The association between rLiHyp1 protein plus adjuvant and amphotericin B is an effective immunotherapy against visceral leishmaniasis in mice.

Treatment of visceral leishmaniasis (VL) is compromised by drug toxicity, high cost and/or the emergence of resistant strains. Though canine vaccines are available, there are no licensed prophylactic human vaccines. One strategy to improve clinical outcome for infected patients is immunotherapy, which associates a chemotherapy that acts directly to reduce parasitism and the administration of an immunogen-adjuvant that activates the host protective Th1-type immune response. In this study, we evaluated an immunotherapy protocol in a murine model by combining recombinant (r)LiHyp1 (a hypothetical amastigote-specific Leishmania protein protective against Leishmania infantum infection), with monophosphoryl-lipid A (MPLA) as adjuvant and amphotericin B (AmpB) as reference antileishmanial drug. We used this protocol to treat L. infantum infected-BALB/c mice, and parasitological, immunological and toxicological evaluations were performed at 1 and 30 days after treatment. Results showed that mice treated with rLiHyp1/MPLA/AmpB presented the lowest parasite burden in all organs evaluated, when both a limiting dilution technique and qPCR were used. In addition, these animals produced higher levels of IFN-γ and IL-12 cytokines and IgG2a isotype antibody, which were associated with lower production of IL-4 and IL-10 and IgG1 isotype. Furthermore, low levels of renal and hepatic damage markers were found in animals treated with rLiHyp1/MPLA/AmpB possibly reflecting the lower parasite load, as compared to the other groups. We conclude that the rLiHyp1/MPLA/AmpB combination could be considered in future studies as an immunotherapy protocol to treat against VL.

Immunotherapy for visceral leishmaniasis: A trapeze of balancing counteractive forces.

The protozoan parasite Leishmania donovani, residing and replicating within the cells of the monocyte-macrophage (mono-mac) lineage, causes visceral leishmaniasis (VL) in humans. While, Leishmania infantum, is the main causative agent for zoonotic VL, where dogs are the main reservoirs of the disease. The chemotherapy is a serious problem because of restricted repertoire of drugs, drug-resistant parasites, drug-toxicity and the requirement for parenteral administration, which is a problem in resource-starved countries. Moreover, immunocompromised individuals, particularly HIV-1 infected are at higher risk of VL due to impairment in T-helper cell and regulatory cell responses. Furthermore, HIV-VL co-infected patients report poor response to conventional chemotherapy. Recent efforts are therefore directed towards devising both prophylactic and therapeutic immunomodulation. As far as prophylaxis is concerned, although canine vaccines for the disease caused by Leishmania infantum or Leishmania chagasi are available, no vaccine is available for use in humans till date. Therefore, anti-leishmanial immunotherapy triggering or manipulating the host's immune response is gaining momentum during the last two decades. Immunomodulators comprised of small molecules, anti-leishmanial peptides, complex ligands for host receptors, cytokines or their agonists and antibodies have been given trials both in experimental models and in humans. However, the success of immunotherapy in humans remains a far-off target. We, therefore, propose that devising a successful immunotherapy is an act of balancing enhanced beneficial Leishmania-specific responses and deleterious immune activation/hyperinflammation just as the swings in a trapeze.

A Chimera of Th1 Stimulatory Proteins of Leishmania donovani Offers Moderate Immunotherapeutic Efficacy with a Th1-Inclined Immune Response against Visceral Leishmaniasis.

Immunotherapy, a treatment based on host immune system activation, has been shown to provide a substitute for marginally effective conventional chemotherapy in controlling visceral leishmaniasis (VL), the deadliest form of leishmaniasis. As the majority of endemic inhabitants exhibit either subclinical or asymptomatic infection which often develops into the active disease state, therapeutic intervention seems to be an important avenue for combating infections by stimulating the natural defense system of infected individuals. With this perspective, the present study focuses on two immunodominant Leishmania (L.) donovani antigens (triosephosphate isomerase and enolase) previously proved to be potent prophylactic VL vaccine candidates, for generating a recombinant chimeric antigen. This is based on the premise that in a heterogeneous population, a multivalent antigen vaccine would be required for an effective response against leishmaniasis (a complex parasitic disease). The resulting molecule rLdT-E chimeric protein was evaluated for its immunogenicity and immunotherapeutic efficacy. A Th1 stimulating adjuvant BCG was employed with the protein which showed a remarkable 70% inhibition of splenic parasitic multiplication positively correlated with boosted Th1 dominant immune response against lethal L. donovani challenge in hamsters as evidenced by high IFN-γ and TNF-α and low IL-10. In addition, immunological analysis of antibody subclass presented IgG2-based humoral response besides considerable delayed-type hypersensitivity and lymphocyte proliferative responses in rLdT-E/BCG-treated animals. Our observations indicate the potential of the chimera towards its candidature for an effective vaccine against Leishmania donovani infection.

Role of Cytokines in Experimental and Human Visceral Leishmaniasis.

Visceral Leishmaniasis (VL) is the most fatal form of disease leishmaniasis. To date, there are no effective prophylactic measures and therapeutics available against VL. Recently, new immunotherapy-based approaches have been established for the management of VL. Cytokines, which are predominantly produced by helper T cells (Th) and macrophages, have received great attention that could be an effective immunotherapeutic approach for the treatment of human VL. Cytokines play a key role in forming the host immune response and in managing the formation of protective and non-protective immunities during infection. Furthermore, immune response mediated through different cytokines varies from different host or animal models. Various cytokines viz. IFN-γ, IL-2, IL-12, and TNF-α play an important role during protection, while some other cytokines viz. IL-10, IL-6, IL-17, TGF-ß, and others are associated with disease progression. Therefore, comprehensive knowledge of cytokine response and their interaction with various immune cells is very crucial to determine appropriate immunotherapies for VL. Here, we have discussed the role of cytokines involved in VL disease progression or host protection in different animal models and humans that will determine the clinical outcome of VL and open the path for the development of rapid and accurate diagnostic tools as well as therapeutic interventions against VL.

Scientometric analysis of chemotherapy of canine leishmaniasis (2000-2020).

BACKGROUND: Zoonotic visceral leishmaniasis by Leishmania infantum is a first-order pathology in canine veterinary clinics in endemic areas. Moreover, canine infections are considered the main reservoir for human disease; despite their importance in the control of the disease within a One Health approach, no scientometric study has been published. Aims of the study included analyzing the impact of canine leishmaniasis (CanL) on the scientific literature, drugs or combinations used, trends in the period from 2000 to 2020 and efficacy criteria employed. METHODS: A Web of Science (WOS)-based analysis of publications on CanL and chemotherapy of the disease in the period 2000-2020 was carried out using a stepwise methodology. Data were analyzed by year, geographical origin, chemical groups, drugs and combinations, and efficacy criteria. RESULTS: Reports on CanL (n = 3324) represented < 16% of all publications on leishmaniasis (n = 20,968), and of these around 18% (n = 596) were related to chemotherapy. Publication records on CanL followed the distribution of the infection by L. infantum in endemic areas although Mediterranean countries were overrepresented in the reports on chemotherapy of CanL. Publications on the main antileishmanial drugs used in clinical practice showed a sustained tendency in the period analyzed. Pentavalent antimonials (SbV), alone or in combination with allopurinol, represented > 50% of all publications on chemotherapy of CanL despite the availability of more recently marketed drugs. CONCLUSIONS: Chemotherapy of CanL still relies on SbV and combinations and to a lesser extent on miltefosine (MIL). Reports on chemotherapy are scarce and mostly publicly funded, and the variability of experimental conditions hampers the direct comparison of the efficacy of drugs, combinations and schedules. The vast majority of reports on efficacy do not include any information on supportive therapy; this reduces the actual value of the studies if intended for the practical management of the disease. Complete reports on the chemotherapy (etiological + symptomatic) would add value to the trials performed.

Treatment effects on IL-9+CD4+ T cells and the cytokines influencing IL-9 production in paediatric visceral leishmaniasis.

AIMS: Given the involvement of IL-9 in the immune responses to parasitic infections, we aimed to determine alterations in the levels of IL-9+CD4+ T cells and the cytokines influencing their differentiations and functions following treatment in paediatric visceral leishmaniasis (VL). METHODS AND RESULTS: Eighteen VL and 20 healthy children were included. The levels of IL-9+CD4+ T cells and cytokines influencing their differentiations and functions were measured in the blood and PBMC culture supernatant at the onset of diagnosis and 1 and 2 weeks and 2 months after treatment, using flow cytometer. IL-9+CD4+ T cells, IL-2 and TNF-α were significantly higher in the blood of VL patients than those in the controls; however, following treatment, IL-9+CD4+ T cells down-regulated and IL-33 and IFN-γ significantly up-regulated. After ex vivo stimulation, although the released cytokines were not significantly different between the study groups, the levels of IL-2, IL-9 and IFN-γ significantly decreased. CONCLUSIONS: The higher frequency of IL-9+CD4+ T cells and its decline following treatment implies their roles in the immunopathogenesis of VL; however, at the diagnosis onset, lower levels of serum IL-9 and its higher level in the culture supernatant may confer in vivo dysfunction of IL-9+CD4+ T cells in the acute phase of human VL.

LeishCare®: A Software Designed for the Management of Individuals with Leishmaniases.

The aims of this study were to describe a smartphone app aimed at healthcare professionals who work in areas endemic for visceral and tegumentary leishmaniases, and to report the user's perception of the app in these areas. The software, called LeishCare®, has the following features: data registration, image filter to record the evolution of skin lesions using photos, calculation of a score set to identify the risk of death from visceral leishmaniasis, and guides to the diseases. LeishCare® was made available to healthcare professionals in endemic municipalities in Brazil, and the perception of potential users was evaluated at baseline and after 6 and 12 months. In the first meeting, 96 (94.1%) of the 102 professionals who knew the app reported positive expectations for its use. The installation of LeishCare® on the individual device and the evaluation of user perception were completed at 6 months with 16 users and at 12 months with 20 users. More than 90% of the professionals evaluated in both assessments found the information of the app useful. The features related to the calculation of visceral leishmaniasis severity score, and the guides to leishmaniases were the most frequently accessed. Users reported competence gain attributed to the app for all items evaluated. In conclusion, LeishCare® was found to be a promising tool to help healthcare professionals in endemic areas with leishmaniasis management.

Application of the Leishmania infantum 21-kDa recombinant protein for the development of an immunochromatographic test.

BACKGROUND: Visceral leishmaniasis (VL), caused by Leishmania infantum, is a systemic parasitic disease and presents a global health problem which can be fatal if not diagnosed and treated. Dogs are the main hosts and provide reservoirs for the transmission of the disease to humans. METHODS: In this study, the gene encoding a 21-kDa protein was cloned and expressed as a fusion protein in Escherichia coli strain BL21 (DE3) for developing a rapid immunochromatographic test (ICT) to identify infected dogs. The expression of the recombinant 21-kDa protein (r21) was investigated using SDS-PAGE and Western blot methods. The purified r21-kDa protein was spotted onto ICT strips and tested by sera from experimentally infected, naturally infected and uninfected dogs. RESULTS: The SDS-PAGE and Western blot methods showed the successful expression of r21-kDa protein. The ICT strip test revealed that the r21-kDa protein was detected by the sera of experimentally and naturally infected dogs. The specificity tests also confirmed no cross-reactivity with animals infected with Trypanosoma cruzi, Toxoplasma gondii and Ehrlichia canis. CONCLUSIONS: Based on these findings, the new r21-kDa protein may be a suitable target for developing a new simple, specific and rapid serological method to detect VL in infected dogs.

Report of the Fifth Post-Kala-Azar Dermal Leishmaniasis Consortium Meeting, Colombo, Sri Lanka, 14-16 May 2018.

The 5th Post-Kala-Azar Dermal Leishmaniasis (PKDL) Consortium meeting brought together PKDL experts from all endemic areas to review and discuss existing and new data on PKDL. This report summarizes the presentations and discussions and provides the overall conclusions and recommendations.

Combination of Mycobacterium indicus pranii and Heat-Induced Promastigotes Cures Drug-Resistant Leishmania Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells.

The major issues in available therapeutic modalities against leishmaniasis are cost, toxicity, and the emergence of drug resistance. The aim of this work was to develop a successful therapeutic adjuvant against drug-resistant Leishmania donovani infection by means of combining Mycobacterium indicus pranii with heat-induced promastigotes (HIP). One-month postinfected BALB/c mice were administered subcutaneously with M. indicus pranii (108 cells) and HIP (100 µg) for 5 days. Spleens were harvested for flow cytometric and reverse transcriptase PCR analysis. The antileishmanial effect of the combination strategy was associated with induction of a disease-resolving Th1 and Th17 response with simultaneous downregulation of CD4+ CD25+ Foxp3+ (nTreg) cells and CD4+ CD25- Foxp3- (Tr1) cells in the spleen. The significant expansion of CD4+ TCM (CD4+ CD44hi CD11ahi CD62Lhi) cells was a further interesting outcome of this therapeutic strategy in the context of long-term protection of hosts against secondary infection. Toll-like receptor 2 (TLR2) was also found instrumental in this antiparasitic therapy. Induced interleukin-6 (IL-6) production from expanded CD11c+ CD8α+ (cDC1) and CD11c+ CD11b+ (cDC2) dendritic cells (DCs) but not from the CD11b+ Ly6c+ inflammatory monocytes (iMOs), was found critical in the protective expansion of Th17 as evidenced by an in vivo IL-6 neutralization assay. It also promoted the hematopoietic conversion toward DC progenitors (pre-DCs) from common dendritic cell progenitors (CDPs), the immediate precursors, in bone marrow. This novel combinational strategy demonstrated that expansion of Th17 by IL-6 released from CD11c+ classical DCs is crucial, together with the conventional Th1 response, to control drug-resistant infection.

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis.

BACKGROUND: The disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown. METHODS: We performed transcriptomics in uninfected and L. donovani-infected macrophages 6 hours post-infection. Glutamine quantification by HPLC was assessed in the supernatant of macrophages throughout the infection course. For experimental L. donovani infections, mice were infected with 1.0 x 108 stationary L. donovani promastigotes. Glutaminase (GLS) chemical inhibition was performed using BPTES and glutamine was administered throughout infection. For combined therapy experiment, a daily administration of miltefosine and glutamine was performed by oral gavage. Parasite burden was determined using a Taqman-based assay. Immune cell phenotyping and cytotoxicity were performed in splenic cells using flow cytometry. FINDINGS: We show that glutamine is essential for the control of L. donovani infection. Transcriptomic analysis of L. donovani-infected macrophages demonstrated an upregulation of genes involved in glutamine metabolism. Pharmacological inhibition of glutaminolysis significantly increased the susceptibility to infection, accompanied by an increased recruitment of anti-inflammatory myeloid cells and impaired T cell responses. Remarkably, the supplementation of glutamine to mice infected with L. donovani during miltefosine treatment potentiates parasite clearance through the development of a more effective anti-Leishmania adaptive immune response. CONCLUSIONS: Our data indicates that dietary glutamine supplementation may act as a promising adjuvant for the treatment of visceral leishmaniasis.

Intensely clustered outbreak of visceral leishmaniasis (kala-azar) in a setting of seasonal migration in a village of Bihar, India.

BACKGROUND: A visceral leishmaniasis outbreak was reported from a village in a low-endemic district of Bihar, India. METHODS: Outbreak investigation with house-to-house search and rapid test of kala-azar suspects and contacts was carried out. Sandfly collection and cone bio-assay was done as part of entomological study. RESULTS: A spatially and temporally clustered kala-azar outbreak was found at Kosra village in Sheikhpura district with 70 cases reported till December 2018. Delay of more than a year was found between diagnosis and treatment of the index case. The southern hamlet with socio-economically disadvantaged migrant population was several times more affected than rest of the village (attack rate of 19.0% vs 0.5% respectively, ORMH = 39.2, 95% CI 18.2-84.4). The median durations between onset of fever to first contact with any health services, onset to kala-azar diagnosis, diagnosis to treatment were 10 days (IQR 4-18), 30 days (IQR 17-73) and 1 day (IQR 0.5 to 3), respectively, for 50 kala-azar cases assessed till June 2017. Three-fourths of these kala-azar cases had out-of-pocket medical expenditure for their condition. Known risk factors for kala-azar such as illiteracy, poverty, belonging to socially disadvantaged community, migration, residing in kutcha houses, sleeping in rooms with unplastered walls and non-use of mosquito nets were present in majority of these cases. Only half the dwellings of the kala-azar cases were fully sprayed. Fully gravid female P. argentipes collected post indoor residual spraying (IRS) and low sandfly mortality on cone-bioassay indicated poor effectiveness of vector control. CONCLUSIONS: There is need to focus on low-endemic areas of kala-azar. The elimination programme should implement a routine framework for kala-azar outbreak response. Complete case-finding, use of quality-compliant insecticide and coverage of all sprayable surfaces in IRS could help interrupt transmission during outbreaks.

Boletim Epidemiológico: leishmaniose visceral em Goiás no ano de 2018 / Epidemiological Bulletin: Visceral Leishmaniasis in Goiás in 2018

A Leishmaniose Visceral (LV) é uma doença negligenciada, que se mantem como um importante problema de saúde pública em todo o mundo, afetando populações economicamente vulneráveis. É uma doença de transmissão vetorial por flebotomíneos Lutzomyia (L. longipalpis e L. cruzi),sendo, portanto, uma zoonose, que tem o protozoário do gênero Leishmania como agente etiológico. Os reservatórios principais em meio urbano são os cães e em ambiente silvestre as raposas (Dusicyon vetulus e Cerdocyon thous) e os marsupiais (Didelphis albiventris). É doença de notificação compulsória devido ao quadro clínico grave causado, podendo levar a óbito quando não tratada . Os pacientes infectados podem ser assintomáticos ou apresentarem sintomas diversos, que em sua maioria se manifestam como febre, fraqueza, emagrecimento, esplenomegalia e hepatomegalia

Visceral Leishmaniasis (VL) is a neglected disease, which remains an important public health problem worldwide, affecting economically vulnerable populations. It is a disease transmitted vector by sand flies Lutzomyia (L. longipalpis and L. cruzi), being, therefore, a zoonosis, which has the protozoan of the genus Leishmania as the etiological agent. The main reservoirs in urban areas are dogs and in the wild, foxes (Dusicyon vetulus and Cerdocyon thous) and marsupials (Didelphis albiventris). It is a notifiable disease due to the severe clinical condition caused, and it can lead to death when untreated . Infected patients may be asymptomatic or have different symptoms, most of which manifest as fever, weakness, weight loss, splenomegaly and hepatomegaly

Biomarkers in Post-kala-azar Dermal Leishmaniasis.

Post-kala-azar dermal leishmaniasis (PKDL) follows visceral leishmaniasis (VL, kala-azar) in 10-60% of cases. It is characterized by an asymptomatic skin rash, usually starting in the face and consisting of macules, papules, or nodules. Diagnosis is difficult in the field and is often made clinically. There is an extensive differential diagnosis, and parasitological confirmation is preferred particularly when drug treatment is considered. The response to treatment is difficult to assess as this may be slow and lesions take long to heal, thus possibly exposing patients unnecessarily to prolonged drug treatment. Biomarkers are needed; these may be parasitological (from microscopy, PCR), serological (from blood, or from the lesion), immunological (from blood, tissue), pathological (from cytology in a smear, histology in a biopsy), repeated clinical assessment (grading, photography), or combinations. In this paper, we will review evidence for currently used biomarkers and discuss promising developments.

Epidemiological aspects of the first human autochthonous visceral leishmaniosis cases in Porto Alegre, Brazil.

Human visceral leishmaniasis is a growing anthropozoonosis in Brazil, and particularly in the southern region of the country. It is an infectious disease transmitted to humans, dogs and other animals in urban and rural areas of the Americas, mainly due to the bite of Lutzomya longipalpis infected with Leishmania infantum. This article aims to portray the current epidemiological situation of the human visceral leishmaniasis arrival in Porto Alegre city, located in the southern region of Brazil. It is a descriptive study, a case series and a critical review. Six human cases with human visceral leishmaniasis were notified by the date of conclusion of the study, all human visceral leishmaniasis cases were diagnosed at late stage, leading to four deaths.

Cytokines: Key Determinants of Resistance or Disease Progression in Visceral Leishmaniasis: Opportunities for Novel Diagnostics and Immunotherapy.

Leishmaniasis is a parasitic disease of humans, highly prevalent in parts of the tropics, subtropics, and southern Europe. The disease mainly occurs in three different clinical forms namely cutaneous, mucocutaneous, and visceral leishmaniasis (VL). The VL affects several internal organs and is the deadliest form of the disease. Epidemiology and clinical manifestations of VL are variable based on the vector, parasite (e.g., species, strains, and antigen diversity), host (e.g., genetic background, nutrition, diversity in antigen presentation and immunity) and the environment (e.g., temperature, humidity, and hygiene). Chemotherapy of VL is limited to a few drugs which is expensive and associated with profound toxicity, and could become ineffective due to the parasites developing resistance. Till date, there are no licensed vaccines for humans against leishmaniasis. Recently, immunotherapy has become an attractive strategy as it is cost-effective, causes limited side-effects and do not suffer from the downside of pathogens developing resistance. Among various immunotherapeutic approaches, cytokines (produced by helper T-lymphocytes) based immunotherapy has received great attention especially for drug refractive cases of human VL. Therefore, a comprehensive knowledge on the molecular interactions of immune cells or components and on cytokines interplay in the host defense or pathogenesis is important to determine appropriate immunotherapies for leishmaniasis. Here, we summarized the current understanding of a wide-spectrum of cytokines and their interaction with immune cells that determine the clinical outcome of leishmaniasis. We have also highlighted opportunities for the development of novel diagnostics and intervention therapies for VL.

Assessment of quality of life using WHOQOL-BREF in patients with visceral leishmaniasis.

BACKGROUND: This study was aimed to assess the impact of quality of life using WHOQOL-BREF in patients with Visceral leishmaniasis (VL). METHODS: A total of 95 VL cases and 95 healthy participants filled out the questionnaires. Data on socio-demographic aspects along with disease duration were collected. Data were compared using a t-test, analysis of variance and chi-square test. RESULTS: VL patients experienced very high impact on their quality of life. Study cohort had male preponderance (72.63%). Majority (64.21%) were aged < 40 years. Longer disease duration was found to have significantly poor quality of life (p < 0.05). The physical domain was found to be most affected domains of quality of life (QOL). QOL was affected most in illiterate, married, housewife, rural population and patients with longer disease duration (p < 0.05). The psychological and environmental domains were significantly affected in > 40 years of age group married patients (p < 0.05). CONCLUSIONS: VL significantly impaired the patients' (QOL) in all four domains (physical, psychological, social relationship and environmental). Physical domain was significantly the most affected domain.

Epidemiological aspects of the first human autochthonous visceral leishmaniosis cases in Porto Alegre, Brazil

ABSTRACT Human visceral leishmaniasis is a growing anthropozoonosis in Brazil, and particularly in the southern region of the country. It is an infectious disease transmitted to humans, dogs and other animals in urban and rural areas of the Americas, mainly due to the bite of Lutzomya longipalpis infected with Leishmania infantum. This article aims to portray the current epidemiological situation of the human visceral leishmaniasis arrival in Porto Alegre city, located in the southern region of Brazil. It is a descriptive study, a case series and a critical review. Six human cases with human visceral leishmaniasis were notified by the date of conclusion of the study, all human visceral leishmaniasis cases were diagnosed at late stage, leading to four deaths.

An Overview of Immunotherapeutic Approaches Against Canine Visceral Leishmaniasis: What Has Been Tested on Dogs and a New Perspective on Improving Treatment Efficacy.

Visceral leishmaniasis (VL), caused by digenetic protozoa of the genus Leishmania, is the most severe form of leishmaniasis. Leishmania infantum is one of the species responsible for VL and the disease caused is considered a zoonosis whose main reservoir is the dog. Canine visceral leishmaniasis (CVL) can lead to the death of the animal if left untreated. Furthermore, the available pharmocologial treatment for CVL presents numerous disadvantages, such as relapses, toxicity, drug resistance, and the fact treated animals continue to be reservoirs when treatment fails to achieve parasitological cure. Moreover, the available VL control methods have not been adequate when it comes to controlling parasite transmission. Advances in immune response knowledge in recent years have led to a better understanding of VL pathogenesis, allowing new treatments to be developed based on immune system activation, often referred to as immunotherapy. In fact, well-defined protocols have been described, ranging from the use of immunomodulators to the use of vaccines. This treatment, which can also be associated with chemotherapy, has been shown to be effective in restoring or inducing an adequate immune response to reduce parasitic burden, leading to clinical improvement. This review focuses on immunotherapy directed at dogs infected by L. infantum, including a literature review of what has already been done in dogs. We also introduce a promising strategy to improve the efficacy of immunotherapy.