|MORAES, MAURO - University Of Connecticut|
|Diaz San Segundo, Fayna|
|DIAS, CAMILLA - Oak Ridge Institute For Science And Education (ORISE)|
|PENA, LINDOMAR - University Of Connecticut|
Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/16/2011
Publication Date: 11/28/2011
Citation: Moraes, M.P., Diaz San Segundo, F.C., Dias, C.C., Pena, L., Grubman, M.J. 2011. Increased efficacy of an adenovirus-vectored foot-and-mouth disease capsid subunit vaccine expressing nonstructural protein 2B is associated with a specific T cell response. Vaccine. 29(51):9431-9440.
Interpretive Summary: Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of cloven-hoofed animals. Vaccines produced by chemical inactivation of the virus are available, but there are concerns about vaccine safety and the ability to distinguish vaccinated animals from infected animals. A possible alternative approach to develop safe, effective FMD vaccines is to produce vaccines from portions of the virus which do not contain infectious FMDV and lack the genetic information for a number of viral nonstructural proteins. We have developed a method to produce the vaccine (Ad5-FMDV)that does not require expensive high-containment manufacturing facilities, and thus can be made in the U.S., which currently prohibits work with infectious FMDV on the mainland. The animals inoculated with this marker vaccine can readily be differentiated from infected animals using available diagnostic tests. Previous work in our laboratory has demonstrated that this Ad5-FMD vaccine can protect both swine and bovines after one inoculation. However, relatively large amounts of the vaccine are required. In this work, we have improved the protective efficacy of the Ad5-FMD vaccine by examining the potential booster effect of certain additions when included as part of the vaccine. Cattle were inoculated with both the original Ad5-FMD vaccine and the modified Ad5-FMD vaccine were infected with FMDV for 21 days. The group inoculated with the modified vaccine had enhanced protection as compared to the groups inoculated with the other Ad5-FMD vaccines. These results suggest that the 2B protein can enhance the potency and efficacy of the Ad5-FMD vaccine platform.
Technical Abstract: We previously demonstrated that an adenovirus-based FMDV serotype A24 subunit vaccine, Ad5-A24, expressed under the control of a cytomegalovirus promoter (CMV) can protect swine and bovines against homologous challenge, but swine vaccinated with an Ad5-vectored FMDV O1 Campos vaccine, Ad5-O1Campos (Ad5-O1C), are only partially protected when challenged with FMDV O1C 21 days post-vaccination (dpv). Recently, we demonstrated that inclusion of the complete coding region of nonstructural protein 2B in the Ad5-A24 vector resulted in improved immune responses in pigs. We also found that inclusion of a modified CMV promoter (pCI), Ad5-CI-A24-2B, enhanced the efficacy of the vector. To address the limited immunogenicity of Ad5-O1C, we have produced a new set of Ad5 vectors with the complete 2B coding region under the control of either the original CMV promoter Ad5-O1C-2B, or the modified promoter, Ad5-CI-O1C-2B. To evaluate the potency and efficacy of the new vectors we performed 2 sets of experiments. In the first experiment we compared the original vector with vectors containing the pCI promoter and partial or full-length 2B. All groups were challenged, intradermally in the tongue, at 21 dpv with FMDV O1C. We found that in all vaccinated groups 2 of 4 animals were protected from clinical disease. In the second experiment we directly compared the efficacy of vectors with a partial or full-length 2B under the control of the original CMV promoter. All animals in the Ad5-Blue inoculated control group developed clinical disease, while 2 of 4 animals in the group receiving Ad5-O1C vaccine and 3 of 4 animals in the group receiving Ad5-O1C-2B vaccine were completely protected. We also observed a 100-fold reduction of virus shedding in Ad5-O1C vaccinated animals and the group receiving Ad5-O1C-2B had an additional 10-fold reduction compared with the Ad5-O1C vaccinated group. There was no difference in the level of neutralizing antibodies in the vaccinated groups. However, we detected a significant antigen specific-CD4+ T cell response as early as 1 day post-challenge (dpc) in both Ad5-O1C and Ad5-O1C-2B groups. Interestingly, although a significant antigen specific-CD8+ T cell response at 3 dpc was also detected in all vaccinated groups, it was higher in the group receiving Ad5-O1C-2B. These results indicate that a vector containing the complete 2B coding region improves the efficacy of Ad5 vaccines against FMDV serotype O and the specific-CD8+ T cell response correlates with protection.