Despite the lack of effective vaccines against parasitic diseases, the prospects of developing a vaccine against leishmaniasis are still high. With this objective, we have tested four DNA based candidate vaccines encoding to immunodominant leishmania antigens (LACKp24, TSA, LmSTI1 and CPa). These candidates have been previously reported as capable of eliciting at least partial protections in the BALB/c mice model of experimental cutaneous leishmaniasis. When tested under similar experimental conditions, all of them were able to induce similar partial protective effects, but none could induce a full protection. In order to improve the level of protection we have explored the approach of DNA based vaccination with different cocktails of plasmids encoding to the different immunodominant Leishmania antigens. A substantial increase of protection was achieved when the cocktail is composed of all of the four antigens; however, no full protection was achieved when mice were challenged with a high dose of parasite in their hind footpad. The full protection was only achieved after a challenge with a low parasitic dose in the dermis of the ear. It was difficult to determine clear protection correlates, other than the mixture of immunogens induced specific Th1 immune responses against each component. Therefore, such an association of antigens increased the number of targeted epitopes by the immune system with the prospects that the responses are at least additive if not synergistic. Even though, any extrapolation of this approach when applied to other animal or human models is rather hazardous, it undoubtedly increases the hopes of developing an effective leishmania vaccine.
"Strategies using a combination of plasmids expressing different antigens were successfully tested in human filariasis; these strategies led to an increase in immunogenicity and protection . In leishmaniasis, the combination of antigens increased the number of targeted epitopes by the immune system and had an additive, perhaps even a synergistic response . Therefore, we hypothesized that vaccinating with the DNA-Sm14 and DNA-Hsp65 plasmids would result in an additive modulation of the immune response. "
[Show abstract][Hide abstract] ABSTRACT: Background
Schistosomiasis is one of the most important neglected diseases found in developing countries and affects 249 million people worldwide. The development of an efficient vaccination strategy is essential for the control of this disease. Previous work showed partial protection induced by DNA-Sm14 against Schistosoma mansoni infection, whereas DNA-Hsp65 showed immunostimulatory properties against infectious diseases, autoimmune diseases, cancer and antifibrotic properties in an egg-induced granuloma model.
C57BL/6 mice received 4 doses of DNA-Sm14 (100 μg/dose) and DNA-Hsp65 (100 μg/dose), simultaneously administrated, or DNA-Sm14 alone, once a week, during four weeks. Three groups were included: 1- Control (no immunization); 2- DNA-Sm14; 3- DNA-Sm14/DNA-Hsp65. Two weeks following last immunization, animals were challenged subcutaneously with 30 cercariae. Fifteen, 48 and 69 days after infection splenocytes were collected to evaluate the number of CD8+ memory T cells (CD44highCD62low) using flow cytometry. Forty-eight days after challenge adult worms were collected by portal veins perfusion and intestines were collected to analyze the intestinal egg viability. Histological, immunohistochemical and soluble quantification of collagen and α-SMA accumulation were performed on the liver.
In the current work, we tested a new vaccination strategy using DNA-Sm14 with DNA-Hsp65 to potentiate the protection against schistosomiasis. Combined vaccination increased the number of CD8+ memory T cells and decreased egg viability on the intestinal wall of infected mice. In addition, simultaneous vaccination with DNA-Sm14/DNA-Hsp65 reduced collagen and α-SMA accumulation during the chronic phase of granuloma formation.
Simultaneous vaccination with DNA-Sm14/DNA-Hsp65 showed an immunostimulatory potential and antifibrotic property that is associated with the reduction of tissue damage on Schistosoma mansoni experimental infection.
"DNA vaccines have proven capable of stimulating antibody production, as well as CD4+ and CD8+ T CMI . In our study, the DNA vaccine induced antibodies against rLACK in one hamster, but antibodies against the other vaccine antigens were not detected, as it has been reported for other DNA candidates . Despite the lack of parasitological protection in blood, the significant parasitological protection in spleen –that achieved sterility in some animals– suggests that some degree of CMI response was induced, although not enough for significant NO production. "
[Show abstract][Hide abstract] ABSTRACT: Parasitic diseases plague billions of people among the poorest, killing millions annually, and causing additional millions of disability-adjusted life years lost. Leishmaniases affect more than 12 million people, with over 350 million people at risk. There is an urgent need for efficacious and cheap vaccines and treatments against visceral leishmaniasis (VL), its most severe form. Several vaccination strategies have been proposed but to date no head-to-head comparison was undertaken to assess which is the best in a clinical model of the disease. We simultaneously assayed three vaccination strategies against VL in the hamster model, using KMPII, TRYP, LACK, and PAPLE22 vaccine candidate antigens. Four groups of hamsters were immunized using the following approaches: 1) raw extracts of baculovirus-infected Trichoplusia ni larvae expressing individually one of the four recombinant proteins (PROT); 2) naked pVAX1 plasmids carrying the four genes individually (DNA); 3) a heterologous prime-boost (HPB) strategy involving DNA followed by PROT (DNA-PROT); and 4) a Control including empty pVAX1 plasmid followed by raw extract of wild-type baculovirus-infected T. ni larvae. Hamsters were challenged with L. infantum promastigotes and maintained for 20 weeks. While PROT vaccine was not protective, DNA vaccination achieved protection in spleen. Only DNA-PROT vaccination induced significant NO production by macrophages, accompanied by a significant parasitological protection in spleen and blood. Thus, the DNA-PROT strategy elicits strong immune responses and high parasitological protection in the clinical model of VL, better than its corresponding naked DNA or protein versions. Furthermore, we show that naked DNA coupled with raw recombinant proteins produced in insect larvae biofactories -the cheapest way of producing DNA-PROT vaccines- is a practical and cost-effective way for potential "off the shelf" supplying vaccines at very low prices for the protection against leishmaniases, and possibly against other parasitic diseases affecting the poorest of the poor.
PLoS ONE 12/2012; 7(12):e51181. DOI:10.1371/journal.pone.0051181 · 3.23 Impact Factor
"Reports have also demonstrated a protective role of peroxidoxin proteins against parasitic infections including Leishmania (Webb et al., 1998; Campos-Neto et al., 2002; Skeiky et al., 2002; Coler et al., 2007) and Entamoeba histolytica (Soong et al., 1995). Leishmania major thiol-specific antioxidant (TSA), homolog of Leishmania donovani peroxidoxin 2 (Pxn2), has been used as one of the components of multigenic Leishmania vaccine candidates (Skeiky et al., 2002; Coler et al., 2007; Ahmed et al., 2009). We have previously isolated three iron superoxide dismutases (Paramchuk et al., 1997; Plewes et al., 2003) and three peroxidoxins (Barr and Gedamu, 2001, 2003) from L. donovani complex in our laboratory. "
[Show abstract][Hide abstract] ABSTRACT: In this study, we assessed the immune response of two Leishmania donovani recombinant proteins: iron superoxide dismutase B1 (SODB1) and peroxidoxin 4 (Pxn4) in BALB/c mice. Assessment of the immunogenicity of these proteins alone or combined with Toll-like receptor 9 (TLR-9) agonist (CpG ODN) or TLR-4 agonist (GLA-SE) showed that they elicit specific antibody as well as cytokine production in response to the respective antigen in vitro. The use of adjuvants augmented immunogenicity of these antigens and more importantly, skewed the immune response to a Th1-type. These results indicate that recombinant SODB1 and Pxn4 proteins are potential vaccine candidates when administered with appropriate adjuvants.
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