Evaluation of a Mycobacterium avium subsp. paratuberculosisleuDMutant as a Vaccine Candidate against Challenge in a Caprine Model

Abstract

f Johne's disease (JD) is prevalent worldwide and has a significant impact on the global agricultural economy. In the present study, we evaluated the protective efficacy of a leuD (⌬leud) mutant and gained insight into differential immune responses after challenge with virulent M. avium subsp. paratuberculosis in a caprine colonization model. The immune response and protective efficacy were compared with those of the killed vaccine Mycopar. In vitro stimulation of peripheral blood mononuclear cells with johnin purified protein derivative showed that Mycopar and ⌬leuD generated similar levels of gamma interferon (IFN-␥) but significantly higher levels than unvaccinated and challenged phosphate-buffered saline controls. However, only with ⌬leuD was the IFN-␥ response maintained. Flow cytometric analysis showed that the increase in IFN-␥ correlated with proliferation and activation (increased expression of CD25) of CD4, CD8, and ␥␦T cells, but this response was significantly higher in ⌬leuD-vaccinated animals at some time points after challenge. Both Mycopar and ⌬leuD vaccines upregulated Th1/proinflammatory and Th17 cytokines and downregulated Th2/anti-inflammatory and regulatory cytokines at similar levels at almost all time points. However, significantly higher levels of IFN-␥ (at weeks 26 and 30), interleukin-2 (IL-2; week 18), IL-1b (weeks 14 and 22), IL-17 (weeks 18 and 22), and IL-23 (week 18) and a significantly lower level of IL-10 (weeks 14 and 18) and transforming growth factor ␤ (week 18) were detected in the ⌬leuD-vaccinated group. Most importantly, ⌬leuD elicited an immune response that significantly limited colonization of tissues compared to Mycopar upon challenge with wild-type M. avium subsp. paratuberculosis. In conclusion, the ⌬leuD mutant is a promising vaccine candidate for development of a live attenuated vaccine for JD in ruminants.

Superior Protection from Live-Attenuated Vaccines Directed against Johne's Disease

“…Due to this limitation, alternative forms of vaccine development have been pursued in an effort to increase the use of JD vaccines in control programs. Recent studies suggest LAVs as a strategy for creating more effective JD vaccine candidates (11)(12)(13)(14)(15)24). The primary goal of this study was to examine the performance of live-attenuated vaccines (represented by pgsH and pgsN) as a viable alternative to inactivated vaccines (represented by Mycopar) to control Johne's disease in dairy herds.…”

“…The primary goal of this study was to examine the performance of live-attenuated vaccines (represented by pgsH and pgsN) as a viable alternative to inactivated vaccines (represented by Mycopar) to control Johne's disease in dairy herds. For this purpose, we used the caprine model that was used previously (12,24,25). Unfortunately, it was difficult to identify a goat herd that was Johne's disease free for our study, which resulted in reducing the group size for the Mycopar vaccine, a well-studied vaccine (12,26,27).…”

“…Live-attenuated vaccines (LAV) are considered advantageous because they are easy to produce and manufacture, and they have been shown to stimulate cell-mediated immunity in mice and ruminant models of JD (11)(12)(13)(14)(15). To develop our novel LAV candidates, our group employed a whole-genome expression profile of M. paratuberculosis exposed to different environmental stress conditions, or shed in cow feces, to identify new virulence genes (16).…”

Therapeutic Potential of a Candidate relA Deletion Mutant Vaccine of Mycobacterium Avium Subsp. Paratuberculosis

“…paratuberculosis (Map) that induces sterile immunity against Johne's disease (JD) or prevents disease progression. These approaches have included development of killed whole vaccines, live attenuated, DNA and subunit vaccines and tests in different animal species (Bull et al 2007;Park et al 2008;Juste et al 2009;Kathaperumal et al 2009;Scandurra et al 2010;Bastida and Juste 2011;Stabel et al 2012;Faisal et al 2013). Although none of the vaccines induced sterile immunity they did slow disease progression and demonstrated that development of a vaccine that induces sterile immunity is feasible (reviewed in (Rosseels and Huygen 2008).…”

Trends and advances in the diagnosis and control of paratuberculosis in domestic livestock

“…(Lu et al 2008). pTb vaccine development has been reported (Hagan 1935;Kalis et al 2001;Windsor et al 2003;Munoz et al 2005;Scandurra et al 2010;Kabra & Coussens 2012;Faisal et al 2013;Singh 2015;Singh et al 2015). Vaccination with pTB vaccine has been shown to improve the productivity and reproductive performance of the animals and has potential to replace the 'test-and-cull policy' for the control and eradication of the disease.…”