Development of Vaccines Toward the Global Control and Eradication of Foot-and-mouth Disease

Luis L Rodriguez; Cyril G Gay


Expert Rev Vaccines. 2011;10(3):377-387. 

In This Article

Inactivated FMD Vaccines

Industrial production of inactivated vaccines began in the 1950s using the Frenkel method of culturing tongue epithelium collected from healthy slaughtered animals and infecting these cultures with FMDV, followed by collection of the virus-containing medium and virus inactivation using formaldehyde.[7] As one can imagine, the method of using primary cells limited large-scale production and was prone to contamination with adventitious agents. In addition, formaldehyde inactivation was often incomplete, resulting in infective vaccines. In the 1960s, cell-suspension cultures replaced tongue epithelium and later on ethylene imines replaced formaldehyde inactivation.[8,9] Current commercial FMD vaccines consist of inactivated purified antigen (killed virus) devoid of nonstructural viral proteins, usually by chromatographic purification, and formulated with various proprietary adjuvant formulations. These vaccine formulations have proven effective in reducing clinical disease in FMD-endemic areas and have been successfully used as an adjunct treatment in disease eradication programs in Africa, South America and Europe.[2]

Foot-and-mouth disease vaccines traditionally represent the largest share of the veterinary vaccine market worldwide in terms of sales, with 26.4% of the entire livestock biological business.[10] Significant steps have been made to improve the quality of FMD vaccines, including changes in the manufacturing process to enable the differentiation of infected from vaccinated animals, but there are important variations between different manufacturers, and between vaccines distributed for FMD-endemic regions versus FMD-free countries. Owing to the high variability of FMDV serotypes and subtypes, the antigen composition of FMD vaccines is tailored for specific world regions and in many cases to specific countries or regions within them. The use of the vaccine in FMD-endemic regions requires an in-depth investigation of the epidemiology of disease and vaccine matching studies to determine whether the vaccine will be effective against the strain(s) circulating in the target area and to ensure the actual profile of the vaccine is suitable for control and eradication.[11] There are primarily three formulations that represent the large majority of all commercial inactivated FMD vaccines worldwide:

  • High-potency vaccines (emergency use)

  • Oil-emulsion conventional vaccines (routine control)

  • Aluminum hydroxide vaccines (for cattle)

Oil-emulsion vaccines are currently prepared as either double oil-emulsion or water-in-oil single emulsion formulations with the former providing higher and longer antibody responses.[12–14] Potency is a major concern with FMD vaccines. The latest revisions of the World Organization for Animal Health Manual of diagnostic tests and vaccines for terrestrial animals states that six protective dose 50 (PD50) per cattle dose is preferred.[15] However, this is not an absolute requirement owing to the acceptance that this would significantly reduce the number of vaccine doses in internationally established FMD vaccine banks. The case for using higher potency vaccines is clear, including greater protection against heterogeneous strains, a quicker onset of immunity, and increased protection from viral shedding and transmission.[16–18]

Emergency Use (High-potency) FMD Vaccines

Due to the instability of the formulated product (12–18 months), vaccines for emergency use are usually stored as frozen antigen concentrates in vaccine banks by FMD-free countries or groups of countries (for review see[19]). For example, the USA, in cooperation with Canada and Mexico, has a tripartite 'North American Foot and Mouth Disease Vaccine Bank'. Vaccines formulated from frozen antigen banks contain at least six PD50, provide an onset of protection from challenge within 4–7 days post-vaccination (dpv; partial immunity as early as 2 dpv) in cattle, swine and sheep, and some provide wider antigenic coverage and protection for heterologous FMDV subtypes within a serotype.[6,18–20] Duration of protective immunity after single vaccination is limited, requiring re-vaccination after 6 months.[11,21,22] Vaccines decrease clinical disease, virus amplification (shed and spread) and reduce the number of persistent infections in vaccinated ruminants challenged with FMDV.[18,23,24] Bulk antigens stored in vaccine banks require at least 3–4 days for formulation and finishing of vaccine from frozen antigen concentrates, and 2–3 additional days for shipping resulting in deployment delays. This does not take into account the time required for completion of quality control tests to demonstrate purity, safety and potency, which might be a requirement of some biological regulatory agencies.

Conventional (Ready-to-use) Oil-emulsion FMD Vaccines

Oil-adjuvanted vaccines formulated with a potency of at least 3 PD50 have been shown to provide an onset of protective immunity within 7 days in cattle, swine and sheep.[6,19,25] Vaccines decrease clinical disease, and virus amplification (shed and spread), but do not prevent the establishment of persistent infections in up to 50% of ruminants vaccinated and later challenged with wild-type FMDV.[5,6,24] Differences in efficacy and potency have been reported between double oil-emulsion versus water-in-oil single-emulsion formulations with a higher antibody response reported for double oil-emulsion.[12,13,26] Enhancement of the immune response induced by the inclusion of saponin in oil-adjuvanted vaccines has been reported.[27] Oil-adjuvanted vaccines are the most used worldwide but, in order to maintain sufficient levels of immunity to suppress occurrence of clinical disease, re-vaccination must be carried out every 6 months.[15] After multiple doses of vaccines in older animals, vaccination frequency could be decreased to once a year, provided that no new strains not covered by the vaccine formulation emerge or are introduced.[28–31]

One of the shortcomings of the current conventional vaccine is the short shelf life once it is formulated either as double-oil emulsion or aluminum gel (for details see [32]).

Aluminum Hydroxide-adjuvanted Vaccines

The aluminum hydroxide–saponin formulation originally developed for FMD vaccines has some advantages such as ease of production and antigen concentration by adsorption to aluminum hydroxide gels.[32] However, aluminium hydroxide-adjuvanted vaccines have several disadvantages over oil-emulsion vaccines, including the fact that they cause granulomas at the inoculation site[33] and are not as effective in swine as oil-emulsion vaccines,[34,35] have a shorter shelf life than oil-emulsion vaccines, are less potent per microgram of antigen, and produce a shorter duration of immunity.[32] However, these vaccines continue to be produced around the world for use mostly in ruminants.