New strategies against an old plague: genetically engineered tuberculosis vaccines (original) (raw)
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Genetic vaccination against tuberculosis
Springer Seminars in Immunopathology, 1997
New weapons are needed in the fight against tuberculosis. Recent research indicates that a vaccine better than BCG may be within reach. A diverse range of protein antigens can give encouragingly high levels of protective immunity in animal models when administered with adjuvants or as DNA vaccines. Accelerated arrest of bacterial multiplication followed by sustained decline in bacterial numbers are key parameters of protection and so the vaccine must target antigens produced by both actively multiplying and growth-inhibited bacteria. Consistent with this, the protective antigens have been found among secreted and stress proteins (e.g. Ag85, ESAT-6, hsp65, hsp70). Species-specific antigens are not needed, hence these remain available for diagnostic tests. Adoptive transfer of protection from vaccinated or infected mice into naive mice by transfer of purified T cells and clones shows that protection is expressed by antigen-specific cytotoxic T cells that produce interferon-3' and lyse infected macrophages. These cells are produced in response to endogenous antigen. DNA vaccination appears to be an excellent way of generating these cells and may be able to give long-lasting protection.
Towards a DNA vaccine against tuberculosis
Vaccine, 1994
Expression of the 9ene for a single mycobacterial antigen (Mycobacterium leprae hsp65) in adult Balb/c mice resulted in substantial cell-mediated protection against challenge with M. tuberculosis. CD4 and CD8 T cells cloned from spleens of such immunized mice passively transferred protection to non-immunized mice, and CD8 cells selectively lysed macrophages infected with M. tuberculosis. Three modes of expressing the gene have been tested." (1) expression,from a retroviral vector (pZIPNeoSV) in implanted J774 tumour cells, (2) expression from the same vector via bone marrow cells transfected in vitro and used to reconstitute irradiated mice, and (3) in a preliminary experiment, from CMV immediate-early and hydroxymethylglutaryl Co-A reductase promoters injected as plasmid DNA into muscle.
Vaccines Against Tuberculosis: Problems and Prospects (Review)
2020
Despite the efforts of the global medical and scientific community, tuberculosis remains the leading cause of death from infectious diseases. The expectation of success associated with the development of new anti-TB drugs was not justified, and the attention of researchers was largely drawn to the creation of new mycobacterial strains for vaccination against tuberculosis. The proposed review contains current information on the existing vaccine strains and the development of new, genetically engineered strains for the prevention of tuberculosis and the prevention and treatment of other diseases. The review includes relevant information on the correlation between BCG vaccination and the frequency and severity of COVID-19 infection.
Recent progress in bacterial vaccines: Tuberculosis
International Journal of Infectious Diseases, 1997
Bacille Calmette-GuBrin (BCG) is the most widely used vaccine worldwide. However, its efficacy varies from 80% to zero among studies. Meta-analysis of all the published prospective trials and case-control studies indicates approximately 50% efficacy against all forms of tuberculosis, but it is even more effective against the invasive forms of the disease, meningitis and miliaty tuberculosis. Geographic latitude accounts for 41% of the variance between studies. The variability between different BCG preparations and the role of environmental nontuberculous mycobacteria are discussed as major factors in the inconsistent results of BCG vaccine trials. New studies to define human genes that code for susceptibility to tuberculosis are reviewed. Despite the great strides being made in identifying vaccine candidates, there is still no reliable surrogate marker of protective immunity to tuberculosis. Human efficacy trials to document prevention of tuberculosis cannot possibly be mounted to test all the vaccine candidates that show promise in animal studies. Recent developments discussed include: the focus on secreted proteins of Mycobacterium tuberculosis as vaccine candidates, the genetic differences between BCG and virulent Mycobacterium bovis, the ability to create recombinant BCG-expressing cytokines that enhance the immune response and express vaccine candidate antigens, the availability of auxatrophic mutants of BCG as vaccine carriers, and the ongoing debate about other potential vaccine carriers, such as Salmonella, vaccinia (particularly modified vaccine Ankara [MVA]) and other avirulent pox viruses that do not replicate in humans.
Improving vaccines against tuberculosis
Immunology & Cell Biology, 2003
Tuberculosis remains a major cause of mortality and physical and economic deprivation worldwide. There have been significant recent advances in our understanding of the Mycobacterium tuberculosis genome, mycobacterial genetics and the host determinants of protective immunity. Nevertheless, the challenge is to harness this information to develop a more effective vaccine than BCG, the attenuated strain of Mycobacterium bovis derived by Calmette and Guérin nearly 90 years ago. Some of the limitations of BCG include the waning of the protective immunity with time, reduced effectiveness against pulmonary tuberculosis compared to disseminated disease, and the problems of a live vaccine in immuno-compromised subjects. Two broad approaches to vaccine development are being pursued. New live vaccines include either attenuated strains of Mycobacterium tuberculosis produced by random mutagenesis or targeted deletion of putative virulence factors, or by genetic manipulation of BCG to express new antigens or cytokines. The second approach utilizes non-viable subunit vaccines to deliver immunodominant mycobacterial antigens. Both protein and DNA vaccines induce partial protection against experimental tuberculosis infection in mice, however, their efficacy has generally been equivalent to or less than that of BCG. The comparative effects of cytokine adjuvants and vaccines targeting antigen presenting cells on enhancing protection will be discussed. Coimmunization with plasmid interleukin-12 and a DNA vaccine expressing Antigen 85B, a major secreted protein, was as protective as BCG. The combination of priming with DNA-85B and boosting with BCG was superior to BCG alone. Therefore it is possible to achieve a greater level of protection against tuberculosis than with BCG, and this highlights the potential for new tuberculosis vaccines in humans.
Mycobacterial Diseases, 2013
Tuberculosis is a significant threat to human health, infecting nearly one third of the world’s population and causing over a million deaths per year. The need for an effective vaccine against tuberculosis is apparent however, the current vaccine has not been successful neither in the prevention nor recovery from infection. The pathogenesis of the causative agent, Mycobacterium tuberculosis has been extensively studied. The mechanisms of immune evasion and modulation that enable persistence of infection through subclinical latency and eventually active tuberculosis have been partially described. Many of these mechanisms are directly antagonistic to the intended benefit of vaccines, leaving a conundrum that has yet to be resolved. This review will first examine the nature of tuberculosis pathogenesis in the context of the immune response and outline the varied processes utilized by the bacterium to cause modulation. The review will also investigate other vaccination options that may overwhelm these microbial mechanisms or avert them entirely, allowing for the engagement of the immune response and clearance of the bacterium.
The Journal of Infectious Diseases, 2004
Mycobacterium microti, the vole bacillus, which was used as a live vaccine against tuberculosis until the 1970s, confers the same protection in humans as does Mycobacterium bovis bacille Calmette-Guérin (BCG). However, because the efficacy of the BCG vaccine varies considerably, we have tried to develop a better vaccine by reintroducing into M. microti the complete region of difference 1 (RD1), which is required for secretion of the potent T cell antigens early secreted antigen target (ESAT)-6 and culture filtrate protein (CFP)-10. The resultant recombinant strain, M. microti OV254::RD1-2F9, induced specific ESAT-6 and CFP-10 immune responses in mice with CD8 + T lymphocytes that had strong expression of the CD44 hi activation marker. This vaccine also displayed better efficacy against disseminated disease in the mouse and the guinea pig models of tuberculosis than was seen in animals vaccinated with M. microti alone or with BCG. The M. microti OV254: :RD1-2F9 vaccine was less virulent and persistent in mice and than was BCG::RD1-2F9 may represent a safer alternative to BCG::RD1-2F9. Mycobacterium tuberculosis is now considered to be responsible for more adult deaths than any other pathogen. Better measures to prevent tuberculosis are urgently needed. Even if antibiotic treatments are very efficient, long-term administration is required, and drug resistance can arise when drugs are not taken appropriately. Two live attenuated vaccines confer some protection against tuberculosis: Mycobacterium bovis bacille Calmette-Guérin (BCG) and Mycobacterium microti. The
Vaccine, 2015
On July 9, 2014, Aeras and the Max Planck Institute for Infection Biology convened a workshop entitled "Whole Mycobacteria Cell Vaccines for Tuberculosis" at the Max Planck Institute for Infection Biology on the grounds of the Charité Hospital in Berlin, Germany, close to the laboratory where, in 1882, Robert Koch first identified Mycobacterium tuberculosis (Mtb) as the pathogen responsible for tuberculosis (TB). The purpose of the meeting was to discuss progress in the development of TB vaccines based on whole mycobacteria cells. Live whole cell TB vaccines discussed at this meeting were derived from Mtb itself, from Bacille Calmette-Guérin (BCG), the only licensed vaccine against TB, which was genetically modified to reduce pathogenicity and increase immunogenicity, or from commensal non-tuberculous mycobacteria. Inactivated whole cell TB and non-tuberculous mycobacterial vaccines, intended as immunotherapy or as safer immunization alternatives for HIV+ individuals, also were discussed. Workshop participants agreed that TB vaccine development is significantly hampered by imperfect animal models, unknown immune correlates of protection and the absence of a human challenge model. Although a more effective TB vaccine is needed to replace or enhance the limited effectiveness of BCG in all age groups, members of the workshop concurred that an effective vaccine would have the greatest impact on TB control when administered to adolescents and adults, and that use of whole mycobacteria cells as TB vaccine candidates merits greater support, particularly given the limited understanding of the specific Mtb antigens necessary to generate an immune response capable of preventing Mtb infection and/or disease.