Submitted to: Annual Conference on Vaccine Research
Publication Type: Abstract Only
Publication Acceptance Date: February 12, 2011
Publication Date: May 18, 2011
Citation: Waters, W.R. 2011. Cattle as a model to evaluate new vaccine strategies for tuberculosis. Annual Conference on Vaccine Research [abstract]. p. 25. Technical Abstract: Vaccines for many chronic intracellular pathogens requiring cell-mediated immunity for protection are lacking. With these pathogens, a serious impediment to vaccine discovery is a lack of animal models that are predictive of efficacy in humans. For tuberculosis (TB), vaccine efficacy studies using Mycobacterium tuberculosis in non-human primates (NHPs) offer a logical model for prediction of efficacy in humans. Availability (especially of neonates) and costs associated with BL-3 care, however, hinder widespread use of NHPs for TB vaccine testing. Thus, many candidate TB vaccines are tested using mice and guinea pigs; yet, only a few of the vaccines deemed effective with rodent models have emerged for evaluation in Phase 1 human trials. Mycobacterium bovis infection of cattle results in disease that is very similar to M. tuberculosis infection in humans. Prior to pasteurization, ~25% of TB cases in humans was attributable to M. bovis and currently it is estimated that 10% of human TB cases in developing countries is due to M. bovis. Infection with M. bovis in humans is clinically indistinguishable from infection with M. tuberculosis and these two organisms have ~99.95% sequence identity. The neonatal calf/TB challenge model is a well-established method for evaluation of TB vaccines, including initial efficacy studies performed by Calmette and Guerin with BCG circa 1911. Experimental infection techniques for infection of cattle with M. bovis, including aerosol inoculation, are standardized and routinely used for vaccine efficacy studies. While the mainstay of bovine TB control has been abattoir inspection and targeted testing, vaccines are now being considered as an additional tool, both in cattle and wildlife reservoirs. Objective vaccine efficacy parameters used in experimental challenge trials include: gross and histologic lesion scoring, qualitative assessment of lesion distribution (and colonization), quantitative assessment of lung-associated lymph node colonization, and morphometric analysis of lung radiographs for granulomas. Currently, M. bovis BCG is the only bovine TB vaccine available. As with humans, BCG efficacy in cattle is variable and responses to BCG may interfere with standard ante-mortem bovine TB tests. With experimental trials, other bovine TB vaccine platforms have been evaluated including DNA, subunit, live-vectored, attenuated M. bovis strains, auxotrophic mutants, and killed mycobacterial preparations. Of these, BCG prime and subunit boost strategies have shown improved efficacy over BCG alone. With calves, effective vaccination is associated with a reduced immune stimulation profile after virulent M. bovis experimental challenge. Positive prognostic indicators based on comparison of responses of protected versus non-protected calves to challenge include: reduced antigen-specific IFN-gamma, iNOS, IL-4, and MIP1-alpha responses; reduced expansion of CD4+ cells in culture; and a diminished activation profile of decreased percentages of CD25+ and CD44+ cells and increased percentages of CD62L+ cells. Also, several recent studies have demonstrated that vaccine-elicited central memory T cell responses to specified antigens (e.g., Ag85A) prior to challenge correlate with reduced pathology and mycobacterial colonization upon experimental M. bovis infection, indicating the potential for screening of vaccine candidates without costly challenge procedures. In contrast, infection-elicited antibody and effector recall IFN-gamma responses positively correlate with pathology. Together, these findings demonstrate significant advances in experimental approaches to development of bovine TB vaccines and the opportunities for use of calves for testing vaccines intended for use in humans.