Abstract
Vaccines are considered by many to be one of the most successful medical interventions against infectious diseases. But many significant obstacles remain, such as optimizing DNA vaccines for use in humans or large animals. The amount of doses, route and easiness of administration are also important points to consider in the design of new DNA vaccines. Heterologous prime-boost regimens probably represent the best hope for an improved DNA vaccine strategy. In this study, we have shown that heterologous prime-boost vaccination against tuberculosis (TB) using intranasal BCG priming/DNA-HSP65 boosting (BCGin/DNA) provided significantly greater protection than that afforded by a single subcutaneous or intranasal dose of BCG. In addition, BCGin/DNA immunization was also more efficient in controlling bacterial loads than were the other prime-boost schedules evaluated or three doses of DNA-HSP65 as a naked DNA. The single dose of DNA-HSP65 booster enhanced the immunogenicity of a single subcutaneous BCG vaccination, as evidenced by the significantly higher serum levels of anti-Hsp65 IgG2a Th1-induced antibodies, as well as by the significantly greater production of IFN-γ by antigen-specific spleen cells. The BCG prime/DNA-HSP65 booster was also associated with better preservation of lung parenchyma.The improvement of the protective effect of BCG vaccine mediated by a DNA-HSP65 booster suggests that our strategy may hold promise as a safe and effective vaccine against TB.
Highlights
Tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, accounting for nearly 2 million deaths annually
DNA-HSP65 boosting of BCGin provides greater protection than other immunization strategies Initially, we tested the ability of different combinations of prime-boost strategies to induce protection against M. tuberculosis and compared the results with those obtained using classical bacillus CalmetteGuérin (BCG) vaccination or naked DNA-HSP65 immunization through the detection of the number of colony-forming units (CFU)
In addition to identifying the cytokines IFN-γ and IL-12, which are associated with the Th1 pattern, we found that the BCGin/DNA immunization schedule stimulated significantly higher IL-10 production (627 ± 174 pg/mL) compared with that provided by BCGsc (237 ± 110 pg/mL) and BCGsc/DNA (393 ± 102 pg/mL) groups (Fig. 2D)
Summary
Tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, accounting for nearly 2 million deaths annually. TB eradication will require the development of an improved vaccine, which, in turn, will require applica-. Genetic Vaccines and Therapy 2007, 5:7 http://www.gvt-journal.com/content/5/1/7 tion of state-of-the-art vaccine technology and new strategies. A new vaccine against TB would need to induce protection superior to that elicited by the BCG vaccine and to permit administration to healthy individuals, infected individuals and perhaps even individuals presenting the active form of the disease. Various strategies have been employed for the development and evaluation of new TB vaccines. Recombinant BCG strains, DNA-based vaccines, live attenuated Mycobacterium tuberculosis vaccines and subunit vaccines formulated with novel adjuvants have shown promise in preclinical animal models [1]. The ability of DNA vaccines to elicit Th1-biased CD4+ responses and strong cytotoxic T lymphocyte responses make them attractive as weapons against M. tuberculosis infection
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