title: Optimal models to evaluate the protective efficacy of tuberculosis vaccines.
abstract: BCG has been used widely as a vaccine to prevent tuberculosis (TB) for 80 years, yet there is still considerable controversy about its efficacy. Many experimental variables have obscured the true efficacy of BCG. The absence of appropriate animal models for the study of protective efficacy and the lack of in vitro correlates of protective immunity have impeded progress. Laboratory animal studies, which have contributed to understanding the pathogenesis, heritability of resistance and immunology of TB, have failed to identify the immunological pathways necessary for protective immunity. In recent years, cattle and deer, which are naturally susceptible to TB, have been used to study protective immunity in vaccinated animals, challenged with virulent bacteria. A deer TB infection model has been developed that can measure protection against TB infection or the development of disease. Data from this model show that, providing live BCG is administered in a short interval prime-boost protocol, significant protection against infection and disease can be obtained. Single dose vaccine provides suboptimal protection that attenuates pathology but does not prevent infection. Low dose BCG vaccine (10(4)cfu), administered in a prime-boost protocol, sufficient to prevent infection, does not cause conversion to delayed type hypersensitivity or produce unacceptable side-effects. Immune memory for protection against infection persists at optimal levels for at least 12 months post vaccination. Used optimally, BCG produces good levels of protection against TB and improved protocols or its use should be explored, before attempts are made to replace it with new-generation vaccines. It is now possible to integrate the fundamental information obtained from laboratory animals with studies of functional immune protection in target host species. Justification for the use of TB vaccines for domestic livestock under field conditions, must be underpinned by scientific evidence that they provide acceptable levels of protection long term.
authors.affiliation: Disease Research Laboratory, University of Otago, Dunedin, New Zealand.
authors.forename: J F
authors.initials: JF
authors.lastname: Griffin
authors.forename: D N
authors.initials: DN
authors.lastname: Chinn
authors.forename: C R
authors.initials: CR
authors.lastname: Rodgers
authors.forename: C G
authors.initials: CG
authors.lastname: Mackintosh
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D003670:Deer; D004334:Drug Administration Schedule; D019317:Evidence-Based Medicine; D006168:Guinea Pigs; D006968:Hypersensitivity, Delayed / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D009163:Mycobacterium bovis / Q000276:immunology; D016896:Treatment Outcome; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*
chemical_list: D001500:BCG Vaccine; D015415:Biomarkers; D016207:Cytokines