Autoclaved Leishmania Major Vaccine for Prevention of Visceral Leishmaniasis: a Randomised, Double-blind, BCG-controlled Trial in Sudan

Background: Visceral leishmaniasis is a major cause of morbidity and mortality in the Sudan. Drug treatment is expensive, and drug resistance is becoming increasingly common. Safe, effective, and cheap vaccines are needed. We report the results of a vaccine trial against human visceral leishmaniasis.

Methods: We undertook a double-blind randomised trial to test the safety and efficacy of an autoclaved Leishmania major (ALM) promastigote vaccine (1 mg per dose). Of 5093 volunteers screened, 2306 had negative leishmanin skin tests and reciprocal titres of less than 6400 in the direct agglutination test. They were randomly assigned two doses of ALM mixed with BCG or BCG alone. Volunteers were followed up for 2 years. The primary endpoint was clinical visceral leishmaniasis or post-kala-azar dermal leishmaniasis. Analyses were by intention to treat.

Findings: Side-effects were confined to the injection site. The cumulative frequency of visceral leishmaniasis at 2 years did not differ significantly between the group assigned ALM plus BCG and that assigned BCG alone (133/1155 [11.5%] vs 141/1151 [12.3%], p=0.6). The vaccine efficacy was 6% (95% CI -18 to 25). The proportion of individuals showing leishmanin skin conversion was significantly higher in the ALM plus BCG group than in the BCG alone group throughout follow-up (303 [30%] vs 72 [7%] at 42 days). Individuals whose leishmanin test converted after vaccination (induration > or =5 mm) had a significantly lower frequency of visceral leishmaniasis than non-responders (27/375 [7.2%] vs 210/1660 [12.7%], p=0.003).

Interpretation: We found no evidence that two doses of ALM plus BCG offered significant protective immunity against visceral leishmaniasis compared with BCG alone. Leishmanin skin conversion with an induration of 5 mm or more in either group was associated with protection from the disease.