A century of attempts to develop an effective tuberculosis vaccine: Why they failed?

Tuberculosis (TB) remains a major global health problem despite widespread use of the Bacillus BCG vaccine. This situation is worsened by co-infection with HIV, and the development of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains. Thus, novel vaccine candidates and improved vaccination strategies are urgently needed in order to reduce the incidence of TB and even to eradicate TB by 2050. Over the last few decades, 23 novel TB vaccines have entered into clinical trials, more than 13 new vaccines have reached various stages of preclinical development, and more than 50 potential candidates are in the discovery stage as next-generation vaccines. Nevertheless, why has a century of attempts to introduce an effective TB vaccine failed? Who should be blamed -scientists, human response, or Mtb strategies? Literature review reveals that the elimination of latent or active Mtb infections in a given population seems to be an epigenetic process. With a better understanding of the connections between bacterial infections and gene expression conditions in epigenetic events, opportunities arise in designing protective vaccines or therapeutic agents, particularly as epigenetic processes can be reversed. Therefore, this review provides a brief overview of different approaches towards novel vaccination strategies and the mechanisms underlying these approaches.