South Indian leprosy vaccine trial: important lessons for mycobacterial immunology.

Between January 1991 and July 1 993, 1 7 1 ,400 individuals living in Chingleput District, South India, were recruited into a major leprosy vaccine trial organized by the Indian Council for Medical Research. The participants were randomized to receive a placebo, a plain BCG vaccine, a combination of BCG plus killed leprosy bacilli, or else a killed environmental mycobacterial vaccine : either 'Mycobacterium W ' , or 'Mycobacterium ICRC' . Eighty-five percent of these individuals were examined for leprosy between August 1 993 and February 1 995 and 75% were examined between January 1 997 and September 1 998. The codes were broken in December 1 998, and revealed that each of the vaccines had provided significant protection over the interval between 4 and 8 years after vaccination: 65 .5% for the ICRC bacillus, 64% for combined BCG and killed Mycobacterium leprae, 34% for BCG alone and 25 ·7% for the W bacillus . l These figures, and the data behind them, include several findings of considerable importance for research on mycobacterial immunology and vaccines. In the first follow-up survey (up to 4 years after vaccination), the incidence of leprosy was higher among each of the active vaccine groups, compared to the placebo recipients . Though these differences were not individually statistically significant, the result is consistent with similar patterns seen in the initial follow up in a leprosy vaccine trial in Burma,2 and a tuberculosis vaccine trial in South India.3,4 This finding provides important further evidence that antigenic challenge can accelerate progression to mycobacterial disease among individuals either incubating infection at time of vaccination (most likely) or infected very soon after vaccination (less likely explanation). The fact that the negative effect was greater for older (> 14 years of age) than younger individuals for recipients of BCG, BCG plus killed M. leprae and Mycobacterium W (this age effect was statistically significant for BCG plus killed M. leprae) is consistent with the prior infection interpretation. In the second follow-up (4-8 years after vaccination), there was significantly less leprosy in each of the active vaccine groups, compared to the controls. The finding of greater protection with the combination BCG plus killed M. leprae than with BCG alone is in contrast to findings in Venezuela5 and Malawi,6 as is the relatively low protection associated with BCG alone. These differences may be added to the long catalogue of variable efficacy results associated with BCG vaccine against leprosy and tuberculosis .7 The finding of greater protection with the ICRC than with the W bacillus is ironic, given that the latter vaccine was