Genetic vaccination against tuberculosis (original) (raw)
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The study of novel DNA vaccines against tuberculosis
Human Vaccines & Immunotherapeutics, 2013
Results: Hsp65 + IL-12 DNa vaccine showed higher protective efficacy compared with BcG in both mouse and monkey models of TB. It induced the TB-specific cTL in the mouse model of TB, while little level of activity was observed after the injection of BcG. It also showed strong therapeutic efficacy against MDR-TB. In the monkey model, the vaccine augmented the production of IFN-γ and IL-2 from pBL and the therapeutic effect was correlated with the level of IL-2. We next evaluated the potential of DNa vaccine encoding a granulysin, which is an important defensive molecule expressed by human T cells. We found that granulysin-encoding vaccine induced the differentiation of the cTL in vitro and in vivo. It also showed therapeutic efficacy against TB in the monkey as well as the mouse model. The DNa vaccine encoding a Ksp37 also induced the TB-specific cTL in vitro and in vivo in the mouse model. It augmented the production of IL-2, IFN-γ and IL-6 from T cells and spleen cells. a synergistic effect on the activation of the TB-specific cTL was observed by the combination of Ksp37 DNa vaccine with granulysin DNa vaccine. purpose and Methods: emergence of the multi-drug resistant (MDR) Mycobacterium tuberculosis (TB) is a big problem in the world. We have developed novel TB vaccines [DNa vaccines encoding Hsp65 + IL-12, granulysin or killerspecific secretory protein of 37kDa (Ksp37)] using Hemagglutinating virus of Japan-envelope (HVJ-e). It is suggested that the activity of the TB-specific cTL is one of the most important factor for the resistance to TB and immunity for TB in chronic human TB disease. Therefore, we examined the level of activation of the TB-specific cTL after the administration of these vaccines. conclusion: These data indicate that our novel vaccines (Hsp65 + IL-12 DNa, granulysin and Ksp37) have a capability to activate the TB-specific cTL and will be very strong protective and therapeutic vaccines against TB.
Enhancement of immunocompetence in tuberculosis by DNA vaccination
Vaccine, 2000
Our studies in mice show that DNA vaccines, initially designed to prevent infection, can have a dramatic therapeutic action too. In heavily infected mice, simply by giving DNA vaccination, the immune response can be caused to switch from one that is relatively inecient and gives bacterial stasis to one that kills the bacteria, and persistent bacteria can be eliminated. Adoptive transfer of protection with T cell clones and in vitro tests of clone function indicate that the eects are probably mainly mediated by antigen speci®c CD8+/CD4À/CD44hi T cells that both produce gamma-interferon and kill the bacteria during granule-dependent lysis of infected macrophages. We can speculate that application of such immunotherapy in conjunction with conventional chemotherapeutic antibacterial drugs might result in faster or more certain cure of the disease in man. Furthermore, similar vaccines used prophylactically and therapeutically might be able to both prevent establishment of this persistent state and eliminate it if it is already established. #
Infection and Immunity, 1999
The development of more-effective antituberculosis vaccines would assist in the control of the global problem of infection with Mycobacterium tuberculosis. One recently devised vaccination strategy is immunization with DNA plasmids encoding individual microbial genes. Using the genes for the M. tuberculosis secreted proteins MPT64 (23 kDa), Ag85B (30 kDa), and ESAT-6 (6 kDa) as candidate antigens, DNA vaccines were prepared and tested for immunogenicity and protective efficacy in a murine model of aerosolized tuberculosis (TB). Intramuscular immunization with DNA-64 or DNA-85B resulted in the activation of CD4 ؉ T cells, which produce gamma interferon (IFN-␥), and high titers of specific immunoglobulin G antibodies. Further, DNA-64 induced major histocompatibility complex class I-restricted CD8 ؉ cytotoxic T cells. The addition of a eukaryotic leader sequence to mpt64 did not significantly increase the T-cell or antibody response. Each of the three DNA vectors stimulated a significant reduction in the level of M. tuberculosis infection in the lungs of mice challenged 4 weeks after immunization, but not to the levels resulting after immunization with Mycobacterium bovis BCG. The vaccines showed a consistent hierarchy of protection, with the most effective being Ag85B, followed by ESAT-6 and then MPT64. Coimmunization with the three vectors resulted in a greater degree of protection than that induced by any single vector. This protective efficacy was associated with the emergence of IFN-␥-secreting T cells earlier than in infected animals immunized with a control vector. The efficacy of these DNA vaccines suggests that multisubunit vaccination may contribute to future vaccine strategies against TB.
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.
DNA vaccines for therapy of tuberculosis: Where are we now?
Vaccine, 2006
DNA vaccines that were being investigated in mice for prophylactic use against tuberculosis were soon found also to be surprisingly effective as treatment against established infection. The immune system was stimulated to kill the bacteria, even including the persistent latent bacteria that are otherwise refractory to the immune system and antibacterial chemotherapeutic drugs alike. Subsequent results from a range of laboratories using diverse DNA vaccines in diverse murine models of infection have been very varied, ranging from enhanced pathology, through negligible effects, to major additive benefit from combined vaccine and chemotherapy. This review summarises the data and assesses future prospects.
Therapy of tuberculosis in mice by DNA vaccination
Nature, 1999
Mycobacterium tuberculosis continues to kill about 3 million people every year, more than any other single infectious agent. This is attributed primarily to an inadequate immune response towards infecting bacteria, which suffer growth inhibition rather than death and subsequently multiply catastrophically. Although the bacillus Calmette-Guerin (BCG) vaccine is widely used, it has major limitations as a preventative measure. In addition, effective treatment requires that patients take large doses of antibacterial drug combinations for at least 6 months after diagnosis, which is difficult to achieve in many parts of the world and is further restricted by the emergence of multidrug-resistant strains of M. tuberculosis. In these circumstances, immunotherapy to boost the efficiency of the immune system in infected patients could be a valuable adjunct to antibacterial chemotherapy. Here we show in mice that DNA vaccines, initially designed to prevent infection, can also have a pronounced ...
Genetic vaccines and therapy, 2007
Background: Vaccination of neonates is generally difficult due to the immaturity of the immune system and consequent higher susceptibility to tolerance induction. Genetic immunization has been described as an alternative to trigger a stronger immune response in neonates, including significant Th1 polarization. In this investigation we analysed the potential use of a genetic vaccine containing the heat shock protein (hsp65) from Mycobacterium leprae (pVAXhsp65) against tuberculosis (TB) in neonate mice. Aspects as antigen production, genomic integration and immunogenicity were evaluated.
Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis
Infection and immunity, 1998
The results of this study provide the first evidence that two completely separate vaccine approaches, one based on a subunit vaccine consisting of a mild adjuvant admixed with purified culture filtrate proteins and enhanced by the cytokine interleukin-2 and the second based on immunization with DNA encoding the Ag85A protein secreted by Mycobacterium tuberculosis, could both prevent the onset of caseating disease, which is the hallmark of the guinea pig aerogenic infection model. In both cases, however, the survival of vaccinated guinea pigs was shorter than that conferred by Mycobacterium bovis BCG, with observed mortality of these animals probably due to consolidation of lung tissues by lymphocytic granulomas. An additional characteristic of these approaches was that neither induced skin test reactivity to commercial tuberculin. These data thus provide optimism that development of nonliving vaccines which can generate long-lived immunity approaching that conferred by the BCG vacci...