Mycobacterium tuberculosis infects a third of the world's population every year, causing 8·6 million new cases and 1·3 million deaths annually (1).BCG, a live-attenuated bacterial vaccine developed in the 1920s, is still used to vaccinate most children worldwide. Although BCG protects infants from severe disseminated disease, it cannot prevent infection. Especially in developing countries, pulmonary tuberculosis can develop mostly during adolescence, and has a high mortality rate in patients who are co-infected with HIV. So far, the development of vaccines that outperform BCG has been difficult.
Recently, 12 new vaccines entered clinical trials as part of a global effort led by Aeras (2). Since most children worldwide are vaccinated with BCG at birth, vaccine development efforts so far have mainly focused on two goals: improvement of primary vaccination by replacing BCG with engineered live-attenuated bacterial strains deriving from BCG or M tuberculosis, and boosting of BCG-induced immunity with M tuberculosis protein antigens delivered in the presence of adjuvants or with viral vectors expressing the same antigens (3). One of the most popular antigens is the tuberculosis antigen 85A (Ag85A), which was first described in 1965 (4) and is present in large quantities in culture supernatants of M tuberculosis. This antigen induces protective immune responses in mice (5) and has been used extensively to boost the immune response elicited by BCG priming. MVA85A is modified vaccinia virus Ankara (MVA)—a live-attenuated poxvirus vector—that expresses Ag85A. The vaccine candidate was developed by an EU-funded consortium (TBVAC) to boost pre-existing immunity induced by BCG vaccination (6). In studies in animals and human beings, this prime—boost regimen has been shown to be safe and to induce strong and polyfunctional CD4+ T-cell responses (6). When challenged with M tuberculosis, BCG-primed MVA85A-boosted animals showed a modest increase in protection compared with those vaccinated with BCG alone (6). However, when intradermally administered MVA85A vaccine was tested in a phase 2b efficacy trial in South Africa involving almost 3000 infants 4—6 months of age (7) the vaccine was confirmed to be safe, but did not show any increase in protection from infection compared with the placebo control. In a recent trial in which adult volunteers were challenged with BCG vaccination MVA85A did not increase the protection elicited by BCG immunisation alone (8).
The results published so far confirm that although intradermal immunisation with MVA85A in human beings induces the expected Th1 and interferon-γ responses, it does not increase the protection induced by BCG vaccination. The question remains of whether the 85A antigen itself is able to induce any protection in people, or whether the type of immune response induced by intradermal immunisation is appropriate for protection. Since several animal models in mice and non-human primates have shown that intranasal or aerosol-delivered Ag85A induces better immunity and protection than does intradermal immunisation (5, 9), the next logical step was to test in human beings whether delivery of MVA85A by aerosol, through the use of a nebuliser, would improve immunity in the lungs, which are the portal of entry for M tuberculosis into the body.
The Article by Imman Satti and colleagues in The Lancet Infectious Diseases reports the first in-human trial of MVA85A delivered by aerosol (10). The authors describe a double-blind phase 1 clinical trial comparing the safety and immunogenicity of MVA85A delivered intradermally or by aerosol in healthy adults from the UK who had previously been vaccinated with BCG. Although the trial had only 12 volunteers in each group, this was sufficient to show that the vaccine delivered by aerosol was safe and elicited an immune response in the lungs that was superior to that induced by the intradermally administered MVA85A. Broncoalveolar lavages (BAL) showed increased frequencies of CD4+ T cells specific for Ag85A that produced interferon-γ, tumour necrosis factor (TNF)α, interleukin 2, and interleukin 17, and had an increased number of CD4+ T cells simultaneously making interferon-γ, TNFα, interleukin 2, and interleukin 17—a response that is known to be important in the control of mycobacterial infection.
Whether or not the increased local immunity in the lungs from the aerosol delivery of MVA85A is going to be able to increase the level of protection from tuberculosis is still an outstanding question. However, the authors will be able to use the BCG challenge model that they recently described (8) to address this issue. Finally, 50 years after its discovery, we might at last be able to answer the question of whether the immunity induced by Ag85A is of any use to protect people from tuberculosis.
1 . Global tuberculosis report 2013. World Health Organisation, 2013. http://www.who.int/tb/publications/global_report/en/. (accessed July 29, 2014).
2 World Malaria Day, 25 April 2014. . http://www.who.int/campaigns/malaria-day/2014/event/en/. (accessed July 29, 2014).
3 Tuberculosis vaccine development at a divide. . Curr Opin Pulm Med 2014; 20: 294-300. PubMed
4 Extracellular proteins of tubercle bacilli. IV. Alpha and beta antigens as major extracellular protein products and as cellular components of a strain (H37Rv) of Mycobacterium tuberculosis. . Biken J 1965; 8: 189-199. PubMed
5 Immunization with different formulations of Mycobacterium tuberculosis antigen 85A induces immune responses with different specificity and protective efficacy. . Vaccine 2013; 31: 4624-4631. PubMed
6 MVA-85A, a novel candidate booster vaccine for the prevention of tuberculosis in children and adults. . Curr Opin Mol Ther 2010; 12: 124-134. PubMed
7 Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. . Lancet 2013; 381: 1021-1028. Summary Full Text PDF(316KB) PubMed
8 Evaluation of a human BCG challenge model to assess antimycobacterial immunity induced by BCG and a candidate tuberculosis vaccine, MVA85A, alone and in combination. . Infect Dis 2014; 209: 1259-1268. PubMed
9 Evaluation of the safety and immunogenicity of a candidate tuberculosis vaccine, MVA85A, delivered by aerosol to the lungs of macaques. . Clin Vaccine Immunol 2013; 20: 663-672. PubMed
10 Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial. . Lancet Infect Dis 2014. published online Aug 21. http://dx.doi.org/10.1016/S1473-3099(14)70845-X.
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Source: The Lancet Infectious Diseases