Evaluation of Ex Vivo Human Immune Response against Candidate Antigens for a Visceral Leishmaniasis Vaccine

Abstract

People cured from visceral leishmaniasis (VL) develop protection mediated by Th1-type cellular responses against new infections. We evaluated cytokine responses against 6 defined candidate vaccine antigens in 15 cured VL subjects and 5 healthy endemic controls with no evidence of previous exposure to Leishmania parasites. Of the 6 cytokines examined, only interferon-gamma (IFN-γ) differentiated cured VL patients from non-exposed individuals, with cured patients mounting a significantly higher IFN-γ response to a crude parasite antigen preparation. Among candidate vaccine antigens tested, the largest number of cured subjects recognized cysteine proteinase B, leading to heightened IFN-γ responses, followed by sterol 24-c-methyltransferase. These two antigens were the most immunogenic and protective antigens in a murine VL model, indicating a relationship between T cell recall responses of humans cured from VL and protective efficacy in an experimental model. Further studies may help prioritize antigens for clinical development of a subunit vaccine against VL.

KSAC, the First Defined Polyprotein Vaccine Candidate for Visceral Leishmaniasis

“…Although a number of defined antigens have been identified as protective against leishmaniasis in experimental animal models, any single antigen may not be sufficient to efficiently protect the human population due to differences in their immunological backgrounds: Although inbred mice with uniform genotypes are often used in experimental models, humans and dogs have divergent genotypes. In mouse models, SMT is the most immunogenic component of KSAC and, in our hands, is the most protective among the four components of KSAC when tested individually (22). In contrast, SMT is not always the strongest antigen in humans cured from VL (22).…”

“…In mouse models, SMT is the most immunogenic component of KSAC and, in our hands, is the most protective among the four components of KSAC when tested individually (22). In contrast, SMT is not always the strongest antigen in humans cured from VL (22). Thus, it is anticipated that one component may not be sufficient to serve as a protective vaccine antigen for every member of a genetically diverse population.…”

“…Recombinant of KMP11, SMT, A2, and CPB proteins were produced as previously described (16,22). L110f, which is an optimized derivative of Leish-111f, was produced as previously described (5).…”

“…Although the vaccine candidate provides some protection against L. infantum infection (9), Leish-111f was originally designed and optimized to target CL. In this study we focused on several proteins previously demonstrated to be protective against VL in animal models, including dogs, and recognized in humans cured from VL (22). The proteins KMP-11 (3), SMT (16), A2 (13,14), and CPB (34,36) were genetically fused to produce a single multiepitope product developed with the goal of achieving a cost-effective product with maximum efficacy.…”

Vaccines for Leishmaniasis: From proteome to vaccine candidates

“…For example, in human VL, the determination of cytokine patterns from patients undergoing drug therapy only identified negative correlations, i.e., high levels of IL-10 being correlated with uncontrolled disease. 17,18 Thus, the big questions in vaccine design are not yet solved: Which antigen(s) should one select and how should these be delivered? Moreover, with no convincing marker of protective immunity yet known, developing appropriate vaccine delivery strategies will have solely to rely on efficacy data from clinical trials.…”