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At least 19 recordsLinked to original sources
PubMed2005

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.

Adenoviridae↗
PubMed2000

Recent advances in improved tuberculosis vaccines.

Tuberculosis continues to be a major infectious cause of global morbidity and mortality, both in children and adults, in spite of widespread vaccination of infants with Bacille Calmette-Guerin (BCG) and the availability of effective antibiotics. The failure of BCG to significantly affect disease incidence in adults in many endemic countries, combined with the growing HIV epidemic and the appearance of multidrug resistant strains of Mycobacterium tuberculosis, threatens to overwhelm current tuberculosis control strategies. This unfortunate state of affairs has driven an intensive search for better tuberculosis vaccines. This article reviews the various vaccine development strategies which are being used e.g., purification or synthesis of protein peptide and non-peptide antigens from M. tuberculosis, creation of rationally-attenuated mutants of BCG and M. tuberculosis, development of DNA vaccines based upon the published genome sequence, the cloning of mycobacterial genes into living vaccine carrier strains (e.g., attenuated Salmonella, vaccinia virus, etc), or the use of naturally attenuated mycobacterial species (e.g., M. vaccae, M. microti). The animal models in which these vaccine candidates are being screened for protective efficacy (e.g., the mouse, guinea pig, rabbit, primate) will be discussed briefly. Finally, some of the challenges inherent in the eventual clinical evaluation of new tuberculosis vaccines are reviewed.

Adult↗
PubMed2001

Prospects for better tuberculosis vaccines.

Tuberculosis remains one of the top three infectious disease killers. Treatment is long and expensive and drug resistant strains of Mycobacterium tuberculosis are already on the rise. The current vaccine, BCG, is ineffective in parts of the world where the disease is most widespread and therefore the search for a novel, more effective vaccine is paramount. In this review we discuss the current state of vaccine research, including the identification of candidate antigens and the current methods used for their evaluation.

Animals↗
PubMed2001

The hunt for new tuberculosis vaccines: anti-TB immunity and rational design of vaccines.

Tuberculosis (TB) remains to be a leading infectious cause of death worldwide. Apparently, the current BCG vaccine that has been used for 80 years, has failed to control the TB epidemic. Hunting for improved TB vaccine formulations represents a daunting task to TB research community. Anti-TB host defense requires T cell-mediated immunity and we are in desperate need of enhanced understanding of how to develop a new generation of TB vaccines that are able to provoke potent and long-lasting protective cell-mediated immunity, different from almost all of the vaccines currently in use. It is of importance to successful TB vaccine development to identify the key cellular and molecular events governing the generation of anti-TB immunity, but unfortunately little has been understood as to why 90% of infected humans never develop active TB. However, waiting would not help us to win the battle and an ever-intensifying effort is being made to develop various new formulations according to the immunology that we have been learning, in large part, from experimental models. This review article attempts to unite the current understanding of anti-TB immunity with the rational design of anti-TB vaccines. It examines what may have confounded the immunogenicity of current BCG vaccine and the major obstacles to successful development of TB vaccines. It also discusses about antigen presentation, activation of Th1 and Tc1 cells, anti-TB immune effectors and the generation of memory T cells. The vaccine section describes four types of major TB vaccines under development: mycobacterial-, subunit-, plasmid DNA- and viral-based vaccines. A special section is dedicated to the rationale and current design of cytokine-based adjuvant formulations for TB vaccines. We also take this opportunity to introduce our recent development in cytokine transgene adjuvanted BCG vaccination and recombinant adenoviral-based TB vaccines.

Antigens, Bacterial↗
PubMed2001

Divergent effect of bacillus Calmette-Guérin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research.

Despite the widespread use of bacillus Calmette-Guérin vaccination, Mycobacterium tuberculosis infection remains globally the leading cause of death from a single infectious disease. The complicated and often protracted dynamics of infection and disease make clinical trials to test new tuberculosis vaccines extremely complex. Preclinical selection of only the most promising candidates is therefore essential. Because macaque monkeys develop a disease very similar to humans, they have potential to provide important information in addition to small animal models. To assess the relative merits of rhesus and cynomolgus monkeys as screens for tuberculosis vaccines, we compared the efficacy of bacillus Calmette-Guérin vaccination and the course of infection in both species. Unvaccinated rhesus and cynomolgus monkeys both developed progressive disease with high levels of C-reactive protein, M. tuberculosis-specific IgG, and extensive pathology including cavitation and caseous necrosis. Bacillus Calmette-Guérin vaccination protected cynomolgus almost completely toward the development of pathology, reflected in a striking 2-log reduction in viable bacteria in the lungs compared with nonvaccinated animals. Rhesus, on the other hand, were not protected efficiently by the bacillus Calmette-Guérin. The vaccinated animals developed substantial pathology and had negligible reductions of colony-forming units in the lungs. Comparative studies in these closely related species are likely to provide insight into mechanisms involved in protection against tuberculosis.

Animals↗
PubMed2003

How far have we reached in tuberculosis vaccine development?

Tuberculosis, a bacterial disease prevalent since ancient times, continues to cause the most deaths globally compared with all other diseases. The causative agent Mycobacterium tuberculosis is responsible for different types of tuberculosis in humans; however, pulmonary tuberculosis is the most common and causes the most deaths. Mycobacterium tuberculosis is an intracellular pathogenic bacterium, which has developed sophisticated mechanisms to survive inside host mononuclear phagocytes and thus evade the host immune system. This is attributed primarily to an inadequate immune response toward infecting bacteria, which results in temporary growth inhibition rather than death and subsequently allows the bacteria to multiply immensely, leading to full-blown disease in an individual. This disease has become a challenge due to poor diagnosis, a low-efficiency tuberculosis vaccine (Mycobacterium bovis Bacillus Calmette-Guerin [BCG]), a long-term antibacterial chemotherapy regimen (approximately 6 months), and an emergence of multiple drug resistant strains of Mycobacterium tuberculosis especially in people with human immune deficiency virus (HIV) infection, for whom researchers worldwide must develop effective short-term chemotherapy and an effective vaccine. In this review different aspects of vaccines in tuberculosis are discussed, and these include the traditional BCG vaccine, the modern auxotrophic vaccine, the subunit or acellular vaccine; and a DNA vaccine. We discuss also the potential of mycobacterial lipids as a vaccine or as an adjuvant in the future. Since complete genome information of Mycobacterium tuberculosis H37Rv and bioinformatics tools are available, it is possible to develop new strategies for a better and effective tuberculosis vaccine, which can replace the traditional BCG vaccine.

Animals↗
PubMed2000

Veterinary tuberculosis vaccine development.

Tuberculosis caused by Mycobacterium bovis in domestic livestock and wildlife is a significant problem in many countries worldwide. Wildlife reservoirs of tuberculosis confound programs for tuberculosis eradication from domestic livestock. Successful vaccination against tuberculosis in domestic animals or wildlife could contribute to tuberculosis eradication. Bacille Calmette-Guérin (BCG) has been used as the prototype vaccine for domestic livestock and wildlife. The majority of studies have been carried out with BCG-vaccinated animals challenged experimentally with M. bovis. Although protection against disease has been evident in all these studies, protection against infection has rarely occurred. Results obtained with BCG vaccination of cattle, deer, ferrets, opossums, and rabbits are presented here and highlight the need for appropriate animal models for vaccination and control of the variables that influence the efficacy of BCG vaccine. Refinement of the existing animal models is essential for the advancement of tuberculosis vaccine research of relevance to animals and humans.

Animals↗
PubMed2006

Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design.

Tuberculosis remains a substantial global health problem despite effective drug treatments. The efficacy of BCG, the only available vaccine, is variable, especially in tuberculosis-endemic regions. Recent advances in the development of new vaccines against tuberculosis mean that the first of these are now entering into early clinical trials. A recombinant modified vaccinia virus Ankara expressing a major secreted antigen from Mycobacterium tuberculosis, antigen 85A, was the first new tuberculosis vaccine to enter into clinical trials in September 2002. This vaccine is known as MVA85A. In a series of phase I clinical trials in the UK, MVA85A had an excellent safety profile and was highly immunogenic. MVA85A was subsequently evaluated in a series of phase I trials in The Gambia, a tuberculosis-endemic area in west Africa. This vaccine is the only new subunit tuberculosis vaccine to enter into clinical trials in Africa to date. Here, we discuss some of the issues that were considered in the protocol design of these studies including recruitment, inclusion and exclusion criteria, reimbursement of study participants, and HIV testing. These issues are highly relevant to early clinical trials with all new tuberculosis vaccines in the developing world.

Acyltransferases↗
PubMed2005

Current progress in tuberculosis vaccine development.

The tuberculosis vaccine field has blossomed in the past 10 years, with over a hundred new candidates going through animal model testing, and several now entering or approaching clinical trial evaluation. In this brief review the current animal screening models are discussed, as are the various types of new vaccines that have been developed. New approaches, especially in the area of BCG boosting in various prime/boost protocols, are starting to show considerable promise. More sophisticated readouts, including imaging approaches such as magnetic resonance imaging, and better definition of the immunopathology of the lung disease process, should help accelerate vaccine development even further in the next decade.

Animals↗
PubMed2006

Advances in tuberculosis vaccine strategies.

Tuberculosis (TB), an ancient human scourge, is a growing health problem in the developing world. Approximately two million deaths each year are caused by TB, which is the leading cause of death in HIV-infected individuals. Clearly, an improved TB vaccine is desperately needed. Heterologous prime-boost regimens probably represent the best hope for an improved vaccine regimen to prevent TB. This first generation of new vaccines might also complement drug treatment regimens and be effective against reactivation of TB from the latent state, which would significantly enhance their usefulness.

BCG Vaccine↗
PubMed2006

Tuberculosis vaccines: past, present and future.

PURPOSE OF REVIEW: The current vaccine against tuberculosis protects against severe forms of the disease in children but confers variable effectiveness against pulmonary disease. With tuberculosis eradication on the horizon new vaccines with better protection than Mycobacterium bovis bacillus Calmette-Guérin (BCG) are needed. This review will outline the most promising tuberculosis vaccine candidates from selected publications. RECENT FINDINGS: The enormous effort of the scientific community in the last 10 years has generated hundreds of tuberculosis vaccine candidates. These include sub-unit vaccines and live vaccines such as recombinant BCG and other attenuated live vaccines. Some of these are being included for the first time in phase I clinical trials. SUMMARY: For more than 80 years now no new tuberculosis vaccine has successfully been developed. There is now renewed optimism that vaccines superior to BCG can be developed in the coming years. The goal is to obtain a new generation of vaccines effective against more transmissible forms of tuberculosis. As a first step, good candidate vaccines able to boost BCG and improve BCG protection could be a reality in the near future. Tuberculosis vaccine candidates, able to replace the currently used BCG and make the eradication of tuberculosis feasible, can be expected in the mid-term, and live vaccines are reliable and promising candidates.

Animals↗
PubMed2002

New tuberculosis vaccine development.

Tuberculosis (TB) is a devastating disease that kills more than three million people each year. Of these, 0.9 million are co-infected with HIV and numbers of infections and death continue to rise with the global spread of HIV. A new vaccine is desperately needed to control this epidemic that threatens to kill 90 million people over the next 3 decades. Outstanding work in research laboratories, combined with the success of genome sequencing, has resulted in a variety of candidate TB vaccines, many of which are sufficiently promising to advance into clinical trials. This review discusses the array of new candidate TB vaccines and the clinical studies that are currently planned.

Animals↗
PubMed1989

Leprosy and tuberculosis vaccine design.

Tuberculosis and leprosy are bacillary infectious diseases which cause severe global health problems with approximately 50 to 60 million people suffering from tuberculosis and 10 to 15 million from leprosy. In the developing countries the currently available vaccine, Bacille Calmette-Guérin (BCG) was found to be less effective than originally thought. This disappointment, as well as recent achievements in biotechnology, has led several researchers to embark on novel avenues towards a rational vaccine design. This strategy stems from the idea that protective antigens exist which can be identified by immunological methods, expressed as recombinant gene products, and administered in a way that induces a protective T cell response.

Antigens, Bacterial↗
PubMed2006

Progress in tuberculosis vaccine development.

The first tuberculosis vaccine candidates have reached clinical testing. Novel subunit vaccine candidates aimed at boosting previous BCG-prime vaccination and novel viable attenuated vaccine candidates aimed at substituting BCG have both completed the preclinical stage. Despite these achievements, rational vaccine design against tuberculosis has not come to an end. Novel findings in basic immunology and microbiology will advance further improvements in vaccine development. These include the potential role of crosspriming to induce more potent T-cell responses, the role of memory T cells and regulatory T cells in sustaining or curtailing optimal immune responses, respectively, as well as the involvement of cytokines in T-cell migration to nonimmunologic tissue sites and in the generation of memory. Knowledge about basic mechanisms underlying optimum protection will not only have a direct impact on future vaccine design against tuberculosis but also help in the formulation of a set of biomarkers with predictive value for vaccine efficacy assessment.

Humans↗
PubMed2007

A tuberculosis vaccine based on phosphoantigens and fusion proteins induces distinct gammadelta and alphabeta T cell responses in primates.

Phosphoantigens are mycobacterial non-peptide antigens that might enhance the immunogenicity of current subunit candidate vaccines for tuberculosis. However, their testing requires monkeys, the only animal models suitable for gammadelta T cell responses to mycobacteria. Thus here, the immunogenicity of 6-kDa early secretory antigenic target-mycolyl transferase complex antigen 85B (ESAT-6-Ag85B) (H-1 hybrid) fusion protein associated or not to a synthetic phosphoantigen was compared by a prime-boost regimen of two groups of eight cynomolgus. Although phosphoantigen activated immediately a strong release of systemic Th1 cytokines (IL-2, IL-6, IFN-gamma, TNF-alpha), it further anergized blood gammadelta T lymphocytes selectively. By contrast, the hybrid H-1 induced only memory alphabeta T cell responses, regardless of phosphoantigen. These latter essentially comprised cytotoxic T lymphocytes specific for Ag85B (on average + 430 cells/million PBMC) and few IFN-gamma-secreting cells (+ 40 cells/million PBMC, equally specific for ESAT-6 and for Ag85B). Hence, in macaques, a prime-boost with the H-1/phosphoantigen subunit combination induces two waves of immune responses, successively by gammadelta T and alphabeta T lymphocytes.

Animals↗