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

Abstract

Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) is the etiological agent of Johne's disease in ruminants. Johne's disease is an important enteric infection causing large economic losses associated with infected herds. In an attempt to fight this infection, we created two novel live-attenuated vaccine candidates with mutations in sigH and lipN (pgsH and pgsN, respectively). Earlier reports in mice suggested these vaccines are promising candidates to fight Johne's disease in ruminants. In this study, we tested the performances of the two constructs as vaccine candidates using the goat model of Johne's disease. Both vaccines appeared to provide significant immunity to goats against challenge from wild-type M. paratuberculosis. The pgsH and pgsN constructs showed a significant reduction in histopathological lesions and tissue colonization compared to nonvaccinated goats and those vaccinated with an inactivated vaccine. Unlike the inactivated vaccine, the pgsN construct was able to eliminate fecal shedding from challenged animals, a feature that is highly desirable to control Johne's disease in infected herds. Furthermore, strong initial cell-mediated immune responses were elicited in goats vaccinated with pgsN that were not demonstrated in other vaccine groups. Overall, the results indicate the potential use of live-attenuated vaccines to control intracellular pathogens, including M. paratuberculosis, and warrant further testing in cattle, the main target for Johne's disease control programs.

Knowledge gaps that hamper prevention and control ofMycobacterium aviumsubspeciesparatuberculosisinfection

“…Although LAV induced strong protection in a mouse model (Ghosh, Shippy, & Talaat, 2015), in a goat model they showed no protective efficacy in some studies (Hines et al, 2014;Park, Allen, Barrington, & Davis, 2014) and strong reduction in shedding in a recent other study (Shippy et al, 2017); they have apparently not been tested in cattle.…”

“…In sheep, specific lymphocyte subsets play a role in protecting against MAP infection, including sheep vaccinated with killed vaccine (de Silva, Plain, Begg, Purdie, & Whittington, ). Although LAV induced strong protection in a mouse model (Ghosh, Shippy, & Talaat, ), in a goat model they showed no protective efficacy in some studies (Hines et al., ; Park, Allen, Barrington, & Davis, ) and strong reduction in shedding in a recent other study (Shippy et al., ); they have apparently not been tested in cattle.…”

A single dose polyanhydride-based nanovaccine against paratuberculosis infection

“…The subcutaneous vaccination regime and intraperitoneal challenge model has been successfully employed before in mouse models and the resulting data translated well to ruminant systems such as in goats. 42,69,70 The dose was confirmed by plating the serially diluted challenge inoculums on 7H10 plates. Mice were monitored daily for adverse reaction(s) from vaccination and for the progression of infection.…”

“…41 Its protective efficacy has been observed in goats challenged by virulent M. paratuberculosis strain. 42 The study was conducted in two phases, viz: Trial I and Trial II. In the trial I studies, the focus was on the safety of the nanovaccine formulations while in the trial II studies, the focus was on the efficacy of nanovaccine formulations ( Fig.…”

Transposon Mutagenesis in Mycobacterium avium Subspecies Paratuberculosis

“…Directed knockouts using insertion sequences have now also been achieved in Map. Examples of genes that have been targeted using this method include sigH [5,6], lipN [5], leuD [7], relA, lsr2, and pknG [8], with relA [9] and leuD [10] mutants showing protection from Map challenge in goats.…”