Abstract
The existing vaccine against tuberculosis (M. bovis BCG) exerts some protection against the extrapulmonary forms of the disease, particularly in young children, but is not very effective against the pulmonary form of TB, which often results from the reactivation of a latent M. tuberculosis (M.tb)infection. Among the new approaches in TB vaccine development, live attenuated M.tb mutants are a promising new avenue. Here we report on the vaccine potential of two highly attenuated M.tb mutants, MGM1991 and M.tbhma::hyg (HMA), lacking all oxygenated mycolates in their cell wall. In C57BL/6 mice, stronger Th1 (IFN-γ, IL-2 and TNF-α) and IL-17 responses could be induced following subcutaneous vaccination with either of the two mutants, than following vaccination with M. bovis BCG. Significantly more mycobacteria specific IFN-γ producing CD4+ and particularly CD8+ T cells could be detected by intracellular cytokine staining in mice vaccinated with the M.tb mutants. Finally, vaccination with either of the two mutants conferred stronger protection against intratracheal M.tb challenge than vaccination with BCG, as indicated by reduced bacterial replication in lungs at 4 to 12 weeks after challenge. Protection against M. tb dissemination, as indicated by reduced bacterial numbers in spleen, was comparable for both mutants to protection conferred by BCG.
Highlights
A better understanding of the protective immune response against M.tb is very important in the quest for better TB vaccines, but the actual “correlates of protection” are unknown so far and will perhaps only be identified from successful vaccine trials [1]
M. tuberculosis mutants MGM1991 and HMA do not replicate in vivo following subcutaneous injection
Mice infected by low-dose aerosol with mutant MGM1995 showed a fifty-fold lower colony forming unit (CFU) count in lungs over a period of 130 days than mice infected with parental MGM 1985 M.tb strain[8]
Summary
A better understanding of the protective immune response against M.tb is very important in the quest for better TB vaccines, but the actual “correlates of protection” are unknown so far and will perhaps only be identified from successful vaccine trials [1]. The importance of CD8+ T cells in the control of latent TB infection and immune protection against reactivation TB in humans was convincingly demonstrated by Bruns et al, who have reported that anti-TNF-α immunotherapy with infliximab (a monoclonal antibody against tumour necrosis factor a (TNF-a) used to treat autoimmune diseases) reduced CD8+ T cell-mediated antimicrobial activity against M.tb in humans through the interaction of the antibody with cell surface TNF on the CD8+ T cell and their subsequent complementmediated lysis [6]. Both CD4+ and CD8+ T cells play an important role in protective immunity against M.tb
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