Recent Developments in Tuberculosis Vaccines

Dessislava Marinova; Jesus Gonzalo-Asensio; Nacho Aguilo; Carlos Martin


Expert Rev Vaccines. 2013;12(12):1431-1448. 

In This Article

The Intimate Relationship Between Mycobacterium Tuberculosis & the Human Host

Human Reservoir of M. Tuberculosis

Human tuberculosis (TB) is mainly caused by Mycobacterium tuberculosis (MTB) and to a lesser extent by Mycobacterium africanum, which are members of the M. tuberculosis complex (MTBC). These are obligate human pathogens with limited survival outside of the human body and no known animal reservoir. In addition to these human-adapted pathogens, MTBC includes various animal-adapted species, such as the bovine pathogen Mycobacterium bovis that can occasionally cause TB in humans. Although MTBC members differ in terms of host tropism and pathogenicity, there exists a strong evidence for a clonal population structure of MTBC, without signs of ongoing horizontal gene transfer. Accordingly, MTBC is a group of phylogenetically related members characterized by 99.9% similarity at the nucleotide level and identical 16S rRNA sequences.[1]

Global Distribution of Clinical Isolates

The ability of MTB members to survive inside human host cells during long latency periods together with the ancient origin of human TB, indicate an intimate host–pathogen co-evolution. Accordingly, the long-standing association between MTBC and its human host has shaped the biology and the epidemiology of human TB. Evolutionary studies show that MTB strains transmitted between humans have adapted to the different populations and display a geographically structured pattern.[2] Today, a large proportion of the global TB disease burden is caused by six lineages: three 'modern' lineages that are overall more successful in terms of their geographical spread compared with the three 'ancient' lineages.[3,4] There is limited evidence for differential efficacy of Bacille Calmette–Guérin (BCG) against these different MTB strains in clinic and it is not clear that the rather small genetic differences, along with phenotypic differences, will actually impact on vaccine efficacy in these populations.

Hyperconservation of Human Epitopes in M. Tuberculosis

The acquired cellular response, as represented largely by CD4+ T cells, provides protective immunity and contributes to establish a latent infection, while also promotes the development of pulmonary lesions and the caseous necrosis required for transmission.[5,6] Since MTBC interacts with humans through antigen-specific CD4+ or CD8+ T cells, we would expect that in order to avoid immune recognition by the host, T-cell antigens were among the most diverse genes in the MTBC genomes. However, human T-cell epitopes of MTBC are evolutionarily hyperconserved and do not reflect any ongoing evolutionary arms race to afford immune evasion.[7] On the basis of hyperconservation of T-cell antigens, MTBC members would benefit from being recognized by the immune system of the host since the immune responses elicited by T-cell epitopes might in fact be more beneficial to the bacteria than to the host. The ensuing host immune responses contribute to tissue destruction and the formation of cavities in the host lung, which ultimately enhances transmission. In the context of host–pathogen co-evolution and supporting the ecological theory, contacts exposed to 'modern' MTBC were more likely to develop active TB compared with individuals exposed to 'ancient' MTBC. Additionally, it has been recently found that genetically diverse strains of MTBC vary widely in induction of an early inflammatory response during infection of human macrophages, with a significantly lower response to evolutionarily 'modern' lineages as compared with 'ancient' lineages.[8]

Susceptibility of the Host: Human Genetics

From a population infected with MTBC, only 5–10% of infected individuals will develop disease during their lifetime. Variation in susceptibility to TB can be attributed to environmental factors such as malnutrition but a portion is thought to be due to host genetic factors.[9] The early use of BCG was marked by a tragic accident in Lubeck (Germany) between 1926 and 1930. Infants received a batch of BCG vaccine contaminated with virulent MTB but not all developed tuberculosis.[10] Another evidence comes from twin studies showing that the rate of TB in monozygotic twins is twice that observed among dizygotic twins (60 and 35%, respectively).[11] There are inter-individual variations in susceptibility to TB with genetic determinants contributing to the immune response to MTB infection. It has been identified multiple rare single-gene mutations linked with Mendelian susceptibility to mycobacterial disease.[12,13] Some studies have identified key immunological pathways involved in protective immunity against TB, such as the IL-12/23 and IFN-γ.[13] Quest for the genetic determinants of susceptibility to TB at the population level has so far been primarily driven by case–control studies of candidate genes. Studies based on such approaches identified over 20 genes genetically associated with susceptibility to pulmonary TB.[12] Recently, a genome-wide approach identified a number of loci that are promising candidate genes for susceptibility to pulmonary TB.[9]