CpG Oligodeoxynucleotides and Interleukin-12 Improve the Efficacy ofMycobacterium bovisBCG Vaccination in Mice Challenged withM. tuberculosis

Abstract

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-␥ 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-␥ 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.Mycobacterium tuberculosis infection is one of the most significant causes of mortality worldwide. Since the onset of the human immunodeficiency virus-AIDS epidemic, awareness of M. tuberculosis infection has resurfaced, as it is now a major cause of mortality for human immunodeficiency virus-infected individuals. Furthermore, the evolution of multidrug-resistant strains represents a significant health problem among normal, nonimmunocompromised individuals. The World Health Organization has recently declared the current situation to be a global emergency and has made it a priority to develop more effective vaccines against M. tuberculosis.The efficacy of M. bovis bacillus Calmette-Guérin (BCG) as a vaccine is dependent on many factors and determined clinically by its ability to prevent pulmonary or systemic disease following exposure to M. tuberculosis. Because the protective efficacy of BCG may range from 0 to 80% worldwide (18), it is necessary to determine the correlates of protection and exploit these issues in future vaccination attempts. For example, it was recently reported that the continued propagation of BCG over the past 60 years has lead to an evolution of BCG substrains marked by deletions in the parental M. bovis genome (1). Although the deletions do not include known bacterial virulence factors, the strain diversity may account for the attenuation or relative lack of efficacy against pulmonary disease. Ident...

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