Strategic evaluation of vaccine candidate antigens for the prevention of Visceral Leishmaniasis

Abstract

Infection with Leishmania parasites results in a range of clinical manifestations and outcomes, the most severe of which is visceral leishmaniasis (VL). Vaccination will likely provide the most effective long-term control strategy, as the large number of vectors and potential infectious reservoirs renders sustained interruption of Leishmania parasite transmission extremely difficult. Selection of the best vaccine is complicated because, although several vaccine antigen candidates have been proposed, they have emerged following production in different platforms. To consolidate the information that has been generated into a single vaccine platform, we expressed seven candidates as recombinant proteins in E. coli. After verifying that each recombinant protein could be recognized by VL patients, we evaluated their protective efficacy against experimental L. donovani infection of mice. Administration in formulation with the Th1-potentiating adjuvant GLA-SE indicated that each antigen could elicit antigen-specific Th1 responses that were protective. Considering the ability to reduce parasite burden along with additional factors such as sequence identity across Leishmania species, we then generated a chimeric fusion protein comprising a combination of the 8E, p21 and SMT proteins. This E. coli –expressed fusion protein was also demonstrated to protect against L. donovani infection. These data indicate a novel recombinant vaccine antigen with the potential for use in VL control programs.

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant

“…L111f has been safely administered and well-tolerated in subjects with and without evidence of prior Leishmania infection [15, 43, 44] and in combination with MPL-SE vaccine as an adjunct immunotherapy with standard chemotherapy for both cutaneous and mucocutaneous leishmaniasis [45]. NS was recently developed for vaccines targeting VL [37, 46], (Fig 1). …”

“…As NS is a more recently developed vaccine antigen [37, 46], we did not know how NS would perform with other TLR agonists when exposed to canine cells. While NS alone did not induce responses in uninfected dogs, NS with TLR4 agonist stimulated significant ( p <0.01) increases in the population of proliferative CD4 + T cells, 4.3-, 1.7-, and 5.8-fold in cells from endemic control, VL-asymptomatic, and symptomatic dogs, respectively (Fig.…”

Not All Antigens Are Created Equally: Progress, Challenges, and Lessons Associated with Developing a Vaccine for Leishmaniasis

“…In an attempt to consolidate information generated across many platforms, we recently selected and expressed 7 candidates as recombinant proteins in E. coli. Each recombinant protein was recognized by VL patients and, when formulated with the Th1-potentiating adjuvant GLA-SE, retained its protective efficacy against the challenge of mice with L. donovani (36). This indicates the possibility of combining candidates that have advanced in diverse vaccine platforms.…”

Memory T cells in cutaneous leishmaniasis

“…The development of a safe live-attenuated parasite that maintains T Eff , T CM , and T RM may be the simplest path to an effective vaccine, but has proven difficult to develop. Another barrier to the generation of a CD4 T cell vaccine has been the lack of well-defined immunodominant CD4 epitopes, as most immunization strategies have required complex polyprotein constructs to induce responses [4,63]. The recent identification of a protein, phosphoenolpyruvate carboxykinase, that reacts with approximately 20% of L. major -specific CD4 T cells and has broad cross-reactivity may help resolve this need, and will also be an invaluable tool for assessing CD4 responses [29].…”