A New Recombinant Bacille Calmette‐Guérin Vaccine Safely Induces Significantly Enhanced Tuberculosis‐Specific Immunity in Human Volunteers

Abstract

Background One strategy for improving anti-tuberculosis (TB) vaccination involves the use of recombinant Bacillus Calmette Guérin (rBCG) overexpressing protective TB antigens. rBCG30, overexpressing the Mycobacterium tuberculosis secreted antigen, Ag85b, was the first rBCG shown to induce significantly greater TB protection in animals than parental BCG. Methods We report the first phase I, double-blind trial of rBCG30 in 35 adults randomized to receive rBCG30 or parental Tice BCG intradermally. Clinical reactogenicity was assessed and state-of-the-art immunological assays used to study Ag85b-specific immune responses induced by both vaccines. Results Similar clinical reactogenicity occurred with both vaccines. rBCG30 induced significantly increased Ag85b-specific T cell lymphoproliferation, IFN-γ secretion, IFN-γ ELISPOT responses, and direct ex vivo intracellular IFN-γ responses. Additional flow cytometric studies measuring CFSE dilution and intracellular cytokine production demonstrated that rBCG30 significantly enhanced Ag85b-specific CD4+ and CD8+ T cells capable of concurrent expansion and effector function. More importantly, rBCG30 significantly increased Ag85b-specific T cells capable of inhibiting intracellular mycobacteria. Conclusions These results provide proof-of-principal that rBCG can safely enhance human TB immunity, and support further development of rBCG overexpressing Ag85b for TB vaccination.

Exploiting the mycobacterial cell wall to design improved vaccines against tuberculosis

“…In the last two decades many attempts have been made and human clinical trials have been initiated for three of the recombinant BCG strains developed: rBCG30, VPM1002 and AERAS-422. rBCG30 is a recombinant BCG expressing one of the most actively secreted antigens of M. tuberculosis, Ag85B, in a five-fold amount compared to that expressed by the wild type strain [15], and results of the phase I clinical trial have already been reported [19]. The rBCG30 was shown to induce enhanced protection in animal models compared to the parental strain while maintaining a good safety record [20].…”

Recombinant Yellow Fever Vaccine Virus 17D Expressing Simian Immunodeficiency Virus SIVmac239 Gag Induces SIV-Specific CD8 + T-Cell Responses in Rhesus Macaques

“…It is also possible that any YF17D/HIV recombinants would likely replicate better in humans than they have in rhesus macaques and thus induce more robust immune responses. Also, rBCG was shown previously to be effective in humans (5,17,33,34) and may be more useful at priming T-cell responses in humans than it has been in our limited study with rhesus macaques. These two vectors have longdistinguished safety and efficacy histories in humans and may therefore be well suited for HIV vaccine development.…”

BCG Vaccine-Beginning of its End

“…Of the two recombinant BCG vaccines, rBCG30 over express certain M. tuberculosis immunodominant antigen Ag85b making the vaccine more immunogenic than the BCG [17], while the other (hly+ rBCG) was equipped with the membrane-perforating listeriolysin (Hly) of Listeria monocytogenes that secrete listeriolysin [18] to make the vaccine more efficacious against aerosol infection with M. tuberculosis. The TB vaccine foundation Aeras, uses a combination of the two approaches described and has developed a recombinant strain of BCG expressing several antigens from M. tb together with perfringolysin [19].…”