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In this phase 2 study, investigators evaluated the potential of two vaccines (H4:IC31 and BCG) to prevent the acquisition of tuberculosis infection and the subsequent development of sustained disease.

Novel approaches to vaccine development include structure-based immunogen design, gene-based vaccine platforms and formulation of recombinant antigens with potent adjuvants. These technologies are producing encouraging results in the development of vaccines for globally important diseases such as tuberculosis, influenza and respiratory syncytial virus. Here we highlight the most important developments in these areas over the past 18 months.New approaches to vaccine development have generated exciting results over the past 18 months. Focusing on respiratory syncytial virus infection, influenza and tuberculosis, Fauci and Mascola discuss the impact of structure-based vaccine design, gene-based vaccine platforms and advances in adjuvant development.

Tuberculosis (TB) kills more individuals in the world than any other disease, and a threat made direr by the coverage of drug-resistant strains of Mycobacterium tuberculosis (Mtb). Bacillus Calmette–Guérin (BCG) is the single TB vaccine licensed for use in human beings and effectively protects infants and children against severe military and meningeal TB. We applied advanced computational techniques to develop a universal TB vaccine. In the current study, we select the very conserved, experimentally confirmed Mtb antigens, including Rv2608, Rv2684, Rv3804c (Ag85A), and Rv0125 (Mtb32A) to design a novel multi-epitope subunit vaccine. By using the Immune Epitopes Database (IEDB), we predicted different B-cell and T-cell epitopes. An adjuvant (Griselimycin) was also added to vaccine construct to improve its immunogenicity. Bioinformatics tools were used to predict, refined, and validate the 3D structure and then docked with toll-like-receptor (TLR-3) using different servers. The constructed vaccine was used for further processing based on allergenicity, antigenicity, solubility, different physiochemical properties, and molecular docking scores. The in silico immune simulation results showed significant response for immune cells. For successful expression of the vaccine in E. coli , in-silico cloning and codon optimization were performed. This research also sets out a good signal for the design of a peptide-based tuberculosis vaccine. In conclusion, our findings show that the known multi-epitope vaccine may activate humoral and cellular immune responses and maybe a possible tuberculosis vaccine candidate. Therefore, more experimental validations should be exposed to it.

Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy. BCG and Mycobacterium tuberculosis (Mtb) share ~98% of their genome and current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study is to design a TB subunit vaccine composed of antigens not shared with BCG and explore the advantages of this design in a BCG + subunit co-administration vaccine strategy. Eight protective antigens are selected to create an Mtb-specific subunit vaccine, named H107. Whereas traditional vaccines containing BCG-shared antigens exhibit in vivo cross-reactivity to BCG, H107 shows no cross-reactivity and does not inhibit BCG colonization. Instead, co-administering H107 with BCG leads to increased adaptive responses against both H107 and BCG. Importantly, rather than expanding BCG-primed T cells, H107 broadens the overall vaccine repertoire with new T cell clones and introduces ‘adjuvant-imprinted’ qualities including Th17 responses and less-differentiated Th1 cells. Collectively, these features of H107 are associated with a substantial increase in long-term protection. Tuberculosis (TB) subunit vaccines have been investigated as boosters for BCG-induced immunity. Here, the authors design a TB subunit vaccine that doesn't share antigens with BCG and show that co-administration of the two vaccines broadens the T cell response to TB and increases protection.

BCG vaccination provides incomplete protection against tuberculosis in infants. A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG. We aimed to assess safety, immunogenicity, and efficacy of MVA85A against tuberculosis and Mycobacterium tuberculosis infection in infants. In our double-blind, randomised, placebo-controlled phase 2b trial, we enrolled healthy infants (aged 4–6 months) without HIV infection who had previously received BCG vaccination. We randomly allocated infants (1:1), according to an independently generated sequence with block sizes of four, to receive one intradermal dose of MVA85A or an equal volume of Candida skin test antigen as placebo at a clinical facility in a rural region near Cape Town, South Africa. We actively followed up infants every 3 months for up to 37 months. The primary study outcome was safety (incidence of adverse and serious adverse events) in all vaccinated participants, but we also assessed efficacy in a protocol-defined group of participants who received at least one dose of allocated vaccine. The primary efficacy endpoint was incident tuberculosis incorporating microbiological, radiological, and clinical criteria, and the secondary efficacy endpoint was M tuberculosis infection according to QuantiFERON TB Gold In-tube conversion (Cellestis, Australia). This trial was registered with the South African National Clinical Trials Register (DOH-27-0109-2654) and with ClinicalTrials.gov on July 31, 2009, number NCT00953927 Between July 15, 2009, and May 4, 2011, we enrolled 2797 infants (1399 allocated MVA85A and 1398 allocated placebo). Median follow-up in the per-protocol population was 24·6 months (IQR 19·2–28·1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1251 [89%] of 1399 MVA85A recipients and 628 [45%] of 1396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1120 [80%] and 1059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1399 MVA85A recipients met the primary efficacy endpoint (tuberculosis incidence of 1·15 per 100 person-years [95% CI 0·79 to 1·62]; with conversion in 178 [13%] of 1398 infants [95% CI 11·0 to 14·6]) as did 39 (3%) of 1395 controls (1·39 per 100 person-years [1·00 to 1·91]; with conversion in 171 [12%] of 1394 infants [10·6 to 14·1]). Efficacy against tuberculosis was 17·3% (95% CI −31·9 to 48·2) and against M tuberculosis infection was −3·8% (–28·1 to 15·9). MVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration. Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC).

•Construction, characterization and preclinical studies of MTBVAC, an attenuated Mycobacterium tuberculosis.•MTBVAC vaccine candidate is genetically engineered to fulfil the Geneva consensus (Vaccine Kamath et al., 2005).•MTBVAC is the first live attenuated M. tuberculosis vaccine to enter clinical evaluation.•MTBVAC Clinical trials started in January 2013 (Swissmedic reference MTBVAC 2012GT1002). The development of a new tuberculosis vaccine is an urgent need due to the failure of the current vaccine, BCG, to protect against the respiratory form of the disease. MTBVAC is an attenuated Mycobacterium tuberculosis vaccine candidate genetically engineered to fulfil the Geneva consensus requirements to enter human clinical trials. We selected a M. tuberculosis clinical isolate to generate two independent deletions without antibiotic-resistance markers in the genes phoP, coding for a transcription factor key for the regulation of M. tuberculosis virulence, and fadD26, essential for the synthesis of the complex lipids phthiocerol dimycocerosates (DIM), one of the major mycobacterial virulence factors. The resultant strain MTBVAC exhibits safety and biodistribution profiles similar to BCG and confers superior protection in preclinical studies. These features have enabled MTBVAC to be the first live attenuated M. tuberculosis vaccine to enter clinical evaluation.

Tuberculosis (TB) vaccine research has reached a unique point in time. Breakthrough findings in both the basic immunology of Mycobacterium tuberculosis infection and the clinical development of TB vaccines suggest, for the first time since the discovery of the Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine more than a century ago, that a novel, efficacious TB vaccine is imminent. Here, we review recent data in the light of our current understanding of the immunology of TB infection and discuss the identification of biomarkers for vaccine efficacy and the next steps in the quest for an efficacious vaccine that can control the global TB epidemic.Vaccine trials against Mycobacterium tuberculosis (Mtb) are showing encouraging results. This Review discusses current Mtb vaccine design in the light of new insights into the immunology of tuberculosis infection.

Tuberculosis represents the leading global cause of death from an infectious agent. Controlling the tuberculosis epidemic thus represents an urgent global public health priority. Epidemiological modelling suggests that, although drug treatments for tuberculosis continue to improve, WHO timelines to control the spread of the disease require a new vaccine capable of preventing tuberculosis, particularly in adolescents and adults. The spread of strains resistant to multiple drugs adds additional urgency to the vaccine development effort yet attempts to develop new vaccines with wider applicability and better, longer-lasting efficacy than BCG—the only tuberculosis vaccine licensed for use globally—have proven challenging. Results from clinical efficacy trials, particularly a completed, phase 2b trial for preventing tuberculosis disease in people infected with Mycobacterium tuberculosis using the adjuvanted protein subunit vaccine M72/AS01E give hope. We review the current status of tuberculosis vaccine candidates and outline the diversified vaccine development that are underway.

Vaccines to protect against tuberculosis (TB) are urgently needed. We performed a case–control analysis to identify immune correlates of TB disease risk in Bacille Calmette–Guerin (BCG) immunized infants from the MVA85A efficacy trial. Among 53 TB case infants and 205 matched controls, the frequency of activated HLA-DR + CD4 + T cells associates with increased TB disease risk (OR=1.828, 95% CI=1.25–2.68, P =0.002, FDR=0.04, conditional logistic regression). In an independent study of Mycobacterium tuberculosis -infected adolescents, activated HLA-DR + CD4 + T cells also associate with increased TB disease risk (OR=1.387, 95% CI=1.068–1.801, P =0.014, conditional logistic regression). In infants, BCG-specific T cells secreting IFN-γ associate with reduced risk of TB (OR=0.502, 95% CI=0.29–0.86, P =0.013, FDR=0.14). The causes and impact of T-cell activation on disease risk should be considered when designing and testing TB vaccine candidates for these populations. BCG vaccine confers only partial protection against tuberculosis. Here the authors show that the risk of tuberculosis infection and progression to disease in BCG-immunized children positively correlates with the frequency of activated HLA-DR + CD4 + T cells.

This phase I trial evaluated the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost, previously demonstrated to be protective in animal studies, in healthy UK adults. We enrolled 42 healthy, BCG-vaccinated adults into 4 groups: low dose Starter Group (n = 6; ChAdOx1 85A alone), high dose groups; Group A (n = 12; ChAdOx1 85A), Group B (n = 12; ChAdOx1 85A prime – MVA85A boost) or Group C (n = 12; ChAdOx1 85A – ChAdOx1 85A prime – MVA85A boost). Safety was determined by collection of solicited and unsolicited vaccine-related adverse events (AEs). Immunogenicity was measured by antigen-specific ex-vivo IFN-γ ELISpot, IgG serum ELISA, and antigen-specific intracellular IFN-γ, TNF-α, IL-2 and IL-17. AEs were mostly mild/moderate, with no Serious Adverse Events. ChAdOx1 85A induced Ag85A-specific ELISpot and intracellular cytokine CD4+ and CD8+ T cell responses, which were not boosted by a second dose, but were boosted with MVA85A. Polyfunctional CD4+ T cells (IFN-γ, TNF-α and IL-2) and IFN-γ+, TNF-α+ CD8+ T cells were induced by ChAdOx1 85A and boosted by MVA85A. ChAdOx1 85A induced serum Ag85A IgG responses which were boosted by MVA85A. A ChAdOx1 85A prime – MVA85A boost is well tolerated and immunogenic in healthy UK adults.