Development of tuberculosis vaccines in clinical trials: Current status

Tuberculosis (TB ) is an important infectious disease worldwide. Currently, Bacillus Calmette‐Guérin (BCG ) remains the only TB vaccine licensed for human use. This TB vaccine is effective in protecting children against severe military TB but offers variable protective efficacy in adults. Therefore, new vaccines against TB are needed to overcome this serious disease. At present, around 14 TB vaccine candidates are in different phases of clinical trials. These TB vaccines in clinical evaluation can be classified into two groups including preventive pre‐ and post‐exposure vaccines: subunit vaccines (attenuated viral vectors or adjuvanted fusion proteins), and whole‐cell vaccines (genetically attenuated Mycobacterium tuberculosis (M. tb ), recombinant BCG , killed M. tb or M. vaccae ). Although, over the last two decades a great progress in the search for a more effective TB vaccine has been demonstrated there is still no replacement for the licensed BCG vaccine. This article summarizes the current status of TB vaccine development and identifies crucial gaps of research for the development of an effective TB vaccine in all age groups.     

Global Efforts in the Development of Vaccines for Tuberculosis: Requirements for Improved Vaccines Against Mycobacterium tuberculosis

Currently, more than 9.0 million people develop acute pulmonary tuberculosis (TB) each year and about 1.5 million people worldwide die from this infection. Thus, developing vaccines to prevent active TB disease remains a priority. This article discusses recent progress in the development of new vaccines against TB and focusses on the main requirements for development of improved vaccines against Mycobacterium tuberculosis (M. tb). Over the last two decades, significant progress has been made in TB vaccine development, and some TB vaccine candidates have currently completed a phase III clinical trial. The potential public health benefits of these vaccines are possible, but it will need much more effort, including new global governance investment on this research. This investment would certainly be less than the annual global financial toll of TB treatment.     

Current challenges and opportunities for bacillus Calmette‐Guérin replacement vaccine candidates

Bacillus Calmette‐Guérin (BCG) remains the only licensed vaccine against human tuberculosis (TB). BCG is a live‐attenuated strain of Mycobacterium bovis, with limitations in efficacy against respiratory TB, the most common form of the disease responsible for transmission. However, continues to be used in the immunization programmes of different countries in the absence of another alternative. In order to improve BCG efficacy against pulmonary TB, in the current clinical TB vaccine pipeline, there are live‐attenuated TB vaccines to replace BCG. This review discusses the current status of the development of live vaccine candidates designed to replace BCG from the rational strategies and immunological challenges to its clinical trial and identify key areas in the next years considered essential to confer improved safety and efficacy over BCG.     

Recent advances in the development of adenovirus- and poxvirus-vectored tuberculosis vaccines

Tuberculosis vaccine research began with the search for a vaccine that might be better than, and thus could replace, the current Bacillus Calmette Guérin (BCG) vaccine. Over the last fifteen years or so, intense research effort has led to the identification of a number of novel tuberculosis (TB) vaccines which can be divided into 4 categories: genetically modified mycobacteria, protein, plasmid DNA and viral. However, it is increasingly believed that the current BCG vaccine will continue to be used as a childhood vaccine and that more effort should be directed to developing appropriate boosting vaccines. Mounting evidence suggests that recombinant genetic vaccines, particularly recombinant viral vaccines, are effective in boosting immune activation and protection by BCG vaccination. Since modified vaccinia virus Ankara (MVA)- and adenovirus-vectored TB vaccines have been most extensively studied, this review will focus on recent advances in the development and applications of these two viral TB vaccines.     

结核分支杆菌重组BCG疫苗研究进展

结核分支杆菌引起的结核病是一种人兽共患的慢性传染病,短程督导化疗是治疗该病的主要措施,卡介苗是预防该病的唯一疫苗,但其免疫效果极不稳定.文章介绍了7种结核分支杆菌重组BCG疫苗构建及其免疫机制等方面的研究进展.     

Mycobacterium-specific human CD8 T cell responses.

Tuberculosis (TB) remains a global health problem. There is an intense effort to identify correlates of protective immunity and to design new TB vaccines. CD8 T cells are thought to play a significant role in controlling Mycobacterium tuberculosis infection. Relatively little has been published about the antigens and epitopes targeted by mycobacteria-specific CD8 T cells. Here we present an update of our 1999 overview of human CD8 T cell epitopes in mycobacterial antigens and discuss related issues relevant to TB diagnosis and vaccine development.     

Using a prime and pull approach,lentivector vaccines expressing Ag85A induce immunogenicity but fail to induce protection against Mycobacterium bovis bacillus Calmette–Guérin challenge in mice

Although bacillus Calmette–Guérin (BCG) is an established vaccine with excellent efficacy against disseminated Mycobacterium tuberculosis infection in young children, efficacy in adults suffering from respiratory tuberculosis (TB) is suboptimal. Prime‐boost viral vectored vaccines have been shown to induce effective immune responses and lentivectors (LV) have been shown to improve mucosal immunity in the lung. A mucosal boost to induce local immunogenicity is also referred to as a ‘pull’ in a prime and pull approach, which has been found to be a promising vaccine strategy. The majority of infants worldwide receive BCG immunization through current vaccine protocols. We therefore aimed to investigate the role of a boost (or pull) immunization with an LV vaccine expressing the promising TB antigen (Ag85A). We immunized BALB/c mice subcutaneously with BCG or an LV vaccine expressing a nuclear factor‐κB activator vFLIP together with Ag85A (LV vF/85A), then boosted with intranasal LV vF/85A. Prime and pull immunization with LV85A induced significantly enhanced CD8⁺ and CD4⁺ T‐cell responses in the lung, but did not protect against intranasal BCG challenge. In contrast, little T‐cell response in the lung was seen when the prime vaccine was BCG, and intranasal vF/85A provided no additional protection against mucosal BCG infection. Our study demonstrates that not all LV prime and pull approaches may be successful against TB in man and careful antigen and immune activator selection is therefore required.     

Novel Recombinant BCG Coexpressing Ag85B, ESAT-6 and Rv2608 Elicits Significantly Enhanced Cellular Immune and Antibody Responses in C57BL/6 Mice

Tuberculosis (TB) remains an enormous global health problem, and a new vaccine against TB more potent than the current inadequate vaccine, the Bacille Calmette‐Guérin (BCG), is urgently needed. BCG has proven to be an effective recombinant delivery vehicle for foreign antigens because of its ability to induce long‐lived specific humoral and cellular immunity. Experimental evidences have revealed that Ag85B, ESAT‐6 and Rv2608 are important immunodominant antigens of Mycobacterium tuberculosis and are all promising vaccine candidate molecules. In this study, we have constructed a novel recombinant BCG (rBCG) expressing fusion protein Ag85B‐ESAT6‐Rv2608 and evaluated the immunogenicity of rBCG in C57BL/6 mice. Results show there is strong TB‐specific CD4⁺ and CD8⁺ T lymphocytes proliferative response in mice immunized with rBCG vaccine, especially the cytotoxic CD8⁺ T cells playing an important role in protection against TB. And rBCG immunization has induced a significantly strong Th1 immune response, characterized by the increased ratio of IgG2b/IgG1. Results also show that rBCG immunization could increase the secretion of Th1 cytokines such as TNF‐α and IL‐2 and could decrease the secretion of Th2 cytokine IL‐10. Moreover, it was shown that rBCG immunization induced a strong humoral response in mice, characterized by the elevated IgG titre. Therefore, we conclude that this rBCG immunization could increase both cellular immune response and antigen‐specific humoral response significantly as compared to BCG immunization in mice. The above results illustrated that rBCG::Ag85B‐ESAT6‐Rv2608 is a potential candidate against M. tuberculosis for further study.     

A review of the literature on the economics of vaccination against TB

The BCG vaccine was introduced in 1921 and remains the only licensed vaccine for the prevention of TB worldwide. Despite its extensive use, the BCG vaccine lacks the ability to fully control the TB-endemic and -pandemic situations. The BCG vaccine is most effective in preventing pediatric TB, in particular, miliary TB and tuberculous meningitis. However, it has a limited effect in preventing pulmonary TB, which occurs more frequently in adults. BCG vaccination has now been implemented in more than 157 countries worldwide. For various countries, the benefits of vaccination are only limited and potentially not cost effective. The International Union Against Tuberculosis and Lung Diseases had set the criteria for discontinuation of BCG vaccination in 1994. This decision, however, was not based on economic considerations. Many developed countries have met the criteria set by the International Union Against Tuberculosis and Lung Disease and stopped universal BCG vaccination. For developing countries, the BCG vaccine is still an effective intervention in protecting young children from TB infection. A lot of effort has been spent on R&D of new TB vaccines, the first of which are expected to be available within 5-7 years from now. Novel TB vaccines are expected to be better and more effective than the current BCG vaccine and should provide a viable strategy in controlling TB morbidity and mortality. In this review, the aim is to explore economic evaluations that have been carried out for vaccination against TB worldwide. In addition to epidemiological evidence, economic evidence can play a crucial role in supporting the governments of countries in making proper public health decisions on BCG vaccination policies, in particular, to implement, continue, or discontinue.     

Host Responses and Antigens Involved in Protective Immunity to Mycobacterium tuberculosis

Tuberculosis (TB) is the largest single infectious cause of human mortality. The incidence of TB has remained high in most of the developing world and the disease has recently re-emerged as a public health problem in industrialized countries. The development of a new improved TB vaccine is a highly prioritized international research area, which has been further stimulated by the appearance of multi-drug resistant strains of Mycobacterium tuberculosis . The present status of the attempts to characterize the protective immune response to TB will be reviewed with special emphasis on recent progress in the identification and characterization of target molecules recognized by protective cells. This paper will focus on proteins released from live bacteria and discuss their role in the host–pathogen interaction and the ongoing attempts to use these molecules in TB subunit vaccines.     

Tuberculosis 2012: biology,pathogenesis and intervention strategies; an update from the city of light

Tuberculosis (TB) remains one of the world's most deadly infectious diseases, with approximately 1.5 million deaths and 9 million new cases of TB in 2010. There is an urgent global need to develop new control tools, with advances necessary in our basic understanding of the pathogen, Mycobacterium tuberculosis, and translation of these findings to public health. It was in this context that the “Tuberculosis 2012: Biology, Pathogenesis, Intervention Strategies” meeting was held in the Institut Pasteur, Paris, France from 11 to 15th Sept 2012. The meeting brought together over 600 delegates from across the globe to hear updates on the latest research findings and how they are underpinning the development of novel vaccines, diagnostics, and drugs.     

Pattern and diversity of cytokine production differentiates between Mycobacterium tuberculosis infection and disease

Tuberculosis (TB) remains a global health problem. The solution involves development of an effective vaccine, but has been limited by incomplete understanding of what constitutes protective immunity during natural infection with Mycobacterium tuberculosis. In this study, M. tuberculosis‐specific responses following an overnight whole‐blood assay were assessed by intracellular cytokine staining and luminex, and compared between TB cases and exposed household contacts. TB cases had significantly higher levels of IFN‐γ⁺TNF‐α⁺IL‐2⁺CD4⁺T cells compared with contacts. TB cases also had a significantly higher proportion of cells single‐positive for TNF‐α, but lower proportion of cells producing IL‐2 alone and these differences were seen for both CD4⁺and CD8⁺ T cells. Cytokine profiles from culture supernatants were significantly biased toward a Th1 phenotype (IFN‐γ and IL‐12(p40)) together with a complete abrogation of IL‐17 secretion in TB cases. Our data indicate that despite a robust response to TB antigens in active TB disease, changes in the pattern of cytokine production between TB infection and disease clearly contribute to disease progression.     

Overcoming the global crisis: “Yes,we can”, but also for TB … ?

Tuberculosis (TB) poses formidable challenges to global health at the public health‐, scientific‐ and political level. Causing almost two million deaths every year, this ancient disease represents a continuing global crisis. The writing on the wall is that TB is resurging in more virulent and treatment‐resistant forms. Our tools to combat TB are dangerously out of date and ineffective. Besides new tools (TB drugs, vaccines, diagnostics), we also need new strategies to identify key Mycobacterium tuberculosis/human host interactions, since it is here that we can most likely find Mtb's Achilles' heel. Equally important is that we build high‐quality clinical trial capacity and biobanks for TB biomarker identification. But most important is a global commitment at all levels to roll back TB before it outwits us again.     

Heterologous boost vaccines for bacillus Calmette-Guérin prime immunization against tuberculosis

The current tuberculosis (TB) epidemic continues to call for the development of effective vaccination strategies. The initial TB vaccine research effort mostly focused on the search for a vaccine that might be better than, and thus could replace, the current bacillus Calmette-Guérin (BCG) vaccine. It has increasingly been realized that BCG or an improved BCG will continue to be used as a prime TB vaccine and there is a need to develop effective boost vaccines that could enhance and prolong the protective immunity of BCG prime immunization. Mounting experimental evidence suggests that recombinant vaccines, including both recombinant protein and genetic vector vaccines, are effective in boosting immune activation and protection by BCG vaccination. This review will discuss recent advances and the authors' views in the development of there boost vaccines.     

Prime–boost bacillus Calmette–Guérin vaccination with lentivirus‐vectored and DNA‐based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice

To prevent the global spread of tuberculosis (TB), more effective vaccines and vaccination strategies are urgently needed. As a result of the success of bacillus Calmette–Guérin (BCG) in protecting children against miliary and meningeal TB, the majority of individuals will have been vaccinated with BCG; hence, boosting BCG‐primed immunity will probably be a key component of future vaccine strategies. In this study, we compared the ability of DNA‐, protein‐ and lentiviral vector‐based vaccines that express the antigens Ag85B and Rv3425 to boost the effects of BCG in the context of immunity and protection against Mycobacterium tuberculosis in C57BL/6 mice. Our results demonstrated that prime–boost BCG vaccination with a lentiviral vector expressing the antigens Ag85B and Rv3425 significantly enhanced immune responses, including T helper type 1 and CD8⁺ cytotoxic T lymphocyte responses, compared with DNA‐ and protein‐based vaccines. However, lentivirus‐vectored and DNA‐based vaccines greatly improved the protective efficacy of BCG against M. tuberculosis, as indicated by a lack of weight loss and significantly reduced bacterial loads and histological damage in the lung. Our study suggests that the use of lentiviral or DNA vaccines containing the antigens Ag85B and Rv3425 to boost BCG is a good choice for the rational design of an efficient vaccination strategy against TB.     

Tuberculosis vaccines: Time to think about the next generation

Efforts over the last 2 decades have led to a rich research and development pipeline of tuberculosis (TB) vaccines. Although none of the candidates has successfully completed the clinical trial pipeline, many are under advanced clinical assessment. These vaccines aim at prevention of active TB, with most of them being considered for preexposure with recent additions for postexposure or multistage administration. A few therapeutic vaccines are under clinical assessment, as well. Preexposure vaccination with the licensed TB vaccine BCG prevents severe forms of TB in children but not in adolescents and adults. The current vaccine pipeline does not include strategies which prevent or eliminate infection with the causative agent Mycobacterium tuberculosis (Mtb). Rather in a best-case scenario, they are quantitatively superior to BCG in preventing active TB over prolonged periods of time, ideally lifelong in the face of latent Mtb infection. Qualitatively superior vaccines should be capable of preventing or eliminating Mtb infection, in this way eliminating the risk of TB reactivation. The time is now ripe to exploit radically new strategies to achieve this goal.     

Do new TB vaccines have a place in the Expanded Program on Immunization?

Several new TB vaccines are currently undergoing clinical trials. Among the most promising is a vaccine based upon the modified vaccinia virus Ankara-expressing mycobacterial antigen 85A (MVA85A). Given the widespread use of the current TB vaccine, BCG, many of the new TB vaccines are being tested for their ability to boost BCG-induced immunity. The introduction of a new TB vaccine into routine use would be facilitated by its coadministration with other vaccines as a part of the WHO's Expanded Program on Immunization (EPI). In the article under review the authors tested the immunogenicity of MVA85A given alone or in combination with EPI vaccines to infants in The Gambia. Antigen 85A-specific production of IFN-γ by peripheral blood cells was reduced significantly in infants coimmunized with EPI vaccines compared with infants who received the MVA85A vaccine alone. This study highlights a potentially important issue, which should be addressed prior to the introduction of new TB vaccines and, perhaps, other vaccines that require the induction of a so-called Type 1 T-cell-mediated immune response.     

Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

Most novel vaccines against infectious diseases are based on recombinant Ag; however, only few studies have compared Ag‐specific immune responses induced by natural infection with that induced by the same Ag in a recombinant form. Here, we studied the epitope recognition pattern of the tuberculosis vaccine Ag, TB10.4, in a recombinant form, or when expressed by the pathogen Mycobacterium tuberculosis (M.tb), or by the current anti‐tuberculosis vaccine, Mycobacterium bovis BCG. We showed that BCG and M.tb induced a similar CD4⁺ T‐cell specific TB10.4 epitope‐pattern, which differed completely from that induced by recombinant TB10.4. This difference was not due to post‐translational modifications of TB10.4 or because TB10.4 is secreted from BCG and M.tb as a complex with Rv0287. In addition, BCG and TB10.4/CAF01 were both taken up by DC and macrophages in vivo, and in vitro uptake experiments revealed that both TB10.4 and BCG were transported to Lamp⁺‐compartments. BCG and TB10.4 however, were directed to different types of Lamp⁺‐compartments in the same APC, which may lead to different epitope recognition patterns. In conclusion, we show that different vectors can induce completely different recognition of the same protein.     

Is intranasal vaccination a feasible solution for tuberculosis?

Bacille Calmette-Guerin (BCG) vaccine has been the only licensed tuberculosis (TB) vaccine administered to humans and, until today, more than 3 billion people have received BCG. However, despite the use of BCG, TB remains a global epidemic with a third of the world population being infected. Regardless of the protection induced by BCG in childhood TB, BCG vaccination fails to protect against pulmonary TB in adults, which represents more than 85% of the total TB burden. Therefore, the development of safe and efficacious TB vaccines that can confer potent protection in the lung mucosa has remained a major challenge to TB vaccinologists. Intranasal vaccination by different antigen formulations has shown promising results in the augmentation of immunity and the combat of the pathogens at the site of infection. This article will focus on the potential of intranasal vaccination and mucosal adjuvants for the development of new-generation TB vaccines.