**5. Shall we ever have an effective immunotherapy or anti-TB vaccine?**

Application of highly effective vaccines across the globe is the only way to control and arrest the spread of infectious diseases. So far BCG is the only available anti-TB vaccine. It is one of the oldest vaccines and has remained unchanged for a long time. It does confer reasonable protection to infants at risk and prevents pediatric TB meningitis. However it is ineffective for protection of large adult populations and has failed to prevent the rise in new infections and active disease patients and especially in MDR and extreme drug resistant (XDR) cases [49]. Therefore many efforts have been invested in trying many forms of various extracts of other mycobacteria, such as M. vaccae, which may be considered as immunostimulants of TH1 responses or a kind of vaccines. Most have resulted in a transient enhancement of the antituberculous inflammatory response, sometimes with severe side-effects, but without longterm clinical benefit [50]. How can this be explained?

The main reason is that decades of research have not, as yet, demonstrated a universal clearly immunodominant and protective T cell epitope to one of the bacterial antigensmainly to cell-wall peptides, lipids or glycolipids. An exception may be the 85A and 85B antigens, which may be suitable candidates for a widely used anti-tuberculous vaccine under various constructs [51]. They show enhancement of TH1-type responses, but longterm clinical results are still unknown. Additional vaccines are under trials, such as MTB subunit and DNA preparations [52].

In addition there is the problem in the variability of the host immunogenetic response, both to BCG and to MTB [53]. Therefore various research projects are trying to identify, already mentioned, polymorphisms in immune-associated and other genes, which may increase or decrease the susceptibility to TB, such as the one which has been recently identified in a Moroccan population [54] and another one in a Chinese ethnic group [55]. This subject lies outside of the scope of this chapter, but it may lead to a better understanding of the processes determining the fate of a MTB infection and assist in designing better vaccines, although they may need to be population-targeted.
