Towards development of novel immunization strategies against leishmaniasis using PLGA nanoparticles loaded with kinetoplastid membrane protein-11

Diego M Santos¹, Marcia W Carneiro¹, Tatiana R de Moura¹, Kiyoshi Fukutani¹, Jorge Clarencio¹, Manuel Soto², Socorro Espuelas^3,4, Claudia Brodskyn^1,5, Aldina Barral^1,5, Manoel Barral-Netto^1,5, Camila I de Oliveira^1,5
1Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Salvador, BA, Brazil; ²Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas, Departamento de Biologia Molecular, Universidad Autonoma de Madrid, Madrid; ³Departamento de Farmacia y Tecnología Farmacéutica, ⁴Instituto de Salud Tropical, Facultad de Farmacia, Universidad de Navarra, Pamplona, Spain; ⁵Instituto de Investigação em Imunologia, Salvador, BA, Brazil

Background: Vaccine development has been a priority in the fight against leishmaniases, which are vector-borne diseases caused by Leishmania protozoa. Among the different immunization strategies employed to date is inoculation of plasmid DNA coding for parasite antigens, which has a demonstrated ability to induce humoral and cellular immune responses. In this sense, inoculation of plasmid DNA encoding Leishmania kinetoplasmid membrane protein-11 (KMP-11) was able to confer protection against visceral leishmaniasis. However, recently the use of antigen delivery systems such as poly(lactic-co-glycolic acid) (PLGA) nanoparticles has also proven effective for eliciting protective immune responses.
Methods: In the present work, we tested two immunization strategies with the goal of obtaining protection, in terms of lesion development and parasite load, against cutaneous leishmaniasis caused by L. braziliensis. One strategy involved immunization with plasmid DNA encoding L. infantum chagasi KMP-11. Alternatively, mice were primed with PLGA nanoparticles loaded with the recombinant plasmid DNA and boosted using PLGA nanoparticles loaded with recombinant KMP-11.
Results: Both immunization strategies elicited detectable cellular immune responses with the presence of both proinflammatory and anti-inflammatory cytokines; mice receiving the recombinant PLGA nanoparticle formulations also demonstrated anti-KMP-11 IgG1 and IgG2a. Mice were then challenged with L. braziliensis, in the presence of sand fly saliva. Lesion development was not inhibited following either immunization strategy. However, immunization with PLGA nanoparticles resulted in a more prominent reduction in parasite load at the infection site when compared with immunization using plasmid DNA alone. This effect was associated with a local increase in interferon-gamma and in tumor necrosis factor-alpha. Both immunization strategies also resulted in a lower parasite load in the draining lymph nodes, albeit not significantly.
Conclusion: Our results encourage the pursuit of immunization strategies employing nanobased delivery systems for vaccine development against cutaneous leishmaniasis caused by L. braziliensis infection.

Keywords: vaccine, nanoparticle, Leishmania, kinetoplastid membrane protein-11

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