FMD is the one of the most feared viral diseases that can affect swine. Although this disease appeared to be eliminated from most developed nations by the end of last century, recent outbreaks in Europe, Japan, Taiwan, South Korea, Eastern Russia, etc, have demonstrated that infection can spread as wild fire affecting any nation and causing devastating economic and social consequences (Figure 1). Furthermore, post 9/11, a new era has emerged showing that any country is vulnerable to national and international terrorism. An outbreak of this disease would be devastating to the US economy which deals with the largest livestock market of the world. Therefore, it is essential to develop new control strategies that could confer very early protection and stop disease spread. FMD is a highly contagious disease that spreads very quickly among susceptible animals. The current FMD vaccine is a formulation of inactivated wild type (WT) virus antigen prepared in high containment bio-security level 3 facilities. This vaccine requires 7 days to induce protection, a time during which vaccinated animals are still susceptible to disease mostly when exposed to FMD virus (FMDV). In addition the vaccine is prepared from highly virulent circulating virus strains that despite extreme caution and care in the manufacturing process, could result in outbreaks by accidental virus release as it happened in the United Kingdom in 2007 (estimated cost $2B). It has been demonstrated for other viral diseases that live-attenuated vaccines are one of the best choices to obtain a strong early and long-lasting protection. Our goal is to develop alternative control strategies that could improve current FMD countermeasure programs based on the development of attenuated vaccines. An attenuated vaccine is expected to elicit more rapid innate immunity and a long lived adaptive immunity to effectively control disease. Moreover, induction of innate immunity could result in early protection against multiple FMDV serotypes. From the production perspective, use of an attenuated FMDV strain will reduce the consequences of accidental outbreaks caused by accidental release of virus from vaccine manufacturing facilities. Importantly, attenuated strains are excellent new tools to study the interactions between FMDV and the host immune system and ultimately could lead to the development of novel strategies to counteract FMD. In the last couple of years with the support of NPB we have successfully derived a mutant strain of FMDV that did not cause disease in swine (FMDV-SAP mutant). Interestingly inoculation of swine with this mutant strain induced a strong immune response that protected animals against infection with the parental WT virus, as early as two days post vaccination. However in rare occasions, revertants with increased virulence spontaneously arose, indicating that improvement is required for safety. Utilizing reverse genetic approaches we had explored the possibility of adding more mutations in the SAP mutant to increase stability and attenuation. We had observed that some mutations in other Leader domains, like FHA domain, (e. g. H*) cause attenuation independently of SAP, however double mutants (SAP, H*) did not produce viable virus. In contrast, other SAP-derived strains with mutations in another domain of the L protein (CTE) are viable. We are currently characterizing the SAP-CTE mutants for further development into a live attenuated vaccine platform. Our results indicated that manipulation of the viral genome in the region that encodes for the leader protein is a viable alternative to derive less pathogenic FMDV strains that could be used as the basis for live attenuated vaccines against FMD or as seeds to grow the virus for manufacturing safer inactivated vaccines. Although this strategy is far from being used in countries that are FMD free without vaccination, it could be an affordable alternative to control FMD in regions of the world where the disease is enzootic thereby decreasing the risks of dissemination to disease-free nations. Ultimately a combination of strategies tailored to each region of the world will eventually succeed to eradicate this feared disease.

(Teresa de los Santos PhD, PIADC, ARS, USDA. TEL: (631) 323-3020"". E-mail: