The relationship between M. tuberculosis and our ancestors is long standing, going back as many as 3 million years (). M. tuberculosis has no other ecological niche, so all of its evolutionary selection is through interactions with humans. Coevolution has resulted in an infection that induces partial immunity, where the host survives most of the time and so does the pathogen. TB is spread through the air by people with active TB, so mechanisms that promote release of bacteria from the lungs benefit the bacteria, and TB may be unique in its ability to exploit adaptive immune responses (through inflammatory lung tissue damage) to promote its transmission. M. tuberculosis is also unusual, as the vast majority of its antigens do not exhibit sequence diversity (). Although the full implications of antigen conservation remain to be determined, the lack of escape mutations is consistent with partial immunity.

Most people that encounter M. tuberculosis do not progress to active TB disease and are considered to have latent TB infection (LTBI). Although only 5%–10% of people progress to active, TB disease, a person with active TB is estimated to transmit TB to an average of 10 other people per year (superspreaders may infect as many as 200), so progression from LTBI to active TB occurs at a rate sufficient to sustain the global epidemic.

Despite the impression that tuberculosis (TB) is a disease of historic () or romantic () interest, TB causes more deaths (1.7 million in 2016) than does HIV ( http://www.who.int/tb/en/ ). Mycobacterium tuberculosis, the bacteria that cause TB, is estimated to have infected 23% of the current human population () and progressed to cause active disease in 10.4 million people in 2016. TB is potentially curable, but there were an estimated 500,000 new cases of drug-resistant TB in 2016. Cure rates are lower with resistant strains, the drugs are more costly and more toxic, and drug-resistant M. tuberculosis can be transmitted to other individuals ().

TB Vaccine History

Rodrigues et al., 1993 Rodrigues L.C.

Diwan V.K.

Wheeler J.G. Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Mangtani et al., 2014 Mangtani P.

Abubakar I.

Ariti C.

Beynon R.

Pimpin L.

Fine P.E.

Rodrigues L.C.

Smith P.G.

Lipman M.

Whiting P.F.

Sterne J.A. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. M. tuberculosis was identified as the cause of TB in 1882, and by 1927 the live attenuated bacille Calmette-Guérin (BCG) TB vaccine became available. Approximately 100 million infants receive BCG annually, due to its low cost, stability, and safety. Although BCG reduces the risk of disseminated tuberculosis in childhood (), its efficacy in preventing pulmonary tuberculosis in adults varies widely (). The variation is attributed to multiple factors, including the BCG strain, dose, and route of administration; prevalence of nontuberculous mycobacteria (NTM); host genetics, microbiota, and coinfections; and prevalence of specific M. tuberculosis lineages. Variations in outcomes notwithstanding, BCG has not been sufficiently effective to prevent the growth of global TB.

Copin et al., 2014 Copin R.

Coscollá M.

Efstathiadis E.

Gagneux S.

Ernst J.D. Impact of in vitro evolution on antigenic diversity of Mycobacterium bovis bacillus Calmette-Guerin (BCG). One mechanism that may limit BCG efficacy is that its antigenic composition is insufficiently related to M. tuberculosis. Analysis of 13 BCG genomes revealed that of the 1,530 known human T cell epitopes in M. tuberculosis, 21%–28% of the epitopes are deleted from BCG (). Besides the deleted antigens, 15 epitopes in 9 antigens differ in sequence compared with M. tuberculosis. Although the evidence is insufficient to conclude that antigen loss and sequence variation account for the limited efficacy of BCG, several immunodominant antigens (ESAT-6, CFP-10, PE35, and PPE68) are lacking from all BCG strains.

The only new TB vaccine examined in phase II trials, MVA85A, lacks efficacy. MVA85A is comprised of the attenuated poxvirus, Modified Vaccinia Ankara (MVA), that expresses the M. tuberculosis antigen 85A (Ag85A). Ag85A is an abundant secreted protein of M. tuberculosis, and during infection, it induces high-frequency T cell responses. After MVA85A was found safe and immunogenic in humans, two groups at high risk of TB were selected for efficacy trials: HIV-infected adults and infants.

Ndiaye et al., 2015 Ndiaye B.P.

Thienemann F.

Ota M.

Landry B.S.

Camara M.

Dièye S.

Dieye T.N.

Esmail H.

Goliath R.

Huygen K.

et al. MVA85A 030 trial investigators

Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. One efficacy study was performed in 650 HIV-infected adults that were randomized to receive MVA85A or a control (). MVA85A induced Ag85A-reponsive T cells that produced IFNγ, as well as cells that produced the cytokines Tumor necrosis factor (TNF), IL-2, or IL-17; low-magnitude CD8 T cell responses were detected, but fewer than 1% of the recipients produced detectable antibodies to Ag85A. There were 6 cases of active TB among the 320 MVA85A recipients and 9 cases in the 325 controls, and this difference was not significant. MVA85A also failed to prevent new infections, as reflected by Quantiferon-TB (QFT) conversion, which reflects an antigen-specific T cell response that develops several weeks after infection with M. tuberculosis.

Tameris et al., 2013 Tameris M.D.

Hatherill M.

Landry B.S.

Scriba T.J.

Snowden M.A.

Lockhart S.

Shea J.E.

McClain J.B.

Hussey G.D.

Hanekom W.A.

et al. MVA85A 020 Trial Study Team

Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. The other trial enrolled 2,797 healthy infants who received BCG at birth and were randomized to MVA85A or control (). MVA85A induced Ag85A-responsive T cells that could produce IFNγ, TNF, and IL-2, as well as IL-17. No Ag85A-responsive CD8 T cells were detected. Thirty-nine MVA85A recipients and 32 controls developed active TB defined by stringent diagnostic criteria, and 178 MVA85A recipients and 171 controls developed evidence of new infection (QFT conversion). Therefore, MVA85A did not confer protection from M. tuberculosis disease or infection.

In the absence of an efficacious vaccine, current TB control consists of identifying people with active TB and treating them effectively. Additionally, close contacts of the patient are also tested for evidence of infection, and those who test positive are administered 3–9 months of preventive chemotherapy. The WHO End TB Strategy program emphasizes the need for new tools, including vaccines, to achieve the goal of 95% reduction in TB deaths and 90% reduction in TB incidence by 2035.