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Research on Improved Foot-and-Mouth Disease Vaccines Facing Challenges 

While a large-scale outbreak of foot-and-mouth disease (FMD) ravaged farms throughout several European countries, officials wrangled over appropriate measures for containing the disease. One major question—whether to initiate wide-scale vaccination efforts—hinged on more than an unwillingness to incur the stigma associated with use of FMD vaccines and the severe export restrictions that such use can impose. Available vaccines, which are made from killed FMD viruses, present several drawbacks in terms of efficacy, cost, and risk. Nor are any specific antiviral agents yet available for treating FMD infections (see box). However, research on these viruses is elucidating how they infect animals and thwart their immune systems, and could eventually lead to better vaccine strategies and identify targets for potential drug development. 

Plum Island, home of the U.S. Department of Agriculture Animal Disease Center. The center is the only place in the United States where certain highly infectious animal diseases— such as foot-and-mouth disease—are studied.

Like rhinoviruses, influenza viruses, and other members of the Picornaviridae family, the FMD viruses spread by aerosol. Capable of traveling intact for many miles, FMD viruses initially settle in the mouth and upper respiratory tract, and as few as 10 virus particles can infect a cow. The FMD viruses have a remarkable capacity to mutate, with seven major serotypes of this single-stranded RNA virus and at least 60 subtypes. Although scientists determined that the virus wreaking havoc in Europe is the PanAsia serotype O, they also know that a vaccine against one type affords little or no protection against others. 

While vaccines can be fairly easily tailored to the FMD viruses now circulating, the vaccines prevent symptoms but do not block infection or further transmission of the viruses. Moreover, commercially available tests do not distinguish antibodies made during natural infections versus those made against vaccines, which contain “a gemisch” of viral proteins and nucleic acids, says Marvin Grubman, lead scientist of the FMD research unit at the U.S. Department of Agriculture Plum Island Animal Disease Center off the coast of New York, the only facility in the United States where research on FMD viruses is permitted.

There are additional problems with the available vaccines, according to Grubman. For instance, the immunity afforded by vaccines wears off quickly, requiring annual or semi-annual revaccination, a costly venture. Production costs are high because of the need for specialized containment facilities to prepare the viruses. And, perhaps most nettlesome, the vaccines ordinarily do not eliminate FMD viruses. While both vaccinated and unvaccinated animals typically recover from the disease, they may continue to harbor a low-grade, asymptomatic, but still contagious infection that can persist for several years. Thus, neither vaccination nor letting the disease run its course guarantees that the virus will disappear.

FMD vaccine research is focusing on alternatives to killed-virus vaccines, particularly the use of specific viral proteins or peptides. One of the most intriguing new vaccine candidates, under development at the Plum Island facility, consists of an empty viral capsid. “We've been trying to use an immunogen that looks like the virus,” Grubman says, adding that it is intended to trigger a more robust immune response. A vaccine that contains only the capsid-building structural genes presents the host immune system with all the triggering epitopes but none of the infectivity of the natural virus, he says. “The question was, how do we deliver it?

After trying a number of vectors, USDA researchers settled on a replication-defective human adenovirus that contains those parts of the FMD viral genome that encode its structural genes. The researchers also added genes for starting transcription and for processing precursor capsid proteins. The results from limited testing of this recombinant vaccine are promising, Grubman says. In pigs, a single inoculation elicits 100% protection within seven days, though how long that protection lasts remains to be determined. 

The capsid-based vaccine appears to overcome several problems associated with current vaccines, he continues. For one thing, because its use would elicit only antibodies specific to the FMD structural proteins, diagnostic tests could easily distinguish vaccinated animals from those that are FMD-infected. Moreover, the recombinant vaccine can be more easily and less expensively produced than the conventional vaccine; in addition, genes from several viral serotypes could be incorporated into the recombinant vaccine to make it versatile.

Perhaps the most pressing question is whether this or other candidate vaccines can reduce viral persistence. Andrew King, head of molecular biology at the Pirbright Laboratories of the Institute for Animal Health in Surrey, England, another of the world's premier research labs for exotic animal diseases, welcomes improved vaccines, but professes skepticism on this front. “I can't see how the vaccines in development will do it,” he says. “We need to look very hard at why the immune systems of affected animals don't clear persistent infections. It's a very, very difficult question.”

The problem of persistence has been a major research focus for King and his Pirbright colleagues, who have compared viral particles from persistent infections to circulating viruses in search of any telling mutations. So far they have found none. King and his colleagues recently discovered that FMD viruses preferentially bind to a specific host receptor, the anb6 integrin protein, by means of a protein loop containing the tripeptide Arg-Gly-Asp, or RGD. The receptor ferries the virus into an intracellular endosome. This preferential interaction with anb6 but not other RGD-binding integrins appears due to the receptor's readiness to bind additional amino acids near the RGD loop in virtually all infectious FMD viruses, he says. 

The anb6 receptor is particularly prevalent on cells in epithelial tissues, such as the mouth and pharynx, where the virus most actively replicates and causes the blisters that are the hallmark of FMD. “As far as we can tell, these tissues are where the virus is residing when it's persistent,” he says, rather than in lymphoid tissue or tonsils, as was previously thought. How persistent viruses fly under the radar of the host immune system is still largely a mystery, King says. “This virus is a very clever little beastie.”

Christine Stencel 
Christine Stencel is a communications manager and science writer at ASM.