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Title: A rational framework for evaluating the next generation of vaccines against Mycobacterium avium subspecies paratuberculosis

item Bannantine, John
item HINES II, MURRAY - University Of Georgia
item BERMUDEZ, LUIZ - Oregon State University
item TALAAT, ADEL - University Of Wisconsin
item SREEVATSAN, SRINAND - University Of Minnesota
item Stabel, Judith
item CHANG, YUNG-FU - Cornell University
item COUSSENS, PAUL - Michigan State University
item BARLETTA, RAUL - University Of Nebraska
item DAVIS, WILLIAM - Washington State University
item COLLINS, DESMOND - Agresearch
item GROHN, YRJO - Cornell University
item KAPUR, VIVEK - Pennsylvania State University

Submitted to: Frontiers in Cellular and Infection Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/20/2014
Publication Date: 9/9/2014
Publication URL:
Citation: Bannantine, J.P., Hines II, M.E., Bermudez, L.E., Talaat, A.M., Sreevatsan, S., Stabel, J.R., Chang, Y., Coussens, P.M., Barletta, R.G., Davis, W.C., Collins, D.M., Grohn, Y.T., Kapur, V. 2014. A rational framework for evaluating the next generation of vaccines against Mycobacterium avium subspecies paratuberculosis. Frontiers in Cellular and Infection Microbiology. 4:126. Available:

Interpretive Summary: Johne’s disease in livestock such as dairy cattle and sheep is caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). A major obstacle to controlling this disease is early detection after infection and before the animal begins shedding the bacterium on the farm and thus providing a source for infecting herd mates. Thus vaccination is considered the best intervention strategy. This manuscript summarizes what has been accomplished in the field of Johne’s disease vaccine research and concludes with a summary of the three-phase trial conducted on a set of 22 live vaccine strains of Mycobacterium avium subspecies paratuberculosis. Several lessons were learned from this project, one principally being that macrophages and the mouse model might not be a good predictor for vaccine efficacy in goats or possibly calves. This research is of primary interest to veterinarians, stakeholders and other researchers in the field.

Technical Abstract: There have been several studies aimed at developing an efficacious vaccine against Johne’s disease. However, since the 1980s most of those studies have focused on killed-whole cell vaccines. This type of vaccine has proven useful in limiting disease progression, but it has not been effective at preventing infection. A modified live vaccine is preferred due to its ability to generate a Th1 response, which is thought to be more protective against this disease. Although live attenuated vaccines had been examined, only recently has the ability to create defined knockouts of specific virulence genes been achieved. These knockout strains were previously created in independent laboratories and the resulting mutants were tested in isolation, making direct comparisons difficult. Members of a multi-institutional USDA-funded research consortium, entitled the Johne’s Disease Integrated Program (JDIP), set up a standardized testing platform for the most promising attenuated mutant vaccine candidates of Mycobacterium avium subspecies paratuberculosis (MAP). A total of 22 vaccine candidates from the United States and New Zealand were entered in the first of three blinded trials with selected candidates moving forward into the next trial. The phase I trial consisted of evaluating survival in cultured primary bovine macrophages. The phase II trial measured spleen and liver colonization of C57/BL6 mice using a vaccination – challenge model with wild-type MAP. The phase III study consisted of evaluating five strong candidate vaccines from the phase I and phase II studies in a goat challenge model to rank the performance of these candidates after challenge with wild type MAP in terms of fecal shedding, tissue colonization and relative lesion scores. This unique, comprehensive, multi-institutional approach yielded several key insights and lessons learned on how future vaccination trials should be conducted for Johne’s disease.