Immunogenicity of anti-leishmaniasis vaccines in man

Abstract: Leishmaniasis represents a serious health problem in Sudan. There is no adequate control measure available against the disease in the country. Vaccination remains the optimal potential control measure. Leishmania vaccines are, however, not currently available although killed Leishmania major vaccines against CL have been developed and are being evaluated. Cross protection by different Leishmania species has been reported. We evaluated the in vivo and in vitro immune response to a vaccine containing autoclaved L. major (ALM) plus BCG in a non-endemic and Leishmania donovani setting. In addition we evaluated the in vitro immune response to a defined vaccine candidate. In a Phase I trial safety and immunogenicity were tested in a double-blind placebocontrolled study in volunteers from Khartoum (non-endemic for leishmaniasis). The vaccine was found to be safe and did not induce clinical side effects over and above the effects of BCG. 61.6% of volunteers in the group vaccinated with ALM + BCG converted into Leishmanin skin test (LST)-reactive following vaccination. 76.9% of the vaccinated volunteers in the ALM+BCG group produced significant levels of IFN-gamma in response to L. major antigen. No significant production of IL-10 was induced. These kinds of cellular immune responses have been associated with protection against leishmaniasis. The phase I trial was to be followed by a trial evaluating the immunogenicity of ALM+BCG in a L. donovani endemic area. LST is used as one of the selection criterion in such studies, and is repeated during the study as a measure of the in vivo immune responses induced by vaccination. We wanted to know if the Leishmanin itself may induce an immune response. Repetition of LST did not induce conversion in reactivity to the LST neither did it modulate the IFN-gamma, IL-4, IL-10 and IL-12 responses of healthy Sudanese volunteers to Leishmania antigen. The immunogenicity of the ALM + BCG vaccine was evaluated in a leishmaniasis endemic area in eastern Sudan. Five hundred healthy volunteers (ages 7-52) were screened for exposure to Leishmania. Of these 98 were negative for LST and had negative antiLeishmania antibodies. The drop out rate of this one and a half-year study was high. The LST conversion was in 4/13 and 3/7 volunteers in the ALM+BCG group one and 18 months after vaccination respectively. Unexpectedly IFN-gamma was not significantly secreted by PBMCs from vaccinated volunteers. Thus the same ALM + BCG vaccine showed completely different results when tested in a non-endemic focus in Northern Sudan and subsequently in a highly endemic focus of VL in the Eastern part of Sudan. The possible reasons for this are discussed and a suggestion is presented implicating inappropriate selection of volunteers in studies of this kind. In addition the in vitro response to a defined vaccine candidate LACK (Leishmania homologue of Receptors for Activated C-Kinase) was tested in healthy Swedish unexposed volunteers. LACK induced secretion of both IFN-gamma and IL-10. Both T cells (mainly CD8+) and NK cells were the sources of IFN-gamma secretion. LACK was used to stimulate cells from healthy individuals from a Ieishmaniasis endemic and non-endemic areas in Sudan and found to induce both IFN-gamma and IL- 10 secretion. Taken together these studies show that a vaccine made from L. major mixed with BCG induced favourable immune responses in volunteers who are unexposed to Leishmania infection, whereas the same preparation showed low immunogenicity when tested in an endemic area. It might be more convenient to carry out such preliminary evaluation in endemic areas or in non-immune individuals travelling to endemic areas. In addition studying immune responses existing in unexposed individuals to candidate vaccines might help in designing and selecting new appropriate vaccines against leishmaniasis.