Submitted to: Biologicals
Publication Type: Peer reviewed journal
Publication Acceptance Date: 9/18/2005
Publication Date: 12/1/2005
Citation: Grubman, M.J. 2005. Development of Novel Strategies to Control Foot-and-Mouth Disease: Marker Vaccines and Antivirals. Biologicals 33 (2005) 227-234. Interpretive Summary: Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of cloven-hoofed animals. Vaccines produced by chemical inactivation of virus are available, but there are concerns about their safety, about the ability to serologically distinguish vaccinated animals from infected animals, and about thier inability to induce protection prior to 7 days postvaccination. In the event of an FMD outbreak in a disease-free country such as the U.S., it is necessary to induce immediate protection to control disease spread. A possible alternative approach to develop safe, effective FMD vaccines is to produce viral subunit vaccines which do not contain infectious FMDV and lack the genetic information for a number of viral nonstructural proteins. Thus, production of this vaccine does not require expensive high-containment manufacturing facilites, can be made in the U.S., which currently prohibits work with infectious FMDV on the mainland, and animls inoculated with this marker vaccine can readily be differentiated from infected animals using diagnostic assays employing the viral nonstructural proteins not present in the vaccine. In addition, we have previously shown that the antiviral agent type I interferon can rapidly inhibit FMDV replication. Therefore, the use of both an FMDV subunit vaccine and type I interfereon can result in rapid protection and clear distinction between vaccinated and infected animals. In this manuscript I discuss the development of a human adenovirus expression vector that contains a noninfectious portion of the FMDV genome. One inoculation of this vector is able to induce a protective response in swine and cattle when challenged by direct infection with virulent FMDV 7 days postvaccination. Furthermore, swine given one inoculation of an adenovirus vector containing type I interferon are protected when challenged one day postinoculation. Thes results demonstrate that this novel combination control strategy addresses the concerns of FMD-free countries with the current FMD disease control approach.
Technical Abstract: Foot-and-mouth disease (FMD) is economically the most important viral-induced livestock disease worldwide. The disease is highly contagious and FMD virus (FMDV) replicates and spreads extremely rapidly. Outbreaks in previously FMD-free countries, including Taiwan, the United Kingdom, and Uruguay, and the potential use of FMDV by terrorist groups, have demonstrated the vulnerabilty of countries and the need to develop control strategies that can rapidly inhibit or limit disease spread. The current vaccine, an inactiviated whole virus preparation, has a number of limitations for use in outbreaks in disease-free countries. We have developed an alternative approach using a genetically engineered FMD subunit vaccine that only contains the portions of the viral genome required for virus capsid assembly and lacks the coding region for most of the viral nonstructural (NS) proteins including the highly immunogenic 3D protein. Thus, animals inoculated with this marker vaccine can readily be differentiated from infected animals using diagnostic assays employing the NS proteins not present in the vaccine and production of this vaccine, which does not contain infectious FMDV, does not require expensive high-containmnet manufacturing facilites. One inoculation of this subunit vaccine delivered in a replication-defective human adenovirus vector can induce rapid, within 7 days, and relatively long-lasting protection in swine. Similarly cattle inoculated with one dose of this recombinant vector are rapidly protected from direct and contact exposure to virulent virus. Furthermore, cattle given two doses of this vaccine developed high levels of FMDV-specific neutralizing antibodies, but did not develop antibodies against viral NS proteins demonstrating the ability of FMD subunit vaccinated animals to be differentiated from infected animals. To stimulate early protection prior to the antiviral agent, type I interferon, and induced complete protection within 1 day. Protection can last for 3-5 days. The combination of the FMD marker vaccine and type I interfereon cna induce immediate, within 1 day, and long-lasting protection against FMD. Thus, this combination approach successfully addresses a number of the concerns of FMD-free countries with the current disease control plan. By rapidly limiting virus replication and spread this strategy may reduce the number of animals that need to be slaughtered during an outbreak.