Showing papers on "Visceral leishmaniasis published in 2005"
TL;DR: A number of tools have been developed for the control of the canine reservoir of L. infantum, including several canine vaccine candidates, in particular an FML Leishmania enriched fraction showing good clinical protection, and a number of insecticide-based preparations for dog protection against sand fly bites.
463 citations
TL;DR: An historical review is given of American visceral leishmaniasis (AVL), with particular reference to the eco-epidemiology of the disease in Brazil, and the presence of such an enzootic in a variety of native animals will render the total eradication of AVL unlikely.
Abstract: An historical review is given of American visceral leishmaniasis (AVL), with particular reference to the eco-epidemiology of the disease in Brazil. Following the first records of AVL in this country, in 1934, the sandfly Lutzomyia longipalpis (Lutz and Neiva, 1912) was incriminated as the principal vector. It is now generally accepted, however, that there exist a number of cryptic species under the name of Lu. longipalpis s.l. and that variations in the quantity of the vasodilatory peptide maxadilan in the saliva of flies from different populations of Lu. longipalpis s.l., may account for the variable clinical manifestations of AVL seen in different geographic regions. Distribution of AVL has been shown to extend throughout most of South and Central America, with the domestic dog serving as the principal reservoir of infection for man. However, while one hypothesis suggests that the causative parasite is Leishmania infantum, imported from Europe with the Portuguese and Spanish colonists, the demonstration of a high rate of benign, inapparent infection in foxes in Amazonian Brazil raised an opposing suggestion that the parasite is indigenous to the Americas. Recent reports of similar infections in native marsupials, and possibly rodents, tend to support this view, particularly as Lu. longipalpis is primordially a silvatic sandfly. Although effective control measures in foci of the disease will diminish the number of canine and human infections, the presence of such an enzootic in a variety of native animals will render the total eradication of AVL unlikely.
450 citations
TL;DR: This review focuses on host responses to infection with the species that cause visceral leishmaniasis, as they contrast with species causing localized cutaneous leish maniasis, which includes asymptomatic self-resolving infection, localized skin lesions, and progressive visceral leishingmaniasis.
271 citations
TL;DR: This article focuses on advances made with second-generation vaccines against leishmaniasis, and identifies several antigens that might be potential vaccine candidates.
256 citations
TL;DR: This is the first report of a vaccine conferring protection to both antimony responsive and resistant Leishmania strains reflecting several aspects of clinical visceral leishmaniasis.
Abstract: The emergence of an increasing number of Leishmania donovani strains resistant to pentavalent antimonials (SbV), the first line of treatment for visceral leishmaniasis worldwide, accounts for decreasing efficacy of chemotherapeutic interventions A kinetoplastid membrane protein-11 (KMP-11)-encoding construct protected extremely susceptible golden hamsters from both pentavalent antimony responsive (AG83) and antimony resistant (GE1F8R) virulent L donovani challenge All the KMP-11 DNA vaccinated hamsters continued to survive beyond 8 mo postinfection, with the majority showing sterile protection Vaccinated hamsters showed reversal of T cell anergy with functional IL-2 generation along with vigorous specific anti-KMP-11 CTL-like response Cytokines known to influence Th1- and Th2-like immune responses hinted toward a complex immune modulation in the presence of a mixed Th1/Th2 response in conferring protection against visceral leishmaniasis KMP-11 DNA vaccinated hamsters were protected by a surge in IFN-γ, TNF-α, and IL-12 levels along with extreme down-regulation of IL-10 Surprisingly the prototype candidature of IL-4, known as a disease exacerbating cytokine, was found to have a positive correlation to protection Contrary to some previous reports, inducible NO synthase was actively synthesized by macrophages of the protected hamsters with concomitant high levels of NO production This is the first report of a vaccine conferring protection to both antimony responsive and resistant Leishmania strains reflecting several aspects of clinical visceral leishmaniasis
246 citations
TL;DR: Clinical studies done in Bihar with different treatments between 1980 and 2004 show that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy, and combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems.
Abstract: Summary The state of Bihar in India carries the largest share of the world's burden of antimony-resistant visceral leishmaniasis. We analysed clinical studies done in Bihar with different treatments between 1980 and 2004. Overall, 53 studies were included (all but one published), of which 15 were comparative (randomised, quasi-randomised, or non-randomised), 23 dose-finding, and 15 non-comparative. Data from comparative studies were pooled when appropriate for meta-analysis. Overall, these studies enrolled 7263 patients in 123 treatment arms. Adequacy of methods used to do the studies and report on them varied. Unresponsiveness to antimony has developed steadily in the past to such an extent that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy. The classic second-line treatments are unsuited: pentamidine is toxic and its efficacy has also declined, and amphotericin B deoxycholate is effective but requires hospitalisation for long periods and toxicity is common. Liposomal amphotericin B is very effective and safe but currently unaffordable because of its high price. Miltefosine—the first oral drug for visceral leishmaniasis—is now registered and marketed in India and is effective, but should be used under supervision to prevent misuse. Paromomycin (or aminosidine) is effective and safe, and although not yet available, a regulatory submission is due soon. To preserve the limited armamentarium of drugs to treat visceral leishmaniasis, drugs should not be deployed unprotected; combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems. India, Bangladesh, and Nepal agreed recently to undertake measures towards the elimination of visceral leishmaniasis. The lessons learnt in Bihar could help inform policy decisions both regionally and elsewhere.
226 citations
TL;DR: It is suggested that the vectorial capacity of R. sanguineus for L. chagasi should be evaluated further, opening new perspectives in the epidemiology of ZVL.
176 citations
TL;DR: The evaluation of clinical trials provided good evidence for recommending the use of meglumine antimoniate at a minimum dosage of 100 mg kg(-1) daily for at least 3-4 weeks, combined with allopurinol in order to obtain a good clinical efficacy and a reduced relapse rate.
Abstract: Canine visceral leishmaniasis is a systemic disease caused by Leishmania infantum. The aim of this systematic review was to identify and evaluate the evidence of efficacy of interventions for treatment or prevention of canine visceral leishmaniasis, and to propose recommendations for or against their use. Forty-seven articles describing clinical trials published between 1980 and 2004 fulfilled selection criteria. The evaluation of clinical trials provided good evidence for recommending the use of meglumine antimoniate at a minimum dosage of 100 mg kg(-1) daily for at least 3-4 weeks, combined with allopurinol in order to obtain a good clinical efficacy and a reduced relapse rate. The evaluation of the articles also provided fair evidence for recommending the use of pentamidine (4 mg kg(-1) twice weekly) and aminosidine (5 mg kg(-1) twice daily) for 3-4 weeks. There was insufficient evidence for recommending the use of allopurinol alone, amphotericin B, buparvaquone, ketoconazole, enrofloxacin, and the combinations of metronidazole with spiramicyn or metronidazole with enrofloxacin. Fair evidence against the use of aminosidine at high dosages (20-80 mg kg(-1) per day) was proposed due to its side effects. Evaluation of articles on repellent measures against sand fly vectors of leishmaniasis provided good evidence for recommending deltamethrin collars and fair evidence for recommending spot-on permethrin.
163 citations
TL;DR: The results suggest that IFN-γ and IL-10 are the molecules most likely involved in determining fate of disease, and that simpler clinical evaluations, as a palpable spleen or liver, can be used.
Abstract: Leishmaniasis remains a serious public health problem in several parts of the developing world. Effective prophylactic measurements are hampered by imprecise comprehension of different aspects of the disease, including its immunoregulation. A better comprehension of immunoregulation in human VL may be useful both for designing and evaluating immunoprophylaxis. To explore immunoregulatory mechanisms, 20 visceral leishmaniasis (VL) patients were evaluated during active disease and at different periods up to one year after treatment determining their plasma cytokine levels, clinical parameters (palpable spleen and liver) and antibody levels. Elevated plasma levels of IFN-γ and of IL-12 p40 were observed during active disease, significantly decreasing after treatment whereas in vitro Leishmania antigen-stimulated IFN-γ production by PBMC exhibited an inverse pattern being low during disease and increasing steadily thereafter. Absence of IFN-γ activity is a hallmark of VL. The main candidate for blunting IFN-γ activity is IL-10, a cytokine highly elevated in plasma with sharp decrease after treatment. Activity of IL-10 is inferred by high levels of anti-Leishmania specific IgG1 and IgG3. TGF-β had elevated total, but not of active, levels lessening the likelihood of being the IFN-γ counterpart. Spleen or liver size presented a steady decrease but return to normal values at only 120 days after treatment. Anti-Leishmania IgG (total and subclasses) levels and DTH or Leishmania-stimulated lymphocyte proliferation conversion to positive also present a slow decrease after treatment. IL-6 plasma levels were elevated in only a few patients. Taken together our results suggest that IFN-γ and IL-10 are the molecules most likely involved in determining fate of disease. After treatment, there is a long delay before the immune profile returns to normal what precludes using plasma cytokine levels as criteria of cure as simpler clinical evaluations, as a palpable spleen or liver, can be used.
144 citations
TL;DR: It is proposed that the combination of DNA and recombinant protein vaccination using CPs could be instrumental to control (VL) in dogs.
137 citations
TL;DR: The results showed that the NH36 DNA vaccine induced a strong immunoprotection against visceral and cutaneous leishmaniasis, suggesting that this DNA vaccine represents a very good candidate for use against several Leishmania species.
Abstract: The fucose-mannose ligand (FML) complex of Leishmania donovani is a promising vaccine candidate against murine and canine visceral leishmaniasis, and its main component is a 36-kDa nucleoside hydrolase (NH36). In this study, we tested the immune response and protection induced by the purified FML, the recombinant NH36 (rNH36), and NH36 DNA vaccines against the agents of visceral (L. chagasi) and cutaneous (L. mexicana) leishmaniasis in BALB/c mice. Mice developed weak humoral response to the vaccines alone, except for those immunized with FML. However, all three vaccine groups presented elevated immunoglobulin G (IgG), IgG1, and IgG2a levels after infection with L. chagasi, whereas no differences were observed between vaccine and control groups after infection with L. mexicana. A strong intradermal reaction to L. donovani and L. mexicana antigens was observed in mice immunized with rNH36 or FML, whereas mice immunized with NH36 DNA only reacted against L. donovani antigens. Experimental infection of immunized mice demonstrated that FML and rNH36 induced significant protection against L. chagasi infection with reductions in parasite loads of 79%. FML also conferred partial protection against L. mexicana infection. The best protection was observed in mice immunized with the VR1012-NH36 DNA vaccine, which induced an 88% reduction in L. chagasi parasite load and a 65% reduction in L. mexicana lesion size. Fluorescence-activated cell sorting analysis indicated the DNA vaccine induced a two- to fivefold increase in gamma interferon-producing CD4+ T cells, indicating a Th1-type immune response. Our results showed that the NH36 DNA vaccine induced a strong immunoprotection against visceral and cutaneous leishmaniasis, suggesting that this DNA vaccine represents a very good candidate for use against several Leishmania species.
TL;DR: This is the first report of maternal transmission of a North American isolate of L. infantum from an experimentally infected dog and DNA was detectable by PCR in liver, bone marrow, and heart from all 3 puppies and in the spleen, lymph node, kidney, and placenta in 2 puppies.
Abstract: Leishmania infantum, an etiologic agent of zoonotic visceral leishmaniasis, is widespread among foxhounds in the United States. Although sand flies are widely distributed throughout the United States, epidemiological data do not support a major role for sand flies in the transmission of L. infantum in foxhounds in this country. Congenital transmission of human visceral leishmaniasis is reported in humans and might also occur in dogs. We have previously isolated L. infantum from Virginia foxhounds and used this isolate (LIVT-1) to experimentally infect beagles. Four female beagles, chronically infected with LIVT-1, were bred to a male beagle chronically infected with L. infantum chagasi. One beagle was able to maintain her pregnancy, and 4 puppies were delivered by cesarean section. One puppy was malformed and autolytic at delivery, and tissues were not collected or analyzed. The remaining puppies were killed at the time of cesarean section, and selected tissues were collected for parasite culture and PCR. Promastigotes were not cultured from tissues in any of the puppies. Leishmania sp. DNA was detectable by PCR in liver, bone marrow, and heart from all 3 puppies and in the spleen, lymph node, kidney, and placenta in 2 puppies. Placental tissue from the dam was PCR negative. This is the first report of maternal transmission of a North American isolate of L. infantum from an experimentally infected dog.
TL;DR: This work is the first report of the detection of L. (L.) chagasi in a naturally infected T. rattus and T. apereoides, and the utility of filter paper as a substrate for PCR analyses and the efficacy of the procedure associated to the hybridization is emphasized.
TL;DR: The present work describes the cytokine expression in peripheral blood mononuclear cells (PBMC) obtained from asymptomatic dogs experimentally infected with L. infantum that present a cellular protective immune response and In vitro stimulation of PBMC with soluble leishmanial antigen (SLA) promoted the expression of IL-2, IFN-gamma, TNF-alpha, IL-18, Il-4, IL -6 and IL-10 mRNA.
TL;DR: A notable difference in the intrinsic sensitivity of Leishmania species to miltefosine in vitro is demonstrated, which may have implications for the interpretation of clinical trials.
Abstract: Clinical isolates of Leishmania, from visceral leishmaniasis (VL) cases in Nepal and from cutaneous leishmaniasis (CL) cases in Peru, were cultured using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to type species and strain. Promastigotes from 38 isolates, within eight passages from isolation, were used to infect mouse peritoneal macrophage cultures in vitro, and the amastigote sensitivity to miltefosine was determined. The concentration required to kill 50% of intracellular amastigotes from Nepalese VL isolates, all typed as Leishmania (L.) donovani (N = 24) from both Sbv responders and nonresponders, ranged from 8.7 to 0.04 microg/mL. In contrast, the concentration required to kill 50% intracellular amastigotes from isolates from Peru, typed as L.(V.) braziliensis (N = 8), was > 30 to 8.4 microg/mL, L.(V.) guyanensis (N = 2) > 30 to 1.9 microg/mL, L.(L.) mexicana (N = 1) > 30 microg/mL, and L. (V.) lainsoni (N = 4) was 3.4 to 1.9 microg/mL. This demonstrates a notable difference in the intrinsic sensitivity of Leishmania species to miltefosine in vitro. If this model can be correlated to therapeutic outcome, it may have implications for the interpretation of clinical trials.
TL;DR: The absence of symptoms and of evidence of Leishmania DNA and parasites in Leishmune-vaccinated animals indicates the non-infectious condition of the LeishMune- Vaccinated dogs.
TL;DR: VL was most commonly associated with renal transplantation and most patients were from Southern European countries, and leucopoenia and anaemia were the most frequent haematological disorders.
TL;DR: A small series of pregnant women with VL observed in the Neapolitan area over a 7 year period and a systematic review of the literature on this topic show the efficacy and safety of amphotericin B formulations for mother and fetus are supported.
Abstract: Methods: Consecutive cases of VL in HIV-negative female patients between 1996 and 2002 were evaluated. Pregnant women who fulfilled criteria for VL diagnosis were included and diagnostic, clinical and therapeutic features were considered. The outcome for both the pregnant woman and the fetus was evaluated over a 24 month period of post-therapy follow-up. A systematic search of English language literature through the MEDLINE database and Cochrane Library with the search strings ‘leishmaniasis AND pregnancy’ and ‘leishmaniasis AND visceral AND congenital’ integrated with a manual search completed our study. Results: Five consecutive pregnant women were diagnosed as having VL. Fever and hepatosplenomegaly were the main presenting symptoms. All received liposomal amphotericin B without any toxicity to either the mothers or newborns. No treatment failure or congenital VL case was observed. The systemic review of the literature revealed 17 cases of VL during pregnancy. Untreated VL resulted in consequences on the fetus or congenital VL. Conclusions: The efficacy and safety of amphotericin B formulations for mother and fetus are supported by the cumulative analysis of our data and literature data.
TL;DR: The study showed that atisine-type C20-diterpenoid alkaloids exhibited promising anti-leishmanial properties with strong molecular selectivity, which might have implications for other intracellular pathogens- or phylogenetically related parasites, such as Trypanosoma spp.
TL;DR: Visceral leishmaniasis in the HIV-infected population should be included in the CDC clinical category C for the definition of AIDS in the same way that other geographically specific opportunistic infections are included.
Abstract: The clinical presentation of visceral leishmaniasis shares similarities with other geographically specific infectious diseases associated with AIDS in terms of relapsing course and atypical presentation. However, visceral leishmaniasis has not, until now, been included in the AIDS case definition. The aim of this study was to describe the clinical features and determinants for relapse and case-fatality of visceral leishmaniasis in HIV-infected patients from a Spanish Mediterranean area. A chart review was conducted in 16 hospitals in the autonomous communities of Valencia and Murcia (Spain). From 1988 to 2001, a total of 228 episodes of visceral leishmaniasis were diagnosed in 155 HIV-infected patients by the detection of amastigotes in bone marrow aspirates or in other tissue samples. Most patients had advanced HIV disease, with a median CD4+ lymphocyte cell count of 55 cells × 109 l, and 56% of them had a previous AIDS-indicator disease. The median duration of follow-up was 8.4 months. HIV-infected patients with visceral leishmaniasis presented with fever (76%), hepatomegaly (77%), splenomegaly (78%), and varying degrees of cytopenias. Leishmania was detected in atypical sites in 22 (14%) patients. A total of 37 (24%) patients had a relapse of visceral leishmaniasis. Female gender was a risk factor for relapse, whereas administration of secondary prophylaxis for visceral leishmaniasis and a completed therapy for visceral leishmaniasis were protective factors against relapse. A total of 86 (54%) patients died. Independent determinants for survival were CD4+ lymphocyte cell count, completed therapy for leishmania, and secondary prophylaxis for visceral leishmaniasis. The findings show that, in HIV-infected patients, visceral leishmaniasis occurs in late stages of HIV disease and often has a relapsing course. Secondary prophylaxis reduces the risk of relapse. Visceral leishmaniasis in the HIV-infected population should be included in the CDC clinical category C for the definition of AIDS in the same way that other geographically specific opportunistic infections are included.
TL;DR: Findings indicate that genital lesions and shedding of Leishmania sp.
Abstract: Although visceral leishmaniasis is primarily transmitted by a biological invertebrate vector, trans- mission in the absence of the vector has been reported, including venereal transmission in humans. Considering the possibility of venereal transmission, we studied genital lesions in dogs naturally infected with visceral leishmaniasis and shedding of Leishmania sp. in the semen. Approximately 200 dogs were serologically tested for anti-Leishmania antibodies and divided into three groups: 1) serologically negative dogs (n 20), 2) asymptomatic serologically positive dogs (n 20), and 3) symptomatic serologically positive dogs (n 20). Samples from both testes, all segments of both epididymes, prostate gland, glans penis, and prepuce were histologically evaluated and processed for immunodetection of Leishmania sp. Semen samples were obtained from 22 symptomatic serologically positive dogs and processed for detecting Leishmania DNA by polymerase chain reaction. A significantly higher frequency of inflammation was observed in the epididymes, glans penis, and prepuce of dogs with visceral leishmaniasis, which was associated with a high frequency of immunohis- tochemically positive tissues (up to 95% of tissues from symptomatic dogs were positive by immunohisto- chemistry). Leishmania DNA was detected in eight of 22 semen samples from symptomatic dogs. Together these findings indicate that genital lesions and shedding of Leishmania sp. (donovani complex) in the semen are associated with visceral leishmaniasis. Additional studies should address the possibility of venereal trans- mission of the disease in the dog.
TL;DR: The relevant epitopes of K9, K26, and K39 antigens were joined by PCR strategy to produce the chimeric recombinant protein, which was found highly expressed in Escherichia coli and efficiently purified by affinity chromatography.
Abstract: Wild canids and domestic dogs are the main reservoir of zoonotic visceral leishmaniasis (VL) caused by Leishmania infantum (syn.: Leishmania chagasi). Serological diagnosis of VL is therefore important in both human and dog leishmaniasis from a clinical and epidemiological point of view. Routine diagnosis of VL is traditionally carried out by immunofluorescent antibody test (IFAT), which is laborious and difficult to standardize and to interpret. In the last decade, however, several specific antigens of Leishmania infantum have been characterized, allowing the development of a recombinant-based immunoassay. Among them, the whole open reading frame encoding K9 antigen, the gene fragment encoding the repetitive sequence of K26, and the 3′-terminal gene fragment of the kinesin-related protein (K39sub) were previously evaluated as diagnostic markers for canine leishmaniasis and proved to be independent in their antibody reactivity. Since sensitivity of serological test is usually higher in multiple-epitope format, in this study the relevant epitopes of K9, K26, and K39 antigens were joined by PCR strategy to produce the chimeric recombinant protein. The resulting mosaic antigen was found highly expressed in Escherichia coli and efficiently purified by affinity chromatography. Antigenic properties of this recombinant antigen were evaluated by indirect enzyme-linked immunosorbent assay (ELISA) using a panel of human and dog sera previously characterized by parasitological and/or serological techniques. Chimeric ELISA showed 99% specificity in both human (n = 180) and canine (n = 343) control groups, while sensitivity was higher in canine VL (96%, n = 213) than in human VL (82%, n = 185). Accordingly, concordance between IFAT and canine chimeric ELISA (k = 0.95, 95% confidence interval = 0.93 to 0.98) was higher than between IFAT and human chimeric ELISA (k = 0.81, 95% confidence interval = 0.76 to 0.87). Results suggest the potential use of this new antigen for routine serodiagnosis of VL in both human and canine hosts.
TL;DR: From the present study, quinoline 5 is the most promising compound against both cutaneous and visceral leishmaniasis.
Abstract: We report in this study the in vivo efficacy of nine 2-substituted quinolines on the Leishmania amazonensis cutaneous infection murine model and on the Leishmania infantum and Leishmania donovani visceral infection murine models. In the case of the L. amazonensis model, quinolines were administered orally at 25 mg/kg twice daily for 15 days. Quinolines 1, 2, 3, and 7 reduced by 80 to 90% the parasite burdens in the lesion, whereas N-methylglucamine antimoniate (Glucantime), administered by subcutaneous injections at 100 mg [28 mg Sb(V)] per kg of body weight daily, reduced the parasite burdens by 98%. In visceral leishmaniasis due to L. infantum, mice treated orally at 25 mg/kg daily for 10 days with quinolines 1, 4, 5, and 6 showed a significant reduction of parasite burdens in the liver and spleen. These quinolines were significantly more effective than meglumine antimoniate to reduce the parasite burden in both the liver and spleen. Also, the oral in vivo activity of three quinolines (quinolines 4, 5, and 2-n-propylquinoline) were determined against L. donovani (LV 9) at 12.5 and 25 mg/kg for 10 days. Their activity was compared with that of miltefosine at 7.5 mg/kg. Miltefosine, 2-n-propylquinoline, and quinoline 5 at 12.5 mg/kg significantly reduced the parasite burdens in the liver by 72, 66, and 61%, respectively. From the present study, quinoline 5 is the most promising compound against both cutaneous and visceral leishmaniasis. The double antileishmanial and antiviral activities of these compounds suggest that this series could be a potential treatment for coinfection of Leishmania-human immunodeficiency virus.
TL;DR: It is found that the determination of serum protein, A/G ratio and the use of two different leishmanial serological tests like IFAT and ELISA are essential in CVL screening.
Journal Article•
TL;DR: Highly active antiretroviral therapy (HAART) need to be given for management of HIV infection along with treatment of other opportunistic infections.
Abstract: Leishmaniasis, a globally prevalent parasitic disease occurs in three forms viz., visceral, cutaneous and mucocutaneous, transmitted by the bite of infected female Phlebotomus sandflies. Visceral leishmaniasis (VL) has 100 per cent fatality rate, if left untreated. India has the largest burden of this disease. HIV infection is also increasing worldwide and several reports indicate rising trend of VL/ HIV co-infection, modifying the traditional anthroponotic pattern of VL transmission. Both VL and HIV tend to lower the cell mediated immunity (CMI) resulting in poor drug response and opportunistic infections involving gastrointestinal, cutaneous, respiratory tract and central nervous system (CNS) may occur. Diagnosis of such co-infected cases is quite difficult. However, newer tests like nested PCR, rk39 immunochromatographic test etc., can be of help. Response to different antileishmanial drugs like sodium antimony gluconate (SAG), amphotericin B is far from satisfactory. However, a new oral drug miltefosine has been found to be promising. Highly active antiretroviral therapy (HAART) need to be given for management of HIV infection along with treatment of other opportunistic infections.
TL;DR: Results point to the possible use of this antigen cocktail formulated with the adjuvant MPL-SE in efficacy field trials against canine VL.
Abstract: Control of canine visceral leishmaniasis (VL) remains a difficult and serious problem mostly because there is no reliable and effective vaccine available to prevent this disease. A mixture of three recombinant leishmanial antigens (TSA, LeIF and LmSTI1) encoded by three genes highly conserved in the Leishmania genus have been shown to induce excellent protection against infection in both murine and simian models of cutaneous leishmaniasis. A human clinical trial with these antigens is currently underway. Because of the high degree of conservation, these antigens might be useful vaccine candidates for VL as well. In the present study, using the dog model of the visceral disease, we evaluated the immunogenicity of these three antigens formulated with two different adjuvants, MPL-SE® and AdjuPrime®. The results were compared with a whole parasite vaccine formulated with BCG as the adjuvant. In order to investigate if sensitization with the recombinant antigens would result in recognition of the corresponding native parasite antigens upon infection, the animals were exposed for four weeks after the termination of the immunization protocol with the recombinant antigens to a low number of L. chagasi promastigotes, an etiological agent of VL. Immune response was evaluated by quantitative ELISA in the animal sera before and after exposure to the viable parasites. Both antigen specific IgG1 and IgG2 antibody levels were measured. Immunization of dogs with the recombinant antigens formulated in either MPL-SE® or AdjuPrime® resulted in high antibody levels particularly to LmSTI1. In addition, this immunization although to low levels, resulted in the development of antibody response to the whole parasite lysate. Importantly, experimental exposure with low numbers of culture forms of L. chagasi promastigotes caused a clear boost in the immune response to both the recombinant antigens and the corresponding native molecules. The boost response was predominantly of the IgG2 isotype in animals primed with the recombinant antigens plus MPL-SE®. In contrast, animals primed with the recombinant antigens formulated in AdjuPrime® as well as animals vaccinated with crude antigen preparation responded with mixed IgG1/IgG2 isotypes. These results point to the possible use of this antigen cocktail formulated with the adjuvant MPL-SE® in efficacy field trials against canine VL.
TL;DR: Comparable levels of protection were found for mice boosted with either LACK-WR or Lack-MVA, supporting the use of an attenuated vaccinia virus-based vaccine against human visceral leishmaniasis.
Abstract: This study reports the efficacy of a heterologous prime-boost vaccination using DNA and vaccinia viruses (Western Reserve [WR] virus and modified [attenuated] vaccinia virus Ankara [MVA]) expressing the LACK antigen (Leishmania homologue of receptors for activated C kinase) and an intradermal murine infection model employing Leishmania infantum. At 1 month postinfection, vaccinated mice showed high levels of protection in the draining lymph node (240-fold reduction in parasite burden) coupled with significant levels of gamma interferon (20 to 200 ng/ml) and tumor necrosis factor alpha/lymphotoxin (8 to 134 pg/ml). Significant but lower levels of protection (6- to 30-fold) were observed in the spleen and liver. Comparable levels of protection were found for mice boosted with either LACK-WR or LACK-MVA, supporting the use of an attenuated vaccinia virus-based vaccine against human visceral leishmaniasis.
TL;DR: In this article, the proportion of CD4+ and CD8+ T cells that produced IFN-gamma and IL-4 after stimulation with PMA (Phorbol 12-myristate 13-acetate) and ionomycin was significantly reduced in VL patients compared to sub-clinical and asymptomatic infections or healthy controls.
TL;DR: A shift from monotherapy to multi-drug combinations of short courses delivered at no or affordable cost, through directly observed therapy, seems to be the only way to develop the treatment of this disease.
Abstract: The Leishmania donovani complex includes L. chagasi and L. infantum, and causes visceral leishmaniasis (VL), a disseminated and potentially fatal form of leishmaniasis. The treatment options for VL are limited. Pentavalent antimonials (Sbv) are the first-line treatment options worldwide except for in Europe and Sbv-unresponsive regions of India. Amphotericin B deoxycholate is the drug of choice in India, as are its lipid formulations in Europe. However, liposomal amphotericin B (AmBisome, Gilead Sciences, Inc.) is the best antileishmanial formulation, but its prohibitive cost limits its use in endemic countries. Preferential pricing of AmBisome for patients with VL may provide hope for these underprivileged patients. Oral miltefosine and paromomycin are the other drugs that have been recently developed. Limited therapeutic options, the potential for development of resistance and serious toxicity associated with antileishmanial drugs necessitates a change in the treatment policy. A shift from monotherapy to multi-drug combinations of short courses delivered at no or affordable cost, through directly observed therapy, seems to be the only way to develop the treatment of this disease.