Evaluation of immune responses and protective efficacy in a goat model following immunization with a coctail of recombinant antigens and a polyprotein of Mycobacterium avium subsp. paratuberculosis

Animal Health Diagnostic Center, Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, UpTwoer Road, Ithaca, NY 14853, USA.
Vaccine (Impact Factor: 3.62). 11/2008; 27(1):123-35. DOI: 10.1016/j.vaccine.2008.10.019
Source: PubMed


The protective efficacy of four recombinant antigens (85A, 85B, superoxide dismutase [SOD], and a fusion polypeptide [Map74F]) of Mycobacterium avium subsp. paratuberculosis (MAP) along with the adjuvant dimethydioctadecyl ammonium bromide (DDA) was assessed in a goat challenge model. Animals were immunized with the four antigens with adjuvant DDA (Group I, eight goat kids) or without the adjuvant (Group II, eight goat kids) or adjuvant only (Group III, nine goat kids). Animals were boostered 3 weeks after the primary vaccination and challenged 3 weeks after the booster. Significant antigen-specific lymphoproliferation was observed in the immunized animals 3 weeks after the booster immunization. This response increased further at 4 weeks after the booster. Similarly, antigen-specific IFN-gamma responses increased in the immunized animals 3 weeks after the booster. The response was significantly higher for 85A and Map74F at 10 weeks after primary vaccination (APV) in Group I animals compared to the other two groups. CD4+ T-cell populations were higher in the vaccinated animals from 6 to 10 weeks APV than those of the control animals. A significant increase in recombinant antigen-specific IFN-gamma gene expression was detected in the vaccinated animals. At necropsy (38 weeks APV), our multicomponent subunit vaccine imparted a significant protection in terms of reduction of MAP burden in target organs as compared to sham-immunized goats. This study indicates that our multicomponent subunit vaccine induced a good Th1 response and conferred protection against MAP infection in a goat challenge model.

13 Reads
  • Source
    • "Subunit vaccines against MAP are likely to obviate some of the shortcomings of whole-cell vaccines, such as severe inflammation and granuloma formation at the injection site. However, subunit vaccines that have been tested thus far have yielded incomplete protection results in murine models of infection (Koets et al., 2006; Stabel et al., 2012) and even when combinations of proteins are used in calves and goats (Koets et al., 2006; Kathaperumal et al., 2008, 2009). For example, MAP was colonized in the lymph node and spleen at similar levels in control and vaccinate mice using a protein cocktail (Stabel et al., 2012). "
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Cellular and Infection Microbiology 09/2014; 4:126. DOI:10.3389/fcimb.2014.00126 · 3.72 Impact Factor
  • Source
    • "As there is no perfect vaccine, MAP vaccination was modeled as vaccination of calves with an imperfect vaccine ('leaky') that partially reduces the susceptibility of the host and has a 'failure in take' effect (Woolhouse et al., 1997; Halloran et al., 2010). In this study we assumed the use of novel MAP vaccines that were able to partially prevent infection, such as recombinant vaccines that prevent MAP from attaching to the intestinal surface (Kathaperumal et al., 2009), rather than heat-killed whole cell-based vaccines that have not been effective in preventing susceptible calves being infected (Whitlock, 2010; Alonso-Hearn et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Paratuberculosis, or Johne's disease (JD), is a chronic enteric disease of ruminants infected by Mycobacterium avium subsp. paratuberculosis (MAP) that causes a significant financial loss in dairy industry. To reduce prevalence and transmission in dairy herds infected with MAP, control programs have been implemented, including test-based culling, improved calf rearing management, and vaccination. The important issue of preventing MAP invasion into a MAP-free herd has been less investigated, however. The objective of this study was to examine whether vaccination was able to prevent MAP invasion in dairy cattle using a stochastic simulation approach. We developed a MAP vaccination model in which calves were vaccinated with a vaccine that is both imperfect in reducing the susceptibility of the host ('leaky') and that does not successfully immunize all calves ('failure in take'). Probability of MAP persistence and the number of infected animals in herds were computed for both control and vaccinated herds over a ten-year period after introduction of an initial infected heifer. Global parameter sensitivity analyses were performed to find the most influential parameters for MAP invasion. Our results show that vaccination of calves is effective in preventing MAP invasion, provided that the vaccine is of high efficacy in both reduction of susceptibility and 'take' effects; however, there is still a small chance (<0.15) that MAP can be sustained in herds over a long time (>10 years) due to vertical transmission. This study indicates that reduction in the transmission rate of high shedders (>50 CFU), the number of infected heifers initially introduced to herds, and vertical transmission are important to further decrease the probability of MAP becoming endemic and the overall number of infected animals in endemic herds. The simulation work is useful for designing vaccination programs aimed at preventing MAP invasion in MAP-free herds.
    Preventive Veterinary Medicine 02/2013; 110(3-4). DOI:10.1016/j.prevetmed.2013.01.006 · 2.17 Impact Factor
  • Source
    • "Studies on MAP vaccine efficacy, including studies of experimental infection challenge on individual animals and field trials, have shown that MAP vaccines do not fully protect susceptible calves from MAP infection, and imperfect vaccine efficacies have been reported. Vaccines may partially reduce the infectiousness or shedding load of animals shedding MAP, prolong the latent period of infected animals, slow the progression of infectious animals from low to high shedding states, or decrease the cumulative incidence of clinical JD cases (Kormendy, 1992, 1994; Wentink et al., 1994; van Schaik et al., 1996; Harris and Barletta, 2001; Kalis et al., 2001; Koets et al., 2006; Rosseels et al., 2006; Kathaperumal et al., 2008, 2009; Rosseels and Huygen, 2008; Keeble and Walker, 2009; Romano and Huygen, 2009; Santema et al., 2009; Behr and Collins, 2010; Alonso-Hearn et al., 2012). The objective of this study was to investigate the potential impact of imperfect MAP vaccines on the dynamics of MAP infection in dairy herds using a mathematical modeling approach. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to investigate the potential impacts of imperfect Mycobacterium avium subsp. paratuberculosis (MAP) vaccines on the dynamics of MAP infection in US dairy herds using a mathematical modeling approach. Vaccine-based control programs have been implemented to reduce the prevalence of MAP infection in some dairy herds; however, MAP vaccines are imperfect. Vaccines can provide partial protection for susceptible calves, reduce the infectiousness of animals shedding MAP, lengthen the latent period of infected animals, slow the progression from low shedding to high shedding in infectious animals, and reduce clinical disease. To quantitatively study the impacts of imperfect MAP vaccines, we developed a deterministic multi-group vaccination model and performed global sensitivity analyses. Our results explain why MAP vaccination might have a beneficial, negligible, or detrimental effect in the reduction of prevalence and show that vaccines that are beneficial to individual animals may not be useful for a herd-level control plan. The study suggests that high efficacy vaccines that are aimed at reducing the susceptibility of the host are the most effective in controlling MAP transmission. This work indicates that MAP vaccination should be integrated into a comprehensive control program that includes test-and-cull intervention and improved calf rearing management.
    Preventive Veterinary Medicine 08/2012; 108(2-3). DOI:10.1016/j.prevetmed.2012.08.001 · 2.17 Impact Factor
Show more

Similar Publications