fig. 1

Production and processing of FMDV proteins. The FMDV RNA (top) encodes a large polyprotein that is processed, during and after translation, to a collection of precursors (P1-2A, P2 and P3) and mature products largely through the action of the 3C protease. Many other processing intermediates are made but are not shown. The cleavage of the myristoylated VP0 to VP4 and VP2 occurs during particle assembly. The myristoylation of the N-terminal glycine of the capsid precursor P1-2A is achieved by a host cell system. The two forms of the Leader protease (Lab and Lb) cleave themselves from the capsid precursor. The 5′ UTR includes extensive secondary structure, one region is the internal ribosome entry site (IRES) required for initiation of protein synthesis on the viral RNA

Fig. 2

The assembly of FMDV particles. The myristoylated capsid precursor protein (P1-2A) is cleaved by the 3C protease to form protomers (5S) consisting of VP0, VP3 and VP1. Five of these protomers assemble into pentamers (12S) and 12 of these combine to form the near spherical capsid particles containing 60 copies of each of the viral capsid proteins. When RNA is packaged, then infectious particles are formed (146S) but non-infectious empty capsid particles (70S), without any viral RNA, can also be made (not shown). The cleavage of VP0 to VP4 and VP2 (see Fig. 1) accompanies the process of particle assembly and, at least for FMDV, does not require the presence of viral RNA

Fig. 3

Alternative strategies to produce novel, safe, FMDV vaccines. a The production of 70S empty capsid particles by the co-expression of the FMDV P1-2A capsid precursor plus the 3C^pro has been achieved using baculovirus and vaccinia virus expression systems. The purified non-infectious particles can be used as a vaccine. b Defective viral vectors (e.g. human adenovirus Ad5 or Semliki Forest virus vectors) have been used to express the P1-2A plus 3C^pro within mammalian cells. These viral vector vaccines can infect the host’s cells but cannot spread within the host. The FMDV P1-2A + 3C proteins are expressed from the vector within the infected cells and thus produce intracellular empty capsid particles. c Defective FMDVs, lacking the Lb coding sequence (c.f. Fig. 1), have been shown to be attenuated in animals and thus can be used to grow FMDV antigen in BHK cells more safely, as infectious virus. It is still expected that the virus will be inactivated prior to use as vaccine, as for current vaccines