Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice

Soto, Manuel; Corvo, Laura; Garde, Esther; Ramírez, Laura; Iniesta, Virginia; Bonay, Pedro; Gómez-Nieto, Carlos; González, Víctor; Martín, M. Elena; Alonso, Carlos; Coelho, Eduardo Antônio Ferraz; Barral, Aldina; Barral‐Netto, Manoel; Iborra, Salvador

doi:10.1371/journal.pntd.0003751

Cited by 16 publications

(13 citation statements)

References 86 publications

(104 reference statements)

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“…Vaccine-induced responses have been studied in depth under experimental Leishmania conditions [48, 51–60], but little is known regarding how these vaccines would serve as a post-exposure prophylaxis or immunotherapy to boost existing responses in already infected animals. This study used dogs, a natural host of Leishmania infantum , to demonstrate possible outcomes of vaccination during subclinical and clinical VL, approximating vaccine responses within an endemic population where vaccination could or would often occur after infection.…”

Section: Discussionmentioning

confidence: 99%

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant

Schaut

Grinnage-Pulley

Esch

et al. 2016

Vaccine

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Visceral leishmaniasis (VL), caused by infection with the obligate intracellular protozoan parasite Leishmania infantum, is a fatal disease of dogs and humans. Protection against VL requires a T helper 1 (Th1) skewed CD4+ T response, but despite this knowledge, there are currently no approved-to-market vaccines for humans and only three veterinary-use vaccines globally. As VL progresses from asymptomatic to symptomatic, L. infantum–specific interferon gamma (IFNγ) driven- Th1 responses become dampened and a state of immune exhaustion established. T cell exhaustion and other immunoregulatory processes, starting during asymptomatic disease, are likely to hinder vaccine-induced responses if vaccine is administered to infected, but asymptomatic and seronegative, individuals. In this study we evaluated how immune exhaustion, shown previously by our group to worsen in concert with VL progression, effected the capacity of vaccine candidate antigen/toll-like receptor (TLR) agonist combinations to promote protective CD4+ T cell responses during progressive VL. In conjunction with Th1 responses, we also evaluated concomitant stimulation of immune-balanced IL-10 regulatory cytokine production by these vaccine products in progressive VL canine T cells. Vaccine antigen L111f in combination with TLR agonists significantly recovered CD4+ T cell IFN-γ intracellular production in T cells from asymptomatic VL dogs. Vaccine antigen NS with TLR agonists significantly recovered CD4+ T cell production in both endemic control and VL dogs. Combinations of TLR agonists and vaccine antigens overcame L. infantum induced cellular exhaustion, allowing robust Th1 CD4+ T cell responses from symptomatic dogs that previously had dampened responses to antigen alone. Antigen-agonist adjuvants can be utilized to promote more robust vaccine responses from infected hosts in endemic areas where vaccination of asymptomatic, L. infantum-infected animals is likely.

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Section: Discussionmentioning

confidence: 99%

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant

Schaut

Grinnage-Pulley

Esch

et al. 2016

Vaccine

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“…The CHAd63-KH vaccine is a replicationdefective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. The vaccine was shown to be safe and immunogenic [51][52][53].…”

Section: Third-generation Vaccinesmentioning

confidence: 99%

Vaccines for Visceral Leishmaniasis: Hopes and Hurdles

Khalil¹

2018

Leishmaniases as Re-Emerging Diseases

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The leishmaniases are vector-borne parasitic diseases with multiple disease phenotypes that range from self-healing cutaneous ulcers to disfiguring post-kala-azar dermal leishmaniasis and fatal visceral leishmaniasis (VL). Infected individuals can develop subclinical infections or overt disease. Current treatments are toxic and expensive. The only successful control measure is case detection and drug treatment. Resistance to antileishmanial drugs are increasing with few drugs in the pipeline. The Leishmania parasites are good candidates for vaccine development, with no change in its antigenic coat and extensive cross-reactivity between species. First-generation vaccines are safe, immunogenic with inconclusive efficiency. These vaccines presented the leishmanin skin test (LST) as a potentially good surrogate marker of immunogenicity/protection that can help in future vaccine studies. First-generation vaccines are the only leishmaniasis vaccines that progressed to phase III. Second-generation vaccines are safe and immunogenic, but none progressed to phase III. Third-generation vaccines recently entered human testing. Alternative approaches include in silico prediction of immunogenic Leishmania epitopes with in vitro immunogenicity testing. New adjuvants can help in the quest to develop efficacious leishmaniasis vaccines. Failure of second-and third-generation vaccines to reach phase III, rising drug resistance and continued VL pandemics make it a necessity to revisit first-generation vaccines.

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“…The recognition of some other parasite proteins implicated in translation by the host immune system has been also demonstrated. In this regard, the parasite PABPs have been found to be antigenic proteins in canine and human VL patients and humans affected by mucocutaneous leishmaniasis (MCL) due to L. braziliensis infection (Guerra et al, 2011 ; Soto et al, 2015 ). In addition, the L. braziliensis initiation factor 5a (LbeIF5A) is an antigenic protein recognized by the sera from human patients infected with L. braziliensis (Duarte et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Antigenic and Prophylactic Properties of the Leishmania Translation Initiation Factors eIF2 and eIF2B in Natural and Experimental Leishmaniasis

Garde

Ramírez

Corvo

et al. 2018

Front. Cell. Infect. Microbiol.

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Different members of intracellular protein families are recognized by the immune system of the vertebrate host infected by parasites of the genus Leishmania. Here, we have analyzed the antigenic and immunogenic properties of the Leishmania eIF2 and eIF2B translation initiation factors. An in silico search in Leishmania infantum sequence databases allowed the identification of the genes encoding the α, β, and γ subunits and the α, β, and δ subunits of the putative Leishmania orthologs of the eukaryotic initiation factors F2 (LieIF2) or F2B (LieIF2B), respectively. The antigenicity of these factors was analyzed by ELISA using recombinant versions of the different subunits. Antibodies against the different LieIF2 and LieIF2B subunits were found in the sera from human and canine visceral leishmaniasis patients, and also in the sera from hamsters experimentally infected with L. infantum. In L. infantum (BALB/c) and Leishmania major (BALB/c or C57BL/6) challenged mice, a moderate humoral response against these protein factors was detected. Remarkably, these proteins elicited an IL-10 production by splenocytes derived from infected mice independently of the Leishmania species employed for experimental challenge. When DNA vaccines based on the expression of the LieIF2 or LieIF2B subunit encoding genes were administered in mice, an antigen-specific secretion of IFN-γ and IL-10 cytokines was observed. Furthermore, a partial protection against murine CL development due to L. major infection was generated in the vaccinated mice. Also, in this work we show that the LieIF2α subunit and the LieIF2Bβ and δ subunits have the capacity to stimulate IL-10 secretion by spleen cells from naïve mice. B-lymphocytes were identified as the major producers of this anti-inflammatory cytokine. Taking into account the data found in this study, it may be hypothesized that these proteins act as virulence factors implicated in the induction of humoral responses as well as in the production of the down-regulatory IL-10 cytokine, favoring a pathological outcome. Therefore, these proteins might be considered markers of disease.

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Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice

Cited by 16 publications

References 86 publications

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant

Vaccines for Visceral Leishmaniasis: Hopes and Hurdles

Analysis of the Antigenic and Prophylactic Properties of the Leishmania Translation Initiation Factors eIF2 and eIF2B in Natural and Experimental Leishmaniasis

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