A novel DNA vaccine for tuberculosis prevention

According to the Global Tuberculosis Report 2014, one third of the world population was latently infected by Mycobacterium tuberculosis (M. tb). The situation of tuberculosis (TB) prevalence is worsened by the global pandemic of HIV/AIDS, the emergence of multi-drug resistant (MDR) and extensively-drug resistant (XDR) strains. In 2013, the TB epidemic continued to grow with 9 million new infections and 1.5 million deaths. Since most of the death could have been prevented, the current treatment of TB is far from satisfactory. Therefore, an effective vaccine for the eradication of TB infection or for the elimination of tuberculosis onset and latent reactivation remains to be a research priority. Bacillus Calmette-Guérin (BCG) has been the only clinically approved TB vaccine since almost a century ago. However, it failed to protect adult tuberculosis or even caused disseminated BCG diseases in HIV-positive population. Live attenuated and recombinant subunit vaccines for the improvement or replacement of BCG have been designed, aiming to provide better-than-BCG protection in tested animals. A dozen of novel vaccines, including VPM1002, AERAS-456 and Aeras-402, have been tested in different phases of clinical trials. Unfortunately, there is still no vaccine with the capacity of TB infection eradication or latent reactivation prevention now or in the near future. DNA vaccines are new generation vaccines that have yet approved for human use, although four have been licensed for veterinary application. In this study, we have investigated four DNA vaccines that express TB antigens Ag85B (Antigen 85B), ESAT-6 (the 6 kDa early secretory antigenic target), Rv2660c (a latency-associated gene) and codon optimized fusion form 〖BER〗^(opt ) in BALB/c mice via intramuscular electroporation (EP). Compared to BCG and other antigens, 〖BER〗^(opt ) vaccine induced high frequency of Ag85B-specific CD8+ and CD4+ T cell responses. Moreover, 〖BER〗^(opt ) conferred significantly better protection against M. tb H37Rv challenge when compared to other DNA or virus vectored vaccines, with lower CFU count in the lungs and improved lung pathology comparable to that provided by BCG. In conclusion, 〖BER〗^(opt )does not have major issues of safety and pre-existing anti-vector immunity (e.g. vaccinia vector). Our findings warrant further investigation of 〖BER〗^(opt ) for TB prevention and immunotherapy, as well as the alleviation of global HIV/AIDS burden.published_or_final_versionMicrobiologyDoctoralDoctor of Philosoph