Preclinical evaluation of novel candidate vaccines in a murine model of tuberculosis

Abstract

Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, yet the currently vaccine available, Mycobacterium bovis Bacille Calmette et Guérin (BCG), is only partially effective against infection with M. tuberculosis. Therefore the development of a new effective TB vaccine is urgently required. A novel fusion protein vaccine, termed CysVac2, was developed by fusing CysD, a major component of the sulphate activation pathway of M. tuberculosis, to the immunodominant-secreted antigen Ag85B. Vaccination of C57BL/6 mice with CysVac2, combined with the adjuvant MPL/DDA, induced the generation of multifunctional CD4+ T cells and conferred protection against challenge with aerosol M. tuberculosis to an extent comparable to BCG. Furthermore, the CysVac2 vaccine could boost the protective effect of BCG. Vaccination with BCG overexpressing CysVac2 (rBCG:CysVac2) resulted in enhanced CD4+ T cell priming and immunogenicity compared to parental BCG, however rBCG:CysVac2 did not demonstrate improve protective efficacy compared to BCG alone. Combination of CysVac2 with the novel polysaccharide adjuvant Advax reduced the bacterial burden in the lungs of M. tuberculosis-challenged mice. This improved protection correlated with the rapid influx of neutrophils and macrophages to the site of vaccination as well as pronounced priming of M. tuberculosis-specific CD4+ T cells with a multifunctional phenotype. In conclusion, this thesis has defined the vaccine potential of CysD-based TB vaccines and identified candidates that merit further preclinical evaluation for progression to human trials.