Immunotherapy for Infectious Diseases

Tuberculosis and Other Mycobacterial Infections 293
and Iran also suggested activity in TB patients with drug-susceptible and drugresistant
tuberculosis (149–152). These studies suffered from methodologic problems
including insufficient sample sizes, nonrandom treatment allocation, high losses to
follow-up, and the use of various TB drug treatment regimens (153).
Three recent clinical trials have examined the role of immunotherapy with heat-killed
M. vaccae in a more rigorous fashion. In Romania, 206 previously untreated patients
with pulmonary TB were randomized to receive M. vaccae immunotherapeutic agent or
placebo 1 month after the beginning of anti-TB treatment (151). In this trial, which
included patients with both drug-susceptible and drug-resistant TB, sputum cultures 1
month after the administration of M. vaccae (i.e., 2 months after the onset of anti-TB
chemotherapy) were negative in 86% of patients in the immunotherapy group compared
with 76% of the placebo arm ( p � 0.08). Patients who received M. vaccae had significantly
greater weight gain after 2 and 6 months of TB treatment and decrement in cavitary
disease at 6 months. In a companion study of 102 patients with chronic or relapsed
TB, 60% of whom were infected with bacilli resistant to at least one first-line drug, 77%
patients treated with M. vaccae had successful treatment outcomes at 1 year compared
with 52% of patients treated with chemotherapy only (p � 0.02) (150). Sputum culture
negativity at 2 months was significantly higher in M. vaccae than placebo recipients.
In contrast, a randomized clinical trial from South Africa found no difference in the
rate of sputum culture conversion, weight gain, radiographic improvement, survival, or
decrease in erythrocyte sedimentation rate after 2 months of TB treatment (154). This
study included 374 HIV-infected and HIV-noninfected patients with pulmonary TB,
treated with standard short-course chemotherapy and a single intradermal injection of
heat-killed M. vaccae or placebo 1 week after the onset of anti-TB treatment. In a similar
clinical trial done in HIV-noninfected TB patients in Uganda, the rate of sputum
culture conversion after 1 month of TB treatment was twofold higher in the M. vaccae
group compared with the placebo arm after 1 month of TB treatment ( p � 0.01) and
was comparable between the groups thereafter (155). Weight gain and improvement in
cough and chest pain did not differ between treatment groups. Treatment with M. vaccae
was also associated with greater improvement in radiographic extent of disease at
the end of anti-TB treatment and at 1-year follow-up.
The reasons underlying the disparate results of these studies are unclear but may
reflect differences in exposure and sensitization to environmental mycobacteria between
the trial sites that might obscure any potential benefit from the immunotherapeutic
agent (148). At the present time, immunotherapy with M. vaccae should continue to be
regarded as experimental therapy. The promising results in several studies suggest that
further research with M. vaccae is warranted. Another large study of M. vaccae
immunotherapy is currently under way in Zambia.
CONCLUSIONS
The evolution of Mycobacterium tuberculosis as an intracellular pathogen has led to
a complex relationship between the organism and its host, the human mononuclear
phagocyte. The products of M. tuberculosis-specific T-lymphocytes, particularly
IFN-�, are essential for macrophage activation for intracellular mycobacterial killing.
However, some cytokines, including products of both lymphocytes and phagocytic cells,
may contribute to disease pathogenesis, by enhancing mycobacterial survival and by
causing many of the pathologic features of the disease. In HIV-associated mycobacterial