The Potency and Durability of DNA- and Protein-Based Vaccines Against Leishmania major Evaluated Using Low-Dose, Intradermal Challenge

Abstract

DNA- and protein- based vaccines against cutaneous leishmaniasis due to Leishmania major were evaluated using a challenge model that more closely reproduces the pathology and immunity associated with sand fly-transmitted infection. C57BL/6 mice were vaccinated s.c. with a mixture of plasmid DNAs encoding the Leishmania Ags LACK, LmSTI1, and TSA (AgDNA), or with autoclaved L. major promastigotes (ALM) plus rIL-12, and the mice were challenged by inoculation of 100 metacyclic promastigotes in the ear dermis. When challenged at 2 wk postvaccination, mice receiving AgDNA or ALM/rIL-12 were completely protected against the development of dermal lesions, and both groups had a 100-fold reduction in peak dermal parasite loads compared with controls. When challenged at 12 wk, mice vaccinated with ALM/rIL-12 maintained partial protection against dermal lesions and their parasite loads were no longer significantly reduced, whereas the mice vaccinated with AgDNA remained completely protected and had a 1000-fold reduction in dermal parasite loads. Mice vaccinated with AgDNA also harbored few, if any, parasites in the skin during the chronic phase, and their ability to transmit L. major to vector sand flies was completely abrogated. The durable protection in mice vaccinated with AgDNA was associated with the recruitment of both CD8+ and CD4+ T cells to the site of intradermal challenge and with IFN-γ production by CD8+ T cells in lymph nodes draining the challenge site. These data suggest that under conditions of natural challenge, DNA vaccination has the capacity to confer complete protection against cutaneous leishmaniasis and to prevent the establishment of infection reservoirs.

Immunogenicity in dogs of three recombinant antigens (TSA, LeIF and LmSTI1) potential vaccine candidates for canine visceral leishmaniasis

“…Here, we began the evaluation of a mixture of the recombinant antigens TSA, LmSTI1 and LeIF as candidate vaccine for VL. These antigens have been successfully shown to induce an excellent protection against cutaneous leishmaniasis in the murine and non-human primate models [9,30,41] and currently are been tested in Phase I/II human vaccine clinical trials. Because these antigens are highly conserved among the Leishmania species and are expressed in both the amastigote and the promastigote forms of the parasites [39,40,46], they could be useful as a component of a panLeishmania vaccine [20].…”

“…Three highly conserved antigens among the Leishmania genus, TSA, LmSTI1 and LeIF, have been shown to induce excellent protection in both the murine and non-human primate models of the human disease [8,41]. Moreover, vaccination with plasmid DNA encoding these antigens conferred protection against L. major infection in BALB/c [9,30,31]. A single recombinant polyprotein comprising the sequences of all three recombinant proteins has been produced and tested in BALB/c mice against L. major infection formulated with MPL-SE ® (Monophosphoryl Lipid A plus squalene) and the results showed excellent protective immunity against the challenge with virulent parasites [41].…”

Immunomodulatory effects associated with a live vaccine against Leishmania major containing CpG oligodeoxynucleotides

“…A dynamic balance of effector T lymphocytes and T reg cells is necessary at the site of latent infection [12]. Depletion or neutralization of CD4 + T cells, CD8 + T cells, IFN-c, IL-12 or NO induces parasite expansion [11,12,22,23]. Conversely, treatment with anti-IL-10R [24][25][26] or anti-CD25 [13] antibodies leads to sterile cure and loss of immunity.…”

Assessment of Protection Induced by DNA and Live Vaccine Encoding Leishmania MHC Class I Restricted Epitopes against L. major Challenge in Balb/c Mice Model

“…These epitopes if evaluated immunogenic in vitro and in vivo, which is the precise mark of previous activation following natural infection, could be further benefited in polytopes or T cell vaccines. Although both unassembled epitopes used individually in cocktail or assembled peptides in tandem are effective in stimulating relevant T cell clones, nucleic acid based constructs or DNA polytopes expressing epitopes in tandem are potentially preferred due to selfadjuvanting characteristics of plasmid DNAs and their intrinsic potential to induce both CD4 + and CD8 + T-cells [34,35]. …”