Leishmania is a genus of protozoan parasites that are transmitted by the bite of phlebotomine sandflies and give rise to a range of diseases (collectively known as leishmaniases) that affect over 150 ...million people worldwide. Cellular immune mechanisms have a major role in the control of infections with all Leishmania spp. However, as discussed in this Review, recent evidence suggests that each host-pathogen combination evokes different solutions to the problems of parasite establishment, survival and persistence. Understanding the extent of this diversity will be increasingly important in ensuring the development of broadly applicable vaccines, drugs and immunotherapeutic interventions.
Leishmaniasis is a neglected tropical parasitic disease endemic in South Asia, East Africa, Latin America and the Middle East. It is associated with low socioeconomic status (SES) and responsible for ...considerable mortality and morbidity. Reports suggest that patients with leishmaniasis may have a higher risk of mental illness (MI), psychosocial morbidity (PM) and reduced quality of life (QoL), but this is not well characterised. The aim of this study was to conduct a systematic review to assess the reported impact of leishmaniasis on mental health and psychosocial wellbeing.
A systematic review of the literature was carried out. Pre-specified criteria were applied to identify publications including observational quantitative studies or systematic reviews. Two reviewers screened all of the titles, abstracts and full-studies and a third reviewer was consulted for disagreements. Data was extracted from papers meeting the criteria and quality appraisal of the methods was performed using the Newcastle-Ottawa Scale or the Risk of Bias in Systematic Review tool.
A total of 14 studies were identified from 12,517 records. Nine cross-sectional, three case-control, one cohort study and one systematic review were included. Eleven assessed MI outcomes and were measured with tools specifically designed for this; nine measured PM and 12 measured QoL using validated measurement tools. Quality appraisal of the studies showed that six were of good quality. Cutaneous leishmaniasis and post kala-azar dermal leishmaniasis showed evidence of associated MI and PM including depression, anxiety and stigma, while all forms of disease showed decreased QoL. The findings were used to inform a proposed model and conceptual framework to show the possible links between leishmaniasis and mental health outcomes.
There is evidence that leishmaniasis has an impact on MI, PM or QoL of patients and their families and this occurs in all the main subtypes of the disease. There are however large gaps in the evidence. Further research is required to understand the full extent of this problem and its mechanistic basis.
Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing ...skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.
We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.
ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.
The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.
This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).
A pressing need exists to develop vaccines for neglected diseases, including leishmaniasis. However, the development of new vaccines is dependent on their value to two key players-vaccine developers ...and manufacturers who need to have confidence in the global demand in order to commit to research and production; and governments (or other international funders) who need to signal demand based on the potential public health benefits of the vaccine in their local context, as well as its affordability. A detailed global epidemiological analysis is rarely available before a vaccine enters a market due to lack of resources as well as insufficient global data necessary for such an analysis. Our study seeks to bridge this information gap by providing a generalisable approach to estimating the commercial and public health value of a vaccine in development relying primarily on publicly available Global Burden of Disease (GBD) data. This simplified approach is easily replicable and can be used to guide discussions and investments into vaccines and other health technologies where evidence constraints exist. The approach is demonstrated through the estimation of the demand curve for a future leishmaniasis vaccine.
We project the ability to pay over the period 2030-2040 for a vaccine preventing cutaneous and visceral leishmaniasis (CL / VL), using an illustrative set of countries which account for most of the global disease burden. First, based on previous work on vaccine demand projections in these countries and CL / VL GBD-reported incidence rates, we project the potential long-term impact of the vaccine on disability-adjusted life years (DALYs) averted as a result of reduced incidence. Then, we apply an economic framework to our estimates to determine vaccine affordability based on the abilities to pay of governments and global funders, leading to estimates of the demand and market size. Based on our estimates, the maximum ability-to-pay of a leishmaniasis vaccine (per course, including delivery costs), given the current estimates of incidence and population at risk, is higher than $5 for 25-30% of the countries considered, with the average value-based maximum price, weighted by quantity demanded, being $5.7-6 $0.3 - $34.5, and total demand of over 560 million courses.
Our results demonstrate that both the quantity of vaccines estimated to be required by the countries considered as well as their ability-to-pay could make a vaccine for leishmaniasis commercially attractive to potential manufacturers. The methodology used can be equally applied to other technology developments targeting health in developing countries.
The development of vaccines against one or all forms of human leishmaniasis remains hampered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed ...estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 300-830 million doses for a vaccine preventing visceral leishmaniasis and 557-1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years ~160,000 doses for prevention and ~7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.
The
Leishmania
granuloma shares some, though not all, properties with that formed following mycobacterial infection. As a simplified, noncaseating granuloma composed of relatively few and largely ...mononuclear cell populations, it provides a tractable model system to investigate intra-granuloma cellular dynamics, immune regulation, and antimicrobial resistance. Here, the occurrence of granulomatous pathology across the spectrum of leishmaniasis, in humans and animal reservoir hosts, is first described. However, this review focuses on the process of hepatic granuloma formation as studied in rodent models of visceral leishmaniasis, starting from the initial infection of Kupffer cells to the involution of the granuloma after pathogen clearance. It describes how the application of intravital imaging and the use of computational modeling have changed some of our thoughts on granuloma function, and illustrates how host-directed therapies have been used to manipulate granuloma form and function for therapeutic benefit. Where appropriate, lessons that may be equally applicable across the spectrum of granulomatous diseases are highlighted.
Highlights • Sodium antimony gluconate contributes towards the pathogenesis of PKDL. • UV light plays a pivotal role in the development of PKDL. • Development of PKDL can be viewed as a reinfection ...or activation of latent Leishmania parasites. • PKDL can be resolved by mounting an effective tissue-specific memory T cell response. • Host genetic factors play a contributory role.
The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated ...macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection. Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated. This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis. Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species. At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1. Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization. Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity. Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration.
Tegumentary leishmaniasis (TL) is a disease of skin and/or mucosal tissues caused by Leishmania parasites. TL patients may concurrently carry other pathogens, which may influence the clinical outcome ...of TL.
This review focuses on the frequency of TL coinfections in human populations, interactions between Leishmania and other pathogens in animal models and human subjects, and implications of TL coinfections for clinical practice. For the purpose of this review, TL is defined as all forms of cutaneous (localised, disseminated, or diffuse) and mucocutaneous leishmaniasis. Human immunodeficiency virus (HIV) coinfection, superinfection with skin bacteria, and skin manifestations of visceral leishmaniasis are not included. We searched MEDLINE and other databases and included 73 records: 21 experimental studies in animals and 52 studies about human subjects (mainly cross-sectional and case studies). Several reports describe the frequency of Trypanosoma cruzi coinfection in TL patients in Argentina (about 41%) and the frequency of helminthiasis in TL patients in Brazil (15% to 88%). Different hypotheses have been explored about mechanisms of interaction between different microorganisms, but no clear answers emerge. Such interactions may involve innate immunity coupled with regulatory networks that affect quality and quantity of acquired immune responses. Diagnostic problems may occur when concurrent infections cause similar lesions (e.g., TL and leprosy), when different pathogens are present in the same lesions (e.g., Leishmania and Sporothrix schenckii), or when similarities between phylogenetically close pathogens affect accuracy of diagnostic tests (e.g., serology for leishmaniasis and Chagas disease). Some coinfections (e.g., helminthiasis) appear to reduce the effectiveness of antileishmanial treatment, and drug combinations may cause cumulative adverse effects.
In patients with TL, coinfection is frequent, it can lead to diagnostic errors and delays, and it can influence the effectiveness and safety of treatment. More research is needed to unravel how coinfections interfere with the pathogenesis of TL.
Leishmaniasis is a disease complex caused by 20 species of protozoan parasites belonging to the genus
Leishmania
. In humans, it has two main clinical forms, visceral leishmaniasis (VL) and cutaneous ...or tegumentary leishmaniasis (CL), as well as several other cutaneous manifestations in a minority of cases. In the mammalian host
Leishmania
parasites infect different populations of macrophages where they multiply and survive in the phagolysosomal compartment. The progression of both VL and CL depends on the maintenance of a parasite-specific immunosuppressive state based around this host macrophage infection. The complexity and variation of immune responses and immunopathology in humans and the different host interactions of the different
Leishmania
species has an impact upon the effectiveness of vaccines, diagnostics and drugs.
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