Abstract
The failure of current Mycobacterium bovis bacille Calmette–Guérin (BCG) vaccines, given to neonates to protect against adult tuberculosis and the risk of using these live vaccines in HIV-infected infants, has emphasized the need for generating new, more efficacious and safer replacement vaccines. With the availability of genetic techniques for constructing recombinant BCG (rBCG) strains containing well-defined gene deletions or insertions, new vaccine candidates are under evaluation at both the preclinical and clinical stages of development. Since most BCG vaccines in use today were evaluated in clinical trials decades ago and are produced by outdated processes, the development of new BCG vaccines offers a number of advantages that include a modern well-defined manufacturing process along with state-of-the-art evaluation of safety and efficacy in target populations. We provide a description of the preclinical development of two novel rBCGs, VPM1002 that was constructed by adding a modified hly gene coding for the protein listeriolysin O (LLO) from Listeria monocytogenes and AERAS-422, which carries a modified pfoA gene coding for the protein perfringolysin O (PFO) from Clostridium perfringens, and three genes from Mycobacterium tuberculosis. Novel approaches like these should be helpful in generating stable and effective rBCG vaccine candidates that can be better characterized than traditional BCG vaccines.
Highlights
Still one of the most widely used vaccines in the world, bacille Calmette–Guérin (BCG) originally developed by Calmette and Guérin more than 90 years ago and first administered to infants in 1921 [1], has not been effective in reducing the global burden of tuberculosis (TB)
We provide the details on the developmental strategies used to design and characterize these two novel recombinant BCG (rBCG) vaccines and in addition, summarize the methods and tests used to manufacture and evaluate the candidate products to meet regulatory requirements and describe the pre-clinical assays developed to characterize the critical parameters of these live TB vaccine candidates
As previously described [29], investigators face a number of challenges in the rational development of new BCG vaccines to demonstrate that they are safer and more efficacious than the current BCG
Summary
Still one of the most widely used vaccines in the world, BCG originally developed by Calmette and Guérin more than 90 years ago and first administered to infants in 1921 [1], has not been effective in reducing the global burden of tuberculosis (TB). This vaccine was shown to demonstrate substantially better protection vs Mtb challenge in an animal model compared to its parental BCG strain, and elicited Ag85B specific CD4 T cell responses in humans [6] This vaccine was found to be safe and immunogenic in a phase I clinical trial [7], it was not pursued further due to the presence of an antibiotic resistance marker. In a separate development rBCG strain, AERAS-422 was constructed using BCG Danish-SSI 1331 as a platform, to express a mutated pfoA gene coding for the protein perfringolysin O (PFO) from Clostridium perfringens, with a mode of action similar to listeriolysin [8] It overexpressed three Mtb antigens (Ag85A, Ag85B and Rv3407). The development of safer BCG replacement vaccines could provide a vaccine that might operate through a mechanism supported by rational design, manufactured by modern cGMP methods and evaluated according to modern cGCP clinical trial designs
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