Improved long-term protection against Mycobacterium tuberculosis Beijing/W in mice after intra-dermal inoculation of recombinant BCG expressing latency associated antigens.

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Vaccine (Impact Factor: 3.77). 08/2011; 29(47):8740-4. DOI: 10.1016/j.vaccine.2011.07.144
Source: PubMed

ABSTRACT Bacille Calmette-Guérin (BCG) is the vaccine against tuberculosis (TB), but has varied efficacy in different geographical locations. Recombinant strategies to genetically modify the organism to enhance the quality of the immune response have aimed at improving BCG efficacy. Here we describe such a strategy using rBCGΔureC∷hly expressing defined latency-associated antigens and test this construct for long-term protection against an isolate of the Mycobacterium tuberculosis (Mtb) Beijing/W lineage. Expression of the antigens Rv2659c, Rv3407 and Rv1733c by rBCGΔureC∷hly improved long-term efficacy in both lung and spleen at day 200 post-infection after intradermal vaccination of mice. Our data support expression of Mtb latency associated antigens by rBCG to improve protection against Mtb.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tuberculosis remains a major health threat and vaccines better than bacillus Calmette-Guérin (BCG) are urgently required. Here we describe our experience with a recombinant BCG expressing listeriolysin and deficient in urease. This potential replacement vaccine has demonstrated superior efficacy and safety over BCG in Mycobacterium tuberculosis aerosol-challenged mice and was safe in numerous animal models including immune-deficient mice, guinea pigs, rabbits and nonhuman primates. Phase I clinical trials in adults in Germany and South Africa have proven safety and a current Phase IIa trial is under way to assess immunogenicity and safety in its target population, newborns in a high tuberculosis incidence setting, with promising early results. Second-generation candidates are being developed to improve safety and efficacy.
    Expert Review of Vaccines 04/2014; · 4.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bacille Calmette-Guérin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB). Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort toward the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG) published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words TB, rBCG vaccine, and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of Mycobacterium tuberculosis (Mtb) immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and overexpression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T-cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGΔureC:hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long-lasting memory.
    Frontiers in Immunology 01/2014; 5:152.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The vaccine discovery paradigm in tuberculosis (TB) has been to mimic the natural immune response to infection. With an emphasis on interferon (IFN)-γ as the main protective cytokine, researchers have selected dominant antigens and administered them in delivery systems to promote strong T helper (Th)1 responses. However, the Bacillus Calmette-Guérin (BCG) vaccine is a strong inducer of Th1 cells, yet has limited protection in adults, and further boosting by the Modified-Vaccinia-Ankara (MVA)85A vaccine failed to enhance efficacy in a clinical trial. We review the current understanding of host-pathogen interactions in TB infection and propose that rather than boosting Th1 responses, we should focus on understanding protective immune responses that are lacking or insufficiently promoted by BCG that can intervene at critical stages of the TB life cycle.
    Trends in immunology. 05/2014;