Making an anti-amastigote vaccine for visceral leishmaniasis: rational, update and perspectives

Fernandes, Ana Paula; Coelho, Eduardo Antônio Ferraz; Machado-Coelho, George Luiz Lins; Grimaldi, Gabriel; Gazzinelli, Ricardo T.

doi:10.1016/j.mib.2012.05.002

Cited by 76 publications

(48 citation statements)

References 80 publications

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“…The kmp-11 (40) and the amastigote A2 (43) contain units encoding CD8+ cytotoxic T lymphocyte epitopes while the polyprotein Leish110f (8, 41), the LACK158–173 peptide (42), the amastigote A2 antigen (43), and the MML-triple fusion L. major vaccine expressed in Adenovirus (44) trigger a Th1-biased CD4+ T cell response.…”

Section: Discussionmentioning

confidence: 99%

Cross-Protective Immunity to Leishmania amazonensis is Mediated by CD4+ and CD8+ Epitopes of Leishmania donovani Nucleoside Hydrolase Terminal Domains

et al. 2014

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The nucleoside hydrolase (NH) of Leishmania donovani (NH36) is a phylogenetic marker of high homology among Leishmania parasites. In mice and dog vaccination, NH36 induces a CD4+ T cell-driven protective response against Leishmania chagasi infection directed against its C-terminal domain (F3). The C-terminal and N-terminal domain vaccines also decreased the footpad lesion caused by Leishmania amazonensis. We studied the basis of the crossed immune response using recombinant generated peptides covering the whole NH36 sequence and saponin for mice prophylaxis against L. amazonensis. The F1 (amino acids 1–103) and F3 peptide (amino acids 199–314) vaccines enhanced the IgG and IgG2a anti-NH36 antibodies to similar levels. The F3 vaccine induced the strongest DTH response, the highest proportions of NH36-specific CD4+ and CD8+ T cells after challenge and the highest expression of IFN-γ and TNF-α. The F1 vaccine, on the other hand, induced a weaker but significant DTH response and a mild enhancement of IFN-γ and TNF-α levels. The in vivo depletion with anti-CD4 or CD8 monoclonal antibodies disclosed that cross-protection against L. amazonensis infection was mediated by a CD4+ T cell response directed against the C-terminal domain (75% of reduction of the size of footpad lesion) followed by a CD8+ T cell response against the N-terminal domain of NH36 (57% of reduction of footpad lesions). Both vaccines were capable of inducing long-term cross-immunity. The amino acid sequence of NH36 showed 93% identity to the sequence of the NH A34480 of L. amazonensis, which also showed the presence of completely conserved predicted epitopes for CD4+ and CD8+ T cells in F1 domain, and of CD4+ epitopes differing by a single amino acid, in F1 and F3 domains. The identification of the C-terminal and N-terminal domains as the targets of the immune response to NH36 in the model of L. amazonensis infection represents a basis for the rationale development of a bivalent vaccine against leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Cross-Protective Immunity to Leishmania amazonensis is Mediated by CD4+ and CD8+ Epitopes of Leishmania donovani Nucleoside Hydrolase Terminal Domains

et al. 2014

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“…49 The vaccine has already completed phase 1 clinical trials in the U.S. to demonstrate safety and the ability to evoke a robust immune response. [46][47][48] The IDRI vaccine, called LEISH-F3 + GLA-SE, is a highly purified, recombinant vaccine which incorporates two fused leishmania parasite proteins, given along with an additive to boost the immune response. It works by activating the immune system to kill the parasite that causes VL, the first of its kind till now developed.…”

Section: New Vaccine Trialsmentioning

confidence: 99%

Current treatment of visceral leishmaniasis (Kala-azar): an overview

Singh

Kumar

2014

Int J Res Med Sci

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“…A comprehensive list of the antigens along with immune responses and protection of respective trials are described in detail elsewhere [21]. Among the recombinant antigens selected as candidates for a prophylactic vaccine against VL, one of specific interest is the amastigote specific antigen A2 from L. donovani [22], [23]. The recombinant A2 (rA2) conferred protection in mice challenged with L. donovani , L. infantum or L. amazonensis when administered as recombinant protein [22], [24], DNA [25], viral vector [26], or transfected parasites (L. tarentolae ) [27].…”

Section: Introductionmentioning

confidence: 99%

Clinical and Parasitological Protection in a Leishmania infantum-Macaque Model Vaccinated with Adenovirus and the Recombinant A2 Antigen

et al. 2014

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BackgroundVisceral leishmaniasis (VL) is a severe vector-born disease of humans and dogs caused by Leishmania donovani complex parasites. Approximately 0.2 to 0.4 million new human VL cases occur annually worldwide. In the new world, these alarming numbers are primarily due to the impracticality of current control methods based on vector reduction and dog euthanasia. Thus, a prophylactic vaccine appears to be essential for VL control. The current efforts to develop an efficacious vaccine include the use of animal models that are as close to human VL. We have previously reported a L. infantum-macaque infection model that is reliable to determine which vaccine candidates are most worthy for further development. Among the few amastigote antigens tested so far, one of specific interest is the recombinant A2 (rA2) protein that protects against experimental L. infantum infections in mice and dogs.Methodology/Principal FindingsPrimates were vaccinated using three rA2-based prime-boost immunization regimes: three doses of rA2 plus recombinant human interleukin-12 (rhIL-12) adsorbed in alum (rA2/rhIL-12/alum); two doses of non-replicative adenovirus recombinant vector encoding A2 (Ad5-A2) followed by two boosts with rA2/rhIL-12/alum (Ad5-A2+rA2/rhIL12/alum); and plasmid DNA encoding A2 gene (DNA-A2) boosted with two doses of Ad5-A2 (DNA-A2+Ad5-A2). Primates received a subsequent infectious challenge with L. infantum. Vaccines, apart from being safe, were immunogenic as animals responded with increased pre-challenge production of anti-A2-specific IgG antibodies, though with some variability in the response, depending on the vaccine formulation/protocol. The relative parasite load in the liver was significantly lower in immunized macaques as compared to controls. Protection correlated with hepatic granuloma resolution, and reduction of clinical symptoms, particularly when primates were vaccinated with the Ad5-A2+rA2/rhIL12/alum protocol.Conclusions/SignificanceThe remarkable clinical protection induced by A2 in an animal model that is evolutionary close to humans qualifies this antigen as a suitable vaccine candidate against human VL.

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Making an anti-amastigote vaccine for visceral leishmaniasis: rational, update and perspectives

Cited by 76 publications

References 80 publications

Cross-Protective Immunity to Leishmania amazonensis is Mediated by CD4+ and CD8+ Epitopes of Leishmania donovani Nucleoside Hydrolase Terminal Domains

Cross-Protective Immunity to Leishmania amazonensis is Mediated by CD4+ and CD8+ Epitopes of Leishmania donovani Nucleoside Hydrolase Terminal Domains

Current treatment of visceral leishmaniasis (Kala-azar): an overview

Clinical and Parasitological Protection in a Leishmania infantum-Macaque Model Vaccinated with Adenovirus and the Recombinant A2 Antigen

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