RESUMEN
An attenuated Mycobacterium bovisRD1 deletion (DeltaRD1) mutant of the Ravenel strain was constructed, characterized, and sequenced. This M. bovis DeltaRD1 vaccine strain administered to calves at 2 weeks of age provided similar efficacy as M. bovis bacillus Calmette Guerin (BCG) against low dose, aerosol challenge with virulent M. bovis at 3.5 months of age. Approximately 4.5 months after challenge, both DeltaRD1- and BCG-vaccinates had reduced tuberculosis (TB)-associated pathology in lungs and lung-associated lymph nodes and M. bovis colonization of tracheobronchial lymph nodes as compared to non-vaccinates. Mean central memory responses elicited by either DeltaRD1 or BCG prior to challenge correlated with reduced pathology and bacterial colonization. Neither DeltaRD1 or BCG elicited IFN-gamma responses to rESAT-6:CFP-10 prior to challenge, an emerging tool for modern TB surveillance programs. The DeltaRD1 strain may prove useful for bovine TB vaccine programs, particularly if additional mutations are included to improve safety and immunogenicity.
Asunto(s)
Mycobacterium bovis/genética , Mycobacterium bovis/inmunología , Vacunas contra la Tuberculosis/inmunología , Tuberculosis Bovina/prevención & control , Aerosoles , Animales , Animales Recién Nacidos , Bovinos , Recuento de Colonia Microbiana , ADN Bacteriano/genética , Femenino , Memoria Inmunológica , Pulmón/patología , Ganglios Linfáticos/microbiología , Ganglios Linfáticos/patología , Ratones , Ratones SCID , Mycobacterium bovis/aislamiento & purificación , Análisis de Secuencia de ADN , Eliminación de Secuencia , Análisis de Supervivencia , Vacunas contra la Tuberculosis/genética , Tuberculosis Bovina/inmunología , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunologíaRESUMEN
An attenuated Mycobacterium tuberculosis RD1 knockout and pantothenate auxotroph (mc(2)6030) vaccine administered at 2 weeks of age failed to protect calves from low dose, aerosol M. bovis challenge at 2.5 months of age. In contrast, M. bovis bacille Calmette Guerin (BCG)-vaccinates had reduced tuberculosis-associated pathology as compared to non- and mc(2)6030-vaccinates. Mycobacterial colonization was not impacted by vaccination. Positive prognostic indicators associated with reduced pathology in the BCG-vaccinated group were decreased antigen induced IFN-gamma, iNOS, IL-4, and MIP1-alpha responses, increased antigen induced FoxP3 expression, and a diminished activation phenotype (i.e., downward arrow CD25+ and CD44+ cells and upward arrow CD62L+ cells) in mycobacterial-stimulated mononuclear cell cultures. The calf sensitization and challenge model provides an informative screen for candidate tuberculosis vaccines before their evaluation in costly non-human, primates.
