ReviewDNA vaccines for therapy of tuberculosis: Where are we now?
Introduction
Tuberculosis is a disease that is driven by the acquired immune response to the tubercle bacillus Mycobacterium tuberculosis. From the very earliest days, soon after the discovery of the bacterium by Robert Koch, it has been apparent that if one attempts to achieve cure by stimulating acquired immunity the disease can be made worse. Scientific investigations have not yet been able to separate the effector components of protective immunity from the effector components of pathology, let alone define the regulatory pathways that determine the balance between the two. Therefore, it should come as no surprise that attempts to devise practical immunotherapeutic interventions to add on to conventional chemotherapy sometimes find ways of exacerbating disease. The issue is not that it happens, or that it is not always predictable from our limited knowledge, but that it is variable under seemingly controlled conditions in laboratory mice. This is hindering progress.
However, we should not be discouraged. On the positive side, it has now been established in a number of independent studies that remarkable therapeutic benefit can indeed be obtained by immune stimulation, even in heavily infected mice. Hitherto, it had been far from clear that protection and pathology could in fact be separated. Much of this advance has come from studies of DNA vaccines.
It is 10 years since the first DNA vaccine against tuberculosis grew serendipitously out of studies directed towards understanding the basic immunobiology of a dominant mycobacterial antigen, heat shock protein 65 (hsp65) [1]. Since then DNA vaccines expressing a range of antigens, singly and in combination, have been found to protect against subsequent challenge with virulent M. tuberculosis in a range of animals, although protection is not always strong with these prototype vaccines and heterologous prime/boost strategies with BCG vaccine are currently the preferred way forward [2], [3], [4], [5], [6]. Refinement is likely to be required before adequate efficacy is attained in humans [7].
Section snippets
A bright start
Tests of prophylaxis led rapidly into tests of therapy. Comparisons between the immune response to prophylactic hsp65 DNA vaccination and the immune response to tuberculosis in mice indicated that DNA vaccination was better at generating protective T cells than was the infection [8], [9]. This raised speculation that the same vaccine, when delivered to infected mice, might enhance production of these protective cells and improve the ongoing immune response therapeutically. The benefits far
A setback
Subsequent results from a range of laboratories using diverse DNA vaccines in diverse models of infection have been very varied (Table 1). For example, I.M. Orme's laboratory in Fort Collins, CO, USA, initially tested 2 doses of DNA expressing another dominant antigen, antigen 85A, by giving it to mice in the plateau phase after aerosol infection. This caused a reduction in the numbers of live bacteria in spleens, but not lungs, and no effect on pathology was detected [11]. However, in further
Disappointment
In the laboratory of S.L. Morris in Bethesda, MD, USA, a mixture of 10 DNA vaccines expressing different antigens was tested therapeutically. The vaccines, individually and in combination, had previously been found to protect mice from subsequent challenge with M. tuberculosis [20]. However, when the vaccine mixture was given in 3 doses after chemotherapy had eliminated culturable bacteria from an established infection, only negligible ability to impair reactivation was seen and there was only
Hope renewed
In the laboratory of S.-N. Cho in Seoul, Korea a DNA vaccine expressing Ag85A was given as 3 doses during chemotherapy of an established infection and significantly reduced the numbers of mice found to be still infected 6 months after completion of treatment [23]. This demonstrated that drug therapy and DNA vaccine immunotherapy could be given simultaneously to advantage. In further studies the DNA vaccine expressing Ag85A and one expressing antigen PstS-3 were given, singly or in combination,
Consolidation
The range of antigens with therapeutic effect when delivered as DNA vaccines continues to be expanded; most recently by studies in China to include Ag85B, but not MPT64 [28]. The therapeutic effect of 4 doses of hsp65 DNA described earlier has now been demonstrated to be accompanied by reduction, not enhancement, of histopathology [29] and additional compelling evidence of the therapeutic activities of hsp65 DNA has been reported from the laboratories of C.L. Silva and J.H. Grosset, again with
Mechanisms
It is now well established that in causing disease M. tuberculosis both blocks the induction and expression of fully protective immune responses, so permitting survival and latency, and subverts the responses towards a pathology that facilitates dispersal through lung cavitation. A number of different mechanisms by which it does these things are beginning to be identified [31], [32], [33], [34], [35], [36]. Successful immunotherapy probably must override both the blocking and subversion
Prospect
Early fears that vaccination with heat shock proteins hsp65 or hsp70 might trigger or exacerbate autoimmune diseases such as arthritis and type 1 diabetes seem to be receding [51]. It appears that regulatory, rather than aetiologic, mechanisms are modulated by cross-reactivity of mammalian and microbial heat shock proteins with mammalian targets and beneficial rather than harmful effects have been found in clinical trials treating arthritis and diabetes with hsp60/65 and hsp70 peptides[51], [52]
Acknowledgement
I thank Min Yang for the antibody assays.
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