Author(s): Neha Dalmia 1 , Alistair J Ramsay [*] 1
BCG; lung immunity; mucosal delivery; prime-boost; recombinant viral vectors; systems biology; tuberculosis; T cell; vaccine
TB is a global emergency
It has been estimated that a third of the human population is latently infected with Mycobacterium tuberculosis and at risk for disease reactivation  . A 2011 WHO report on global TB control indicated that there were 8.8 million new TB cases registered and 1.45 million TB-related deaths  . Coinfection with HIV-1 is the most common cause of immune suppression in latently infected individuals, raising this risk from a 10% lifetime chance to 10% annually  . Increases in TB incidence are also fueled by infections caused by multi-drug resistant and extensively-drug resistant M. tuberculosis strains. The WHO has declared TB a global health emergency and estimates that 70 million people will die from the disease in the next 20 years without adequate treatment and preventive measures, primarily effective vaccines [4,5] . Mycobacterium bovis BCG is the only licensed TB vaccine available for human use. It is effective in reducing childhood incidence of TB; however, its variable efficacy in adults warrants the development of novel and more effective prophylactic measures that will generate protective responses against acute TB infection and could potentially control latent infection by clearing the pathogen or preventing disease reactivation. Successful immunization strategies may therefore need to induce immune responses in susceptible individuals that are comparable with those generated in latently infected individuals, and which are capable of achieving sterile M. tuberculosis eradication [1,6] . A TB elimination target set by the WHO for 2050 would seem unlikely to be achieved without new tools in place, including new drugs, vaccines and vaccination strategies  . In response to this challenge, a variety of preclinical and clinical vaccine trials of new vaccine candidates are underway. A variety of mechanisms of immune evasion appear critical in determining the outcome of M. tuberculosis infection  , while dysregulation of host immune defenses by mycobacteria favor their persistence, even within normal hosts, and this has been a critical barrier to effective vaccine development  . Immune responses induced by effective pre-exposure vaccines could potentially contain TB infection at an earlier time point than could responses induced in unvaccinated individuals, and lower bacterial loads. In mouse models of M. tuberculosis infection, vaccines that can reduce bacterial loads by tenfold compared with naive controls are considered to confer reasonable protection. Since clinical disease progression corresponds with bacterial load, such a reduction might have significant implications - correlating with the formation of fewer granulomas and a decreased chance of developing active disease  . Immune correlates of vaccine-mediated protection against M. tuberculosis infection have not yet been fully defined; however, Th1 cell-mediated immune responses mediated by CD4+ and CD8+ T cells are crucial [11-16] . Consistently sterilizing immunity against TB infection has not been achieved through any vaccination strategy tested to date.
BCG - efficacy & failure
The BCG vaccine was developed by Albert Calmette and Camille Guerin and first administered to...