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Infection and Immunity, May 2000, p. 2948-2953, Vol. 68, No. 5
0019-9567/00/$04.00+0

CpG Oligodeoxynucleotides and Interleukin-12 Improve the Efficacy of Mycobacterium bovis BCG Vaccination in Mice Challenged with M. tuberculosis

Brenda L. Freidag,1 Genevieve B. Melton,1 Frank Collins,2 Dennis M. Klinman,3 Allen Cheever,4 Laura Stobie,1 Winnie Suen,1 and Robert A. Seder1,*

Clinical Immunology Section, Laboratory of Clinical Investigation,1 and Immunobiology Section, Laboratory of Parasitic Diseases,4 National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Laboratory of Mycobacteria2 and Section of Retroviral Immunology,3 Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland

Received 21 December 1999/Returned for modification 24 January 2000/Accepted 5 February 2000

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only vaccine approved for prevention of tuberculosis. It has been postulated that serial passage of BCG over the years may have resulted in attenuation of its effectiveness. Because interleukin-12 (IL-12) and oligodeoxynucleotides (ODN) containing cytidine phosphate guanosine (CpG) motifs have been shown to enhance Th1 responses in vivo, they were chosen as adjuvants to increase the effectiveness of BCG vaccination. In this report, mice were vaccinated with BCG with or without IL-12 or CpG ODN and then challenged 6 weeks later via the aerosol route with the Erdman strain of M. tuberculosis. Mice vaccinated with BCG alone showed a 1- to 2-log reduction in bacterial load compared with control mice that did not receive any vaccination prior to M. tuberculosis challenge. Moreover, the bacterial loads of mice vaccinated with BCG plus IL-12 or CpG ODN were a further two- to fivefold lower than those of mice vaccinated with BCG alone. As an immune correlate, the antigen-specific production IFN-gamma and mRNA expression in spleen cells prior to challenge were evaluated. Mice vaccinated with BCG plus IL-12 or CpG ODN showed enhanced production of IFN-gamma compared with mice vaccinated with BCG alone. Finally, granulomas in BCG-vaccinated mice were smaller and more lymphocyte rich than those in unvaccinated mice; however, the addition of IL-12 or CpG ODN to BCG vaccination did not alter granuloma formation or result in added pulmonary damage. These observations support a role for immune adjuvants given with BCG vaccination to enhance its biologic efficacy.

* Corresponding author. Mailing address: LCI, NIAID, 10 Center Dr., Room 10/11C215, NIH, Bethesda, MD 20892. Phone: (301) 402-4816. Fax: (301) 480-1936. E-mail: rseder{at}niaid.nih.gov.

Infection and Immunity, May 2000, p. 2948-2953, Vol. 68, No. 5
0019-9567/00/$04.00+0


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