Abstract
Since the early 1980s, several investigations have focused on developing a vaccine against Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne's disease in cattle and sheep. These studies used whole-cell inactivated vaccines that have proven useful in limiting disease progression, but have not prevented infection. In contrast, modified live vaccines that invoke a Th1 type immune response, may improve protection against infection. Spurred by recent advances in the ability to create defined knockouts in MAP, several independent laboratories have developed modified live vaccine candidates by transpositional mutation of virulence and metabolic genes in MAP. In order to accelerate the process of identification and comparative evaluation of the most promising modified live MAP vaccine candidates, members of a multi-institutional USDA-funded research consortium, the Johne's disease integrated program (JDIP), met to establish a standardized testing platform using agreed upon protocols. A total of 22 candidates vaccine strains developed in five independent laboratories in the United States and New Zealand voluntarily entered into a double blind stage gated trial pipeline. In Phase I, the survival characteristics of each candidate were determined in bovine macrophages. Attenuated strains moved to Phase II, where tissue colonization of C57/BL6 mice were evaluated in a challenge model. In Phase III, five promising candidates from Phase I and II were evaluated for their ability to reduce fecal shedding, tissue colonization and pathology in a baby goat challenge model. Formation of a multi-institutional consortium for vaccine strain evaluation has revealed insights for the implementation of vaccine trials for Johne's disease and other animal pathogens. We conclude by suggesting the best way forward based on this 3-phase trial experience and challenge the rationale for use of a macrophage-to-mouse-to native host pipeline for MAP vaccine development.
Highlights
Johne’s disease is caused by Mycobacterium avium subspecies paratuberculosis, an acid-fast bacillus that can be distinguished from other closely related mycobacteria by its unique requirement for the mycobactin J siderophore in artificial culture media (Merkal and Curran, 1974)
RelA in M. tuberculosis synthesizes the hyperphosphorylated guanine nucleotides that accumulate in nutrient limiting conditions and inactivating this gene severely reduced long-term survival in mice (Dahl et al, 2003). Two of these Mycobacterium avium subspecies paratuberculosis (MAP) mutants, pknG and relA, were later tested as vaccine candidates in cultured macrophages, calves and kid goats (Park et al, 2011). Both were attenuated in bovine macrophages compared to the wild-type strain on day 6, it was shown that relA was the better vaccine candidate since no MAP was found in the tissues of calves vaccinated with the relA mutant
Several lessons were learned from the three-phase Johne’s disease integrated program (JDIP) vaccine project as discussed below, and provide a rational framework for testing future vaccines against Johne’s disease
Summary
Johne’s disease is caused by Mycobacterium avium subspecies paratuberculosis (hereafter referred to as MAP), an acid-fast bacillus that can be distinguished from other closely related mycobacteria by its unique requirement for the mycobactin J siderophore in artificial culture media (Merkal and Curran, 1974). We here present the state-of-thefield summary for vaccination against Johne’s disease, describe current candidate live attenuated mutants of MAP, and present an overview of the JDIP three-phase vaccine trial and lessons learned.
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