Tuberculosis prevention trial Madras
The protective effect of BCG vaccination in man has been evaluated in a number of controlled trials. In these trials, the protection observed varied from none to 80 percent. In view of these conflicting results, a large scale BCG trial was planned In India and the protective effect of BCG vaccination evaluated in a controlled, double-blind, community trial near Madras in south India in a population of about 360,000 persons, In this trial, all Individuals aged 1 yr and above were tested with 3 IU of PPD-S and 10 units of PPD-B, and simultaneously, BCG vaccines and placebo were allocated randomly to all those aged 1 mo and above. All Individuals aged 10 yr and above were X-rayed, and from such persons whose photofluorograms were interpreted as abnormal two specimens of sputum were collected and bacteriologically examined. Intensive efforts were made, by means of regular follow-up surveys every 2 1/2 yr and more frequently, by selective case-finding among suspects and further by maintaining permanent diagnostic services for symptomatic, to identify all new cases of tuberculosis occurring in the community. Mutually exclusive random samples of the population were retested with tuberculin at 2 1/2 mo, 2 1/2 and 4 yr after the intake in order to evaluate the tuberculin sensitivity over time in the study, population.
The study population was characterized by a high prevalence of tuberculous infection and disease as also by a very high prevalence of nonspecific sensitivity. This report presents findings of the first 7 1/2 yr of follow-up. The tuberculin sensitivity Induced by BCG vaccination was highly satisfactory at 2 1/2 mo but waned considerably between 2 1/2 mo and 2 1/2 yr with no further waning in sensitivity thereafter. Incidence of infection was high in the study population. However, incidence of bacillary disease was more frequent among initial tuberculin reactors, especially among the older persons, than among non-reactors of whom the majority were in the younger age groups. The distribution of new cases of pulmonary tuberculosis among those not infected at Intake did not show any evidence of a protective effect of BCG. Certain hypotheses that may explain the findings have been discussed.
Potential of Mw as a prophylactic vaccine against pulmonary tuberculosis
Mycobacterium w (Mw), is a cultivable, non-pathogenic mycobacterium and has been tried extensively as an immunomodulator in leprosy. This has been found to be safe and has shown beneficial immunoprophylactic effect in population based, double blind placebo controlled trials in North India. These effects were also observed in the vaccine trials in South India. Keeping in view these beneficial effects and its earlier reported protective effect against tuberculosis in animals, its protective efficacy was evaluated in a rural population of about 28,948 people belonging to 272 villages in Ghatampur, Kanpur (India). The population was vaccinated with two doses (1st dose of 1x10(9) heat killed organisms followed 6 months later with a 2nd dose of 5x10(8) organisms) of Mw 10-13 years ago originally to investigate its effect against leprosy. The vaccine/placebo was given to healthy contacts of leprosy patients who had no evidence of suffering from tuberculosis. Incidence and prevalence of pulmonary tuberculosis in the present study was assessed in a blind manner by an active field survey and also retrospectively by history of anti tuberculosis treatment received by the patient in the intervening period (since vaccination), which was also corroborated by scrutinizing the medical records. Diagnosis was confirmed by standard clinical and bacteriological criteria. A total of 69 patients were diagnosed to be suffering from pulmonary tuberculosis during the survey which included 17 new sputum smear positive cases and 52 previously partially treated but still active pulmonary tuberculosis cases. The difference in the new sputum positive cases between the vaccinated (5/17) and placebo groups (12/17) was significant at 5% level of significance for 1 tailed test (Z>1.64). As 75% (52/69) of the cases had been diagnosed as suffering from pulmonary tuberculosis but had not taken adequate therapy all the cases diagnosed during the intervening period were recorded and re-analysis done. The differences are more significant at 1% level of significance for 1 tail test (Z>2.59) when all cases were analysed as a group. A small proportion 12.85% (total number=3036) of the contacts in the study population had BCG scars. On analysis of results on protection against tuberculosis in this group, BCG did provide protection against tuberculosis (p<0.01). In the placebo group the prevalence of tuberculosis was 1.11% which reduced to 0.70% for those who received Mw vaccine (p<0.01) which further decreased to 0.53% in those who had BCG scars and received Mw. These results thus provide evidence suggesting protective efficacy of Mw against pulmonary tuberculosis and that Mw merits investigation in future prospective immunoprophylactic trials along with other candidates for protection against pulmonary tuberculosis.
Mycobacterium indicus pranii as stand-alone or adjunct immunotherapeutic in treatment of experimental animal tuberculosis
Background & objectives:
Mycobacterium w (M.w) is a saprophytic cultivable mycobacterium and shares several antigens with M. tuberculosis. It has shown good immunomodulation in leprosy patients. Hence in the present study, the efficacy of M.w immunotherapy, alone or in combination with multi drug chemotherapeutic regimens was investigated against drug sensitive M. tuberculosis H37Rv and three clinical isolates with variable degree of drug resistance in mice.
BALB/c mice were infected with M. tuberculosis H37Rv (susceptible to all first and second line drugs) and three clinical isolates taken from the epository of the Institute. The dose of 200 bacilli was used for infection via respiratory route in an aerosol chamber. Chemotherapy (5 days/wk) was given one month after infection and the vaccinated group was given a dose of 1×107 bacilli by subcutaneous route. Bacterial load was measured at 4 and 6 wk after initiation of chemotherapy.
M.w when given along with chemotherapy (4 and 6 wk) led to a greater reduction in the bacterial load in lungs and other organs of TB infected animals compared to. However, the reduction was significantly (P<0.05) more in terms of colony forming units (cfu) in both organs (lungs and spleen).
M.w (as immunomodulator) has beneficial therapeutic effect as an adjunct to chemotherapy.
Efficacy and Safety of Mycobacterium indicus pranii as an adjunct therapy in Category II pulmonary tuberculosis in a randomized trial
Prolonged treatment of tuberculosis (TB) often leads to poor compliance, default and relapse, converting primary TB patients into category II TB (Cat IITB) cases, many of whom may convert to multi-drug resistant TB (MDR-TB). We have evaluated the immunotherapeutic potential of Mycobacterium indicus pranii (MIP) as an adjunct to Anti-Tubercular Treatment (ATT) in Cat II pulmonary TB (PTB) patients in a prospective, randomized, double blind, placebo controlled, multicentric clinical trial. 890 sputum smear positive Cat II PTB patients were randomized to receive either six intra-dermal injections (2 + 4) of heat-killed MIP at a dose of 5 × 108 bacilli or placebo once in 2 weeks for 2 months. Sputum smear and culture examinations were performed at different time points. MIP was safe with no adverse effects. While sputum smear conversion did not show any statistically significant difference, significantly higher number of patients (67.1%) in the MIP group achieved sputum culture conversion at fourth week compared to the placebo (57%) group (p = 0.0002), suggesting a role of MIP in clearance of the bacilli. Since live bacteria are the major contributors for sustained incidence of TB, the potential of MIP in clearance of the bacilli has far reaching implications in controlling the spread of the disease.
Fifteen year follow up of trial of BCG vaccines in south India for tuberculosis prevention
A large scale community-based double blind randomized controlled trial was carried out in Chingleput district of south India to evaluate the protective effect of BCG against bacillary forms of pulmonary tuberculosis. From among 366,625 individuals registered, 281,161 persons were vaccinated with BCG or placebo by random allocation. Two strains of BCG were used, the French and Danish, with a high dose (0.1 mg/0.1 ml) and a low dose (0.01 mg/0.1 ml) in each strain. The entire population was followed up for 15 years by means of resurveys every 30 months, and selective follow up every 10 months and continuous passive case finding. There were 560 cases (189, 191 and 180 from the high dose, low dose and placebo groups respectively) arising over 15 years, among 109,873 persons who were tuberculin negative and had a normal chest X-ray at intake. This represents a small fraction of the total incidence of 2.6 per 1000 person-years most of which came from those who were initially tuberculin positive. The incidence rates in the three "vaccination" groups were similar confirming the complete lack of protective efficacy, seen at the end of 7 1/2 years. BCG offered no overall protection in adults and a low level of overall protection (27%; 95% C.I. -8 to 50%) in children. This lack of protection could not be explained by methodological flaws, or the influence of prior sensitization by non-specific sensitivity, or because most of the cases arose as a result of exogenous re-infection. The findings at 15 years show that in this population with high infection rates and high nonspecific sensitivity, BCG did not offer any protection against adult forms of bacillary pulmonary tuberculosis.