Abstract
Visceral leishmaniasis (VL) is a vector-borne disease affecting humans and domestic animals that constitutes a serious public health problem in many countries. Although many antigens have been examined so far as protein- or DNA-based vaccines, none of them conferred complete long-term protection. The use of the lizard non-pathogenic to humans Leishmania (L.) tarentolae species as a live vaccine vector to deliver specific Leishmania antigens is a recent approach that needs to be explored further. In this study, we evaluated the effectiveness of live vaccination in protecting BALB/c mice against L. infantum infection using prime-boost regimens, namely Live/Live and DNA/Live. As a live vaccine, we used recombinant L. tarentolae expressing the L. donovani A2 antigen along with cysteine proteinases (CPA and CPB without its unusual C-terminal extension (CPB-CTE)) as a tri-fusion gene. For DNA priming, the tri-fusion gene was encoded in pcDNA formulated with cationic solid lipid nanoparticles (cSLN) acting as an adjuvant. At different time points post-challenge, parasite burden and histopathological changes as well as humoral and cellular immune responses were assessed. Our results showed that immunization with both prime-boost A2-CPA-CPB-CTE-recombinant L. tarentolae protects BALB/c mice against L. infantum challenge. This protective immunity is associated with a Th1-type immune response due to high levels of IFN-γ production prior and after challenge and with lower levels of IL-10 production after challenge, leading to a significantly higher IFN-γ/IL-10 ratio compared to the control groups. Moreover, this immunization elicited high IgG1 and IgG2a humoral immune responses. Protection in mice was also correlated with a high nitric oxide production and low parasite burden. Altogether, these results indicate the promise of the A2-CPA-CPB-CTE-recombinant L. tarentolae as a safe live vaccine candidate against VL.
Highlights
Leishmaniasis is a vector-borne disease caused by different Leishmania species that ranges from self-limiting cutaneous leishmaniasis to fatal visceral leishmaniasis (VL) and is endemic in 88 tropical and subtropical countries [1]
We used DNA/Live and Live/Live prime-boost vaccination strategies against visceral leishmaniasis in BALB/c mice consisting of the A2-CPA-CPB-C-terminal extension (CTE) tri-fusion genes formulated with cationic solid lipid nanoparticles and a recombinant L. tarentolae expressing the tri-fusion
Assessments of cytokine production, humoral responses, parasite burden and histopathological studies support that the recombinant L. tarentolae A2-CPA-CPB without its unusual C-terminal extension (CPB-CTE) candidate vaccine elicits a protective response against visceral leishmaniasis in mice and represents an important step forward in the development of new vaccine combinations against Leishmania infections
Summary
Leishmaniasis is a vector-borne disease caused by different Leishmania species that ranges from self-limiting cutaneous leishmaniasis to fatal visceral leishmaniasis (VL) and is endemic in 88 tropical and subtropical countries [1]. VL is caused by members of the L. donovani complex with a wide and growing prevalence and incidence (http://www.who.int/en/) [2] and is considered as the most severe form of leishmaniasis and is often fatal, if left untreated [3,4]. Drugresistant forms have developed from current chemotherapeutic interventions [9,10]. Various vaccination strategies have been explored against experimental leishmaniasis, with particular emphasis on their efficacy against CL rather than VL [12,13]. First-generation antileishmanial vaccines based on live parasites (leishmanization) are the only successful intervention against leishmaniasis [14,15]. Multicomponent vaccines have been shown to protect against VL in experimental infection
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