Antibiotic resistance free plasmid DNA expressing LACK protein leads towards a protective Th1 response against Leishmania infantum infection

Abstract

Canine visceral leishmaniasis is a serious public health concern in the Mediterranean basin since dogs are the main Leishmania infantum reservoir. However, there is not a vaccination method in veterinary use in this area, and therefore the development of a vaccine against this parasite is essential for the possible control of the disease. Previous reports have shown the efficacy of heterologous prime-boost vaccination with the pCIneo plasmid and the poxvirus VV (both Western Reserve and MVA strains) expressing L. infantum LACK antigen against canine leishmaniasis. As pCIneo-LACK plasmid contains antibiotic resistance genes, its use as a profilactic method is not recommended. Hence, the antibiotic resistance gene free pORT-LACK plasmid is a more suitable tool for its use as a vaccine. Here we report the protective and immunostimulatory effect of the prime-boost pORT-LACK/MVA-LACK vaccination tested in a canine experimental model. Vaccination induced a reduction in clinical signs and in parasite burden in the liver, an induction of the Leishmania-specific T cell activation, as well as an increase of the expression of Th1 type cytokines in PBMC and target organs.

Head-to-Head Comparison of Three Vaccination Strategies Based on DNA and Raw Insect-Derived Recombinant Proteins against Leishmania

“…Moreover, a lower parasite-specific humoral response was observed in the DNA-PROT group in relation to the C group after challenge. This phenomenon –also described in hamsters vaccinated with PAPLE22 DNA [63] and in other protective vaccines against VL in hamsters [61] and dogs [12], [21]– might be due to a redirection of the Th2-like response towards a Th1-like response and/or to the lower antigenic stimulation caused by lower parasite loads. In this sense, our results showed a positive correlation between parasite load in spleen and blood samples and the L. infantum -specific humoral response, as previously described in hamsters [40].…”

“…This strategy selectively amplifies memory T cells specific for the vaccine antigen [18]. Prime-boost assays carried out against Leishmania with the antigen LACK achieved protection in mice [19], but was only moderate in dogs [16], [20], [21]. In contrast, prime-boost vaccination using CPA and CPB antigens was highly protective in both mice [22] and dogs [23].…”

High Quality Long-Term CD4+ and CD8+ Effector Memory Populations Stimulated by DNA-LACK/MVA-LACK Regimen in Leishmania major BALB/c Model of Infection

“…Since it has been proposed that the quality of a CD4 + T cell cytokine response can be a crucial determinant in whether a vaccine is protective [15], we have defined in this investigation the immunological profile of cellular responses induced in heterologous DNA-LACK prime and MVA-LACK boost vaccination approach in mice. We have previously shown efficacy of this protocol against L. major in mice and dogs [19], [20] and protection levels in those studies were associated with an overall Th1 response against LACK antigen [19], [27]. Thus, vaccinia virus worked as a strong adjuvant and delivery vector altogether, modifying natural Th2-IL-4 response to LACK antigen dependent of Vβ4 Vα8 CD4 + T cells [7].…”

“…In particular, CD4 + and CD8 + T cells can be important in controlling disease development [9]. In the case of leishmaniasis, several studies have been performed to dissect the relevance of CD4 + and CD8 + T cell subsets and their relative role in natural infection [10], [11], [12], [13], [14], prophylaxis [15], [16], [17] or therapy [18]. However, due to the heterogeneity of T cell cytokine responses generated by different vaccines, there are still few defined immune correlates of protection for infections requiring T cell responses.…”

The Evolution of Poxvirus Vaccines

“…Malaria ME-TRAP clinical [374,375] AMA1 clinical [376][377][378][379][380] MSP1 clinical [377][378][379]381] CS clinical [375,382] Polyprotein consisting of six pre-erythrocytic antigens from P. falciparum clinical [383] Leishmaniasis LACK preclinical [88,271,[384][385][386] TRYP (Leishmania major substrain LV39) preclinical [387] TRYP (Leishmania infantum) preclinical [388] TRYP (Leishmania (Viannia) panamensis) preclinical [389] Toxoplasmosis ROP2 preclinical [390] Chagas disease Trypanosoma cruzi TcG2 and TcG4 preclinical [391] Abbreviations…”