Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

Abstract

Active disease of tuberculosis (TB) can be developed decades later by either a relapse of the initial infection (endogenous reactivation) or by an entrance of the secondary infection (exogenous reinfection), since the current chemotherapy cannot lead to complete elimination of tuberculosis. Although the immunotherapeutic approaches in conjunction with conventional chemotherapy were tried to prevent TB growth via boosting the immune system, their therapeutic effects are still controversial. Here, we found that TB DNA vaccination completely blocked tuberculosis reactivation and significantly prevented from the secondary infection when chemotherapy was combined simultaneously.In particular, double-gene DNA vaccine composed of Ag85A and PstS-3 genes could reduce bacteria growth better than single-gene DNA vaccine after a secondary reinfection, indicating a correlation between the breadth of Th1 IFN-g response and the efficacy of the protection from reinfection. Thus, we propose that multigene TB DNA immunotherapy including Ag85A and PstS-3 genes during the period of chemotherapy could benefit patients undergoing TB chemotherapy in prevention from exogenous reinfection as well as endogenous reactivation. Gene Therapy (2005) Tuberculosis (TB) holds the dubious honor of being the leading single-agent infectious disease killer in the world 1,2 and the situation is worsened by the increasing incidence of both multidrug resistant (MDR) stains and combination with AIDS. 1,3 After Mycobacterium tuberculosis infection, active disease arises in about 5% of exposed individuals and most of the others will develop a latent infection in which the tubercle bacilli can persist in vivo without causing any clinical symptoms. However, active disease may also develop decades later either as a relapse of the initial infection or because of a secondary infection. Although most cases of tuberculosis were once believed to result from a endogenous reactivation acquired in the past, 4 recent studies indicate that onethird of tuberculosis cases are due to recent transmission by exogenous reinfection of multiple M. tuberculosis strains, [5][6][7][8][9] implicating that the exogenous reinfection significantly contributes to disease transmission. Therefore, novel immunotherapeutic approaches will be required to prevent reinfection as well as reactivation of M. tuberculosis in individuals with latent tuberculosis.DNA vaccination has become a promising strategy for developing an effective vaccine against TB, since it efficiently induces Th1 immunity, an essential arm of immune system to clear the bacteria. In prophylactic settings, there are several reports that DNA vaccines expressing M. tuberculosis antigens are effective for limiting the bacterial growth in mice. 10-13 However, it is still controversial whether DNA vaccines work against TB reactivation in postexposure models. 14-16 For example, the vaccination of plasmid DNA expressing hsp65 after completion of chemotherapy was shown to be effective in preventing the reactivation of intravenou...

Mtb32 is a promising tuberculosis antigen for DNA vaccination in pre- and post-exposure mouse models

“…The immunotherapeutic effect of PstS3 is consistent with the previous reports. 15 In contrast, another group showed that PstS3 DNA vaccination reduced CFU from 8 to 12 weeks after infection. 8 This discrepancy may be attributed to varying experimental conditions, such as challenge route (intravenous vs aerosol), antigen engineering (PstS3 vs F-PstS3) and protocols.…”

“…We previously demonstrated that Ag85A and PstS3 DNA vaccinations completely block TB reactivation, and significantly prevent secondary infection when combined with chemotherapy. 15 In contrast, reduction of bacterial loads by MPT64 DNA vaccination was not significant compared with that in control mice. 16 As there are no general criteria for defining protective antigens from different vaccination protocols, a comparative study between TB antigens and M. tuberculosis exposure models under a single experimental condition is essential.…”

“…We have previously demonstrated the therapeutic and synergistic effects of Ag85A and PstS3 DNA vaccines during 12 weeks of chemotherapy on reactivation and reinfection of M. tuberculosis. 15 Accordingly, we investigated the immunogenicities and relative protective effects of seven TB DNA vaccines in a modified Cornell model, as described previously. 21 However, in this setting, the drug treatment period for bacterial clearance was shortened from 12 weeks to 6 weeks, compared to the previous study, as we previously found that there was no viable bacterium after 12 weeks of drug treatment, hence, it was not possible to compare the therapeutic effect of DNA vaccines.…”

Efficient tuberculosis treatment in mice using chemotherapy and immunotherapy with the combined DNA vaccine encoding Ag85B, MPT-64 and MPT-83

“…12 A double-gene DNA vaccine composed of Ag85A and PstS-3 genes could reduce bacterial growth better than the single-gene DNA vaccines during the period of chemotherapy after a secondary reinfection. 13 Therapeutic effects of Ag85B and MPT64 DNA vaccines indicated that Ag85B DNA vaccination had immunotherapeutic effects on TB in mice, whereas MPT64 DNA did not. 15 More importantly, it seems that the timing of DNA vaccination may be a major factor in determining the efficacy of the vaccine in a latent model because DNA vaccination against TB may minimize granuloma formation and/or necrosis induction when simultaneously combined with chemotherapy; DNA vaccine-induced Th1 and cytotoxic T-lymphocyte responses may act together with chemotherapy to eliminate M. tuberculosis.…”

“…Prophylactic DNA vaccines expressing various M. tuberculosis antigens, including Ag85A, Ag85B, MTP-64, ESAT-6, 65-kDa heat-shock protein and PstS-3, were found to be effective at limiting the growth of M. tuberculosis in heavily infected mice. [11][12][13][14] After the completion of chemotherapy in mice infected with M. tuberculosis intravenously, vaccination with plasmid DNA expressing 65-kDa heat-shock protein was effective in preventing reactivation. 14 Ag85A DNA vaccine, when simultaneously administered with chemotherapy, could effectively prevent reactivation of aerogenically transmitted M. tuberculosis.…”