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Infection and Immunity, January 2002, p. 292-302, Vol. 70, No. 1
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.1.292-302.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

DNA Vaccine Combinations Expressing Either Tissue Plasminogen Activator Signal Sequence Fusion Proteins or Ubiquitin-Conjugated Antigens Induce Sustained Protective Immunity in a Mouse Model of Pulmonary Tuberculosis

Giovanni Delogu,,{dagger} Amy Li, Charlene Repique, Frank Collins, and Sheldon L. Morris*

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

Received 15 June 2001/ Returned for modification 26 July 2001/ Accepted 18 September 2001

DNA vaccination has emerged as a powerful approach in the search for a more efficacious vaccine against tuberculosis. In this study, we evaluated the effectiveness of immunizing with combinations of 10 different tuberculosis DNA vaccines that expressed mycobacterial proteins fused at the N terminus to eukaryotic intracellular targeting sequences. In one vaccine combination, the genes were fused to the tissue plasminogen activator signal sequence (TPA), while in a second combination the same 10 genes were expressed as ubiquitin (Ub)-conjugated proteins. In ex vivo studies in which the secretion of gamma interferon was measured, cellular immune responses were detected in mice vaccinated with either the TPA DNA vaccine combination or the Ub DNA vaccine combination at 7 and 14 days following a low-dose Mycobacterium tuberculosis challenge. Moreover, mice vaccinated with the TPA combination, the Ub combination, and Mycobacterium bovis BCG were able to limit the growth of tubercle bacilli in the lung and spleen after a virulent tuberculous aerosol challenge. Histopathological analyses also showed that mice immunized with the DNA vaccine combinations had substantially improved postinfection lung pathology relative to the naïve controls. Finally, in three different long-term experiments, the survival periods following aerogenic challenge were extended as much as sevenfold for vaccinated mice compared to naïve controls. Interestingly, in all three experiments, no significant differences were detected in the mean times to death for mice immunized with the TPA combination or the Ub combination relative to the BCG controls. In conclusion, these studies demonstrate the effectiveness of immunization with DNA vaccine combinations against tuberculosis and suggest that further testing of these plasmid cocktails is warranted.

* Corresponding author. Mailing address: LMDCI/OVRR/CBER/FDA, HFM-431, Building 29, Room 502, 29 Lincoln Dr., Bethesda, MD 20892. Phone: (301) 496-5978. Fax: (301) 402-2776. E-mail: morris{at}cber.fda.gov.

Editor: J. D. Clements

{dagger} Present address: Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.

Infection and Immunity, January 2002, p. 292-302, Vol. 70, No. 1
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.1.292-302.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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