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Infection and Immunity, November 2005, p. 7727-7735, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7727-7735.2005

Vaccination with a Sindbis Virus-Based DNA Vaccine Expressing Antigen 85B Induces Protective Immunity against Mycobacterium tuberculosis

Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland 20892

Received 4 March 2005/ Returned for modification 29 March 2005/ Accepted 8 August 2005

To improve DNA vaccination against Mycobacterium tuberculosis, we evaluated the effectiveness of a Sindbis virus-based DNA construct expressing the tuberculosis antigen 85B (Sin85B). The protective efficacy of Sin85B was initially assessed by aerogenically challenging immunized C57BL/6 mice with virulent Mycobacterium tuberculosis. At 1 and 7 months postinfection, the lung bacterial burdens were considerably reduced and the lung pathology was improved in vaccinated mice compared to naive controls. Furthermore, the mean survival period for Sin85B-immunized mice (305 ± 9 days) after the tuberculous challenge was extended 102 days relative to the naive mice (203 ± 13 days) and was essentially equivalent to the survival time of Mycobacterium bovis BCG-vaccinated mice (294 ± 15 days). The essential role of gamma interferon (IFN-) in Sin85B-mediated protection was established by showing that significantly increased levels of IFN- mRNA were present postinfection in lung cells from vaccinated mice relative to control mice and by demonstrating that IFN- depletion prior to challenge abolished the vaccine-induced protection. The substantial antituberculosis protective responses induced by Sin85B immunization of CD4^–/– mice strongly suggested that CD8 cells partially mediate Sin85B-induced protective immunity. Interestingly, Sin85B vaccination did not protect RNase L^–/– (a key enzyme in the innate antiviral response) mice while significant protection was detected in RNase L^–/– mice immunized with either BCG or a conventional DNA plasmid expressing antigen 85B. These data show that immunization with Sin85B offers protection similar to BCG in a murine model of pulmonary tuberculosis and suggest that Sin85B-induced protection is dependent upon both innate and acquired immune mechanisms.

Editor: J. L. Flynn

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