Yes for serological diagnosis, no for culture of the organism or for molecular (PCR) diagnosis.
GAP: General need for diagnostics of higher sensitivity to detect asymptomatic or to differentiate highly infectious cases.
Yes for serological diagnosis, no for culture of the organism or for molecular (PCR) diagnosis.
GAP: General need for diagnostics of higher sensitivity to detect asymptomatic or to differentiate highly infectious cases.
Not available as of today. Critical currently for Brazil.
DIVA tests based on recombinant antigens have already been developed for human disease.
GAP: DIVA tests based on recombinant antigens are not yet commercially available for canine applications.
The FDA approved rK39 rapid serology test provides results in 10 min, is user friendly and non invasive. Sensitivity and specificity are very high in Indian, Nepalese and Brazilian patients. This test provides a valid improvement over gold standards for VL diagnosis (microscopy of spleen or bone marrow aspirates) which are low sensitivity and extremely invasive.
Urine based test for the Leishmania antigen differentiate current from past infections, and are used as a non invasive test of cure in human patients.
rK39 rapid test has lower sensitivity in Africa. Additional antigens are needed to complement rK39 in Africa.
Further developments are still required to allow testing on non invasive samples of minimal volume (e.g. PCR methods on finger prick blood drop).
Rapid test sensitivity to detect asypmtomatic and pre-patent infections needs improvemen.
Tests in tissues more likely to be infected by Leishmania, such as conjunctival epithelial cells are pending.
Only one commercial canine vaccine subunit rA2 protein–saponin vaccine is available in Brazil but under a conditional license (i.e., temporary authorisation of use). Two commercial vaccines are available in the EU to control the infection and the disease in dogs.GAP: Despite availability, the annual costs of these vaccines are too high for most endemic regions (developing countries).
LiESP/QA-21 vaccine, Recombinant Protein Q from Leishmania infantum MON-1.
1. recombinant Protein Q from L. infantum MON-1.
2. purified excreted-secreted proteins of L. infantum and with QA-21 saponin as adjuvant.
Purified excreted-secreted proteins of L. infantum and with QA-21 saponin significantly reduces the risk of progressing to active infection or overt disease, with a clinical efficacy of 68%. In vaccinated dogs that developed disease and that were exposed to the bites of reared P. perniciosus vectors the reduction in parasite transmission was significant when compared to matched controls. However, vaccine does not differentiate vaccinated from infected animals (DIVA) which creates an issue. l. In addition, some safety concerns have been reported in purified excreted-secreted proteins -vaccinated dogs. A dog vaccinated with recombinant Protein Q from L. infantum MON-1 has 5 times less risk to develop clinical disease than a non-vaccinated dog. Information about the interruption of Leishmania transmission by recombinant Protein Q from L. infantum MON-1 is lacking.
Tools to differentiate CaniLeish® vaccinated dogs from infected are needed.
No data available regarding interruption of Leishmania transmission in Letifend® vaccinated dogs.
High in Western EU, lower in the rest of the Mediterranean basin (due to lower disposable income).GAP: Affordability of a canine vaccine may be an issue in the Mediterranean basin outside Western EU.
Both vaccines comply with EMEA regulations. Provided a vaccine candidate meets all expected specifications (including manufacturing under GMP conditions) no specific unmanageable regulatory challenge is expected.
Will depend on the selected technology supporting the vaccine candidate.
Unlikely due to travel and transport of dogs combined with the presence of competent vectors in currently non-endemic areas.
Numerous. A canine vaccine is expected to benefit greatly from on-going upstream research on human leishmaniasis but also - in a more fundamental way - from the rapidly progressing understanding of immune mechanisms of protection against intracellular pathogens and from progress in recombinant vaccines platforms in general. It is anticipated that the development of a powerful vaccine for dogs (representing a natural model of Leishmania-induced immunosuppression) would be of benefit for further developments in human Leishmania vaccinology.GAPS: Longer term vaccine developments will require strategic studies on how to achieve effective and sustained delivery, particularly pertinent in remote developing regions.
Several therapeutical options developed for human leishmaniasis exist based on different drug classes (see above). Only 2 drugs have been granted official licenses for use in dogs in the EU, injectable meglumine antimoniate and oral miltefosine. Several others are used off-label. None of these drugs is known to have prophylactic properties or radical cure efficacy in dogs.GAP: Existing therapies for dogs provide clinical cure without definitive parasitological cure. Multiple modalities/protocols are described for canine therapy, creating confusion regarding therapeutical best practices. There is the potential for increase in resistance of parasites associated with administering the human drugs to dogs.
New candidates in early research and pre-clinical phases.
High in Western EU for canine leishmaniasis, lower in the rest of the Mediterranean basin (due to lower disposable income).
Any commercial drug in the EU needs to comply with national or EMEA regulations. Provided a drug candidate meets all expected specifications (including manufacturing under GMP conditions) no specific unmanageable regulatory challenge is expected.
GAP: Risk of inducing resistance mechanisms with potential impact on therapeutical drug effectiveness in humans needs careful consideration.
Will depend on the selected technology supporting the drug candidate.
None of the currently available drugs leads to a definitive cure in dogs. Low amounts of parasite can remain quiescent in various organs with a risk that the infection relapses, particularly following - for example - immunosuppression. Unsuccessful cure of anthroponotic VL is thought to contribute to a rise in Post Kala-azar Dermal Leishmaniasis (a potentially intensive source of transmissible parasites). Drugs applied to patients with anthroponotic leishmaniasis are expected to impact on population level transmission.GAP: The role of post treatment resurgent infections in long-term transmission remains poorly understood.
Estimation 2 years.
GAP: Will depend on the vaccine technology.
This largely depends on the type of diagnostics.
This largely depends on the type of diagnostics.
Technology capable to differentiate exposed dogs from dogs with progressing disease.
Technology to predict latently infectious dogs from infected dogs.
Parasite freedom may not be a critical requirement as long as the infection is sufficient stable and controlled to limited transmissibility of infection from infected reservoirs via sand fly bites.
Several requirements should be considered for the development of a successful canine vaccine with broad applicability across the world. They include an unbiased clinical methodology for efficacy and safety evaluation. Indeed, in the past, several evaluations of canine vaccine candidates were performed using non-optimized experimental challenge models (e.g., insufficient numbers of experimental dogs) limiting the possibility for solid statistical analysis of data significance. This has led to some confusion on the true potential of some vaccine candidates. In addition, there is a need to further develop immunomonitoring laboratory tools to assess surogate markers of protection in dogs and to ensure that vaccine candidates are designed using a scalable industrialization platform. Development of a DIVA vaccine is a critical feature for a vaccine targeted at countries with an existing culling program of seropositive dogs (e.g.Brazil), but also in endemic EU countries due to interference with ongoing monitoring and surveillance activities on the spread of the disease.GAPS: Several gaps currently limit the possibility to accelerate access to a successful canine vaccine with broad applicability. A relevant, reliable and affordable/accessible vaccine clinical evaluation methodology based on natural transmission of the infection (ideally in the target species). Better understanding of immune correlates of protection (biomarkers) in dogs and development/validation of the corresponding analytical technologies. Selection of a scalable manufacturing vaccine technology. Collectively all these aspects are critical for the development of an improved vaccine. Although several manufacturing technologies of interest are readily accessible, an appropriate clinical evaluation methodology and biomarkers remain critical unmet needs/gaps.
Will depend on several key aspects: the maturity of the selected technology platform, availability of appropriate clinical methodology and biomarkers. Estimation 5 to 10 years.
Estimation € 10M.
Need to ensure that comprehensive expertise/experience is available for collaborative translational research program.GAP: Comprehensive collaborative expertise. Stable financial support.
Definitive (parasitological) cure, low toxicity, convenience of use (avoid multiple parenteral injections).
Financial rationale for a new CanL pharmaceutical development is questionable.GAP: Market attractiveness for a new CanL therapeutical is limited due to already licensed products and to the wide off-label use of several unlicensed drugs.
Leishmaniasis is not a single disease but represents a complex spectrum of diseases caused by intracellular protozoan parasites belonging to the Leishmania species and transmitted by blood-sucking female phlebotomine sand flies. The flagellated forms (promastigotes) are transmitted by the bite of the vector and multiply as aflagellated forms (amastigotes) within cells of the mononuclear phagocyte system. Each parasite species circulates in natural foci of infection where susceptible phlebotomines and mammals coexist. The epidemiology and clinical manifestations of the diseases are largely diverse, being usually grouped into 2 main entities: zoonotic leishmaniases, where domestic or wild animal reservoirs are involved in the transmission cycle and humans play a role of an accidental host, and anthroponotic leishmaniases, where man is the sole reservoir and source of vector’s infection. Clinically, leishmaniases are broadly divided into systemic forms (visceral leishmaniasis, VL) and cutaneous/mucocutaneous forms (CL/MCL).GAP: The intrinsic virulence factors that make Leishmania species either dermotropic with benign evolution of the infection, or viscerotropic resulting in lethal outcome, need to be fully elucidated.
Each nosogeographical entity of leishmaniasis is characterized by a specific pathogen, a main reservoir host and one or more - closely related - species of phlebotomine vectors. About 20 named Leishmania species and subspecies are pathogenic for humans, and 98 sand fly species are proven or suspected vectors. Molecular taxonomy studies suggest that Leishmania species are indeed a complex of close-related genotypes which may differ in the clinical outcome of the infections (e.g. some strains of L. infantum may cause VL, others CL in humans). Being eukaryotic organisms, variability and mutations are not expected to occur during short timescales, although drug pressure can select drug-resistant parasites transmissible in nature (e.g. antimony resistance in Indian L. donovani). Most of leishmaniasis entities are zoonotic by nature and reservoir hosts are usually wild mammals. Zoonotic VL, a severe disease of humans, represents the most widespread and sole entity characterized by a domestic reservoir host, the dog. L. infantum (syn. L. chagasi) is the agent which causes a severe chronic disease in dogs (canine leishmaniasis, CanL) over a wide geographical range: Mediterranean basin, Middle East, parts of Central Asia and China, where the disease is transmitted by Phlebotomus sand flies of the subgenus Larroussius; and in Latin America, mainly Brazil, where the vector is Lutzomyia longipalpis. Other leishmaniasis entities with major impact on human health include anthroponotic VL, caused by L.donovani in East Africa and the Indian subregion (vectors: P.martini, P.orientalis, P.argentipes; reservoir: humans); anthroponotic CL, due to L.tropica in north Africa and Middle East (vector: P.sergenti; reservoir: humans, but dogs and rock hyraxes may play a role of reservoir in some settings); zoonotic CL, caused by L. major in Africa, Middle East and Central Asia (vector: P.papatasi; reservoir: wild rodents); New World sylvatic CL/MCL, caused by several Leishmania species (e.g. L. mexicana, L. braziliensis, L. amazonensis, L. panamensis, etc.) transmitted by various Lutzomyia Nyssomyia, Psathyromyia, Psychodopygus and Verrucarum subgenera sand flies and hosted by a wide range of wild mammals. The role of dogs in the life cycle of L.braziliensis and L.peruviana is unclear.GAP: Pathogenicity related to L. tropica or L. braziliensis in dogs is far less well understood than the pathogenicity of L. infantum but could represent a yet underestimated infection and/or disease in this species in specific parts of the world (potential role of dogs as a reservoir?).
By itself the parasite is unstable in the environment but the leishmaniasis foci, representing particular biotopes, are stable whenever conditions for the sand fly vector and the reservoir host are appropriate. There is no evidence that contaminated biotopes are able to clear themselves spontaneously from the infection. In contrast, there is evidence of infection and disease emergences in new biotopes and species over the last decade.GAP: Mechanisms underlying recent northward spread of the canine infection in the EU are not fully understood. Ability to predict canine incidence remains limited. The mechanisms involved in the persistence of anthroponotic VL during interepidemic periods (especially in the Indian subcontinent) remains poorly understood. Do humans with chronic post-kalazar dermal leishmaniasis (PKDL) represent a significant reservoir for anthroponotic VL? There is also a need to elucidate the role of some domestic ruminants, and especially goats, as potential secondary reservoirs. Along the same lines, it will be necessary to further explore the role of dogs as part of the anthroponotic cycle of VL inSudan. There is also the need to better understand the role of "deadend" livestock hosts in maintaining sand fly populations.
As the important reservoir, domestic dogs are infected by L infantum in endemic areas. The prevalence of infection is variable but can be very high in some areas (up to 60% depending on the diagnostic method used). However, often the large majority of infections remain subpatent or asymptomatic for a long time before eventually becoming patent and symptomatic. Therefore, symptomatic patent disease is often limited to a smaller proportion of dogs in cross-sectional population studies. Some dogs are able to control spontaneously the infection and - potentially - to eliminate it.
Although infection with L infantum is reported in cats and (exceptionally) in horses, there is no evidence that these species act as reservoirs for human or canine infection. Cat appears to be susceptible to the infection, but clinical expression appears limited and inconsistent in this species. Likewise, wild canid (wolf, fox and jackal) populations can show similar infection rates as in dogs, however the prevalence of progressive clinical signs in these species is substantially lower, consequently they may not be as infectious as dog populations to support a primary transmission cycle.
GAPS: The role of infected prepatent dogs in zoonotic VL infection transmissibility remains poorly understood e.g. the parasitaemia threshold in dogs required for parasite transmission to the sand fly vector is unknown. Factors determining the ratios of prepatent, asymptomatic patent and symptomatic patent infections are not well understood; ratios will depend on the analytical tools used to quantify infections. The relative importance of immune-based protection vs. genetic resistance in dogs is poorly understood. See also belowIt will be necessary to explore the potential role of cats in the epidemiology of L. infantum.
Human infection with L. infantum or L. donovani can lead to severe systemic disease (VL) which is usually lethal in the absence of therapy. In several areas (e.g. Mediterranean countries) strains of L. infantum can also cause CL lesions. The number of asymptomatic infections is overwhelming as compared to symptomatic patent infections in humans, with reported ratios ranging from 1:4 to 1:50 or lower. As previously described, humans are also susceptible to several other Leishmania species leading to a spectrum of clinical diseases.GAP: The factors (e.g. genetic, immunological, environmental) that govern human infection outcomes (e.g. asymptomatic, progressive and carrier state), requires further multidisciplinary studies.
In temperate areas (Mediterranean basin, Middle East, Central Asia and China) the transmission of L. infantum occurs only during warm months, coinciding with the activity period of adult sand flies, but due to the variable and lengthy pre-patent period, seasonal variation in the disease incidence in dogs and humans may not be apparent. By contrast, in warmer regions such as much of endemic Brazil, sand fly activity and human and canine transmission of zoonotic VL is year round.
GAP: Important parameters need to be elucidated, such as biological and environmental conditions that affect the sand fly fecundity, survival, dissemination, or host's relative abundance and distribution affecting human and canine transmission dynamics.
Dogs are the primary reservoir for zoonotic VL due to L. infantum. InBrazil, it is thought that wildlife (e.g. foxes) is unable to maintain a transmission cycle independently of dogs. As previously described, a wide range of wild mammals (mainly rodents) are reservoirs of the other zoonotic entities of leishmaniasis, in different environments such as desert areas, steppe, rural settings, primary forest, etc.GAP: The role of wildlife as reservoir for L. infantum around the Mediterranean basin and central Asia is not well understood but could be more significant than inBrazil. There are suggestions that additional zoonotic hosts could be secondary reservoirs of L. infantum (e.g. cats) and L. donovani (e.g. goats). Should these be confirmed, the classical transmission cycles of these parasite(s) may need to be revisited with implications for prevention and control strategies. This could be significant during inter-epizootic periods. The presence of fox hound infections in theUS is still poorly understood and further investigations on the role of local sand flies or alternative modes of transmission are warranted. Which populations and/or species of rodent are significant reservoirs of L. braziliensis requires xenodiagnosis population studies.
Natural transmission of Leishmania occurs exclusively by the bite of infected phlebotomine sand flies. In zoonotic VL it has been suggested that dog-to-dog transmission may occur in some circumstances.GAP: Although symptomatic patent infections play an important role in infection transmission, the role of prepatent or asymptomatic patent infections in transmission is less well understood. There are suggested putative non-sand fly-based transmission routes of fox hound infection in theUS. The parasite-sandfly-host immunological interactions governing successful parasite establishment and transmission remains poorly understood.
The infectious stage of the parasite is the metacyclic promastigote transmitted by the sand fly to the host during a bloodmeal, which subsequently evolves into an amastigote form responsible for the disease in the host. Intracellular (phagocyte) amastigotes are taken up by the vector sand fly during a bloodmeal. In some circumstances, L. infantum can be transmitted artificially by shared needles contaminated with amastigote-infected material (e.g. blood).
Symptomatic patent infections in dogs are typically attributed to a combination of skin/cutaneous and visceral pathologies. In dogs, many of these clinical signs are not specific and may vary in intensity and kinetics. In the absence of therapy, symptomatic patent infections are almost always lethal, and relapses to canine patent infection post treatment are common.
The time course of infection is highly variable in dogs, ranging from a few weeks to 2 years. However, in most cases, progression eventually occurs even after prolonged pre-patent periods.GAP: Parameters influencing the duration of the incubation period are unknown. Overall health and nutritional status, genetic background, inoculum load, and the effects of confounding infections, to name a few, are suspected to play a role.
In dogs, in the absence of therapy, symptomatic patent infections are almost always lethal. Human VL is also lethal if left untreated, whereas CL is a chronic skin disease in humans and non-human hosts alike and which tends to resolve spontaneously e.g. within months following infection with L. major.GAP: Infection-induced population mortality rates are important demographic values for mathematical modelling, but which, especially for canine VL, remain uncertain due to the non-specific signs of this disease and normal absence of differential diagnosis.
Parasites are not spontaneously shed from natural infected hosts.
GAP: Role of vertical transmission is poorly understood but may play a role in fox hound infections in parts of the US.
Largely dominated by immunopathologies. In dogs, the severity of signs (renal, ocular, cutaneous, etc) is associated to the abnormal secretion of immunoglobulins which deposit on the blood vessel's endothelium to form immunocomplexes. In humans, the exacerbatory contribution of IL-10 is well established in the development of the visceral form of the disease. Similarly in murine models of L. major, the role of IL-4 and IL-13 in exacerbatory CL disease is relatively well understood. Marked cutaneous delayed hypersensitivity, exuberant lymphoproliferation and mixed Th1 and Th2 cytokine responses characterize MCL presentation. Polymorphism in TNF-a promotor sequences has been associated with mucosal leishmaniasis.GAP: The precise mechanisms underlying immunopathologies in dogs and humans are not fully understood. Whether similar physiopathological mechanisms are involved in canines and humans is suspected but not definitively established.
About 1.3 million new cases of human leishmaniases (0.3 million visceral) are considered to occur every year in the endemic zones of Latin America, Africa, the Indian subcontinent, the Middle East, Central Asia, China, and the Mediterranean region. Overall estimated prevalence is 12 million people with Disability Adjusted Life Years burden of 2 million. Among different entities of the disease, it is estimated that clinical cases of zoonotic VL amount to 1,500 - 2,000/year in the Mediterranean basin and Middle East, and some 5,000 cases inLatin America. These statistics are expected to be underestimates due to significant under reporting (see below).GAP: Standardization of recording and reporting procedures particularly in developing countries is desirable. See also below.
Zoonotic VL due to L. infantum affects essentially infants throughout its endemic range, with variable incidences. Adults are less at risk unless exposed to immunosuppressive conditions such as HIV co-infection or drug treatments after transplant or prescribed to cure immunopathological disorders. Other risk factors include famine, malnutrition, mass migration, civil disturbance, poor economic conditions, and crowding. The proximity to an infected person is a major risk factor for anthroponotic VL and CL, and proximity to infected dogs is a risk factor for both human and canine zoonotic VL infection.GAP: The significance of livestock ownership patterns in ‘zooprophylaxis’ (reducing transmission) or ‘zoopotentiation’ (increasing transmission) has not been adequately researched.
Visceral disease includes anaemia, splenomegaly and fever. The clinical incubation period is 4-6 months on average. Death is the usual outcome in the absence of therapy. In HIV-co-infected patients, the symptomatology is more polymorphic. The onset of clinical disease associated with anthroponotic VL is sometimes fulminant (i.e. sudden and severe) leading to rapid death. The cutaneous disease consists of nodular or ulcerative lesions which tend to resolve spontaneously in a variable period of time. In mucosal disease, which may develop from CL lesions caused by L. braziliensis and L.panamensis, parasitic metastasis occur in the nasal mucosal that eventually extends to the oropharynx and larynx. MCL evolves slowly and does not heal spontaneously.
Very high in developing countries. Notification is compulsory in only 32 of the 98 countries where 350 million people are at risk. In Europe, human leishmaniasis (any form of the disease) is notifiable inGreece,Italy andPortugal, and in endemic regions inSpain. Canine leishmaniasis is notifiable inGreece and at municipality level in the endemic regions of the countries mentioned above. Neither disease is notifiable inFrance.
Standardization of recording and reporting procedures particularly in developing countries is desirable.Under-reporting in humans and dogs is also common in those countries where notification of compulsory.
The link between the canine reservoir and human VL due to L. infantum is well established throughout its distribution. The role of dogs in other Leishmania species cycles is unclear.GAP: A detailed understanding of the link between the canine reservoir and human epidemiology in East Africa and for L. tropica around the Mediterranean basin and centralAsia is still limited.
In the absence of therapy, canine leishmaniasis is a severe lethal disease in dogs. Sick dogs will express both cutaneous and visceral clinical signs and they experience severe body weight losses overtime. The levels of stress associated with the disease in dogs is important. Existing prevention methods (insecticides) have no known negative impact on animal welfare. In contrast, some of the commonly used therapies are associated with significant side effects and toxicity. No known impact on biodiversity. The ethicality of dog culling methods (in parts ofBrazil) remains a serious issue.
Two South American canid species, the Hoary fox Pseudalopex vetulus (=Lycalopex vetulus, Dusicyon vetulus) and Maned wolf Chrysocyon brachyurus, are IUCN Red List classified respectively as "of insufficiently known extinction risk" (DD), and "near threatened" (NT) status. Both species show occasional Leishmania infection. Similarly, the European wolf Canis lupus classified as of “Least Concern” in the IUCN Red list, has been reported occasionally infected by L. infantum.GAP: Hares have been also reported to be infected by L. infantum in many Mediterranean countries. The role of the pathogen in this species should be further elucidated as well as the potential impact of hare infection in the distribution of the pathogen.
According Brazilian law, euthanasia of infected dogs is mandatory, but since 2017 in some areas it is now possible to treat infected dogs. No culling policy is in place in the rest of the world.
In countries of the Mediterranean basin and in some parts ofBrazil up to 60% of the dogs have serological signatures of exposure to the parasite. In southern Europe (Italy andSpain) there is evidence of recent northward spreading of zoonotic VL, from coastalMediterranean to continental climates. L. infantum is probably now endemic in southernGermany. InBrazil, zoonotic VL has expanded its range from a typically rural disease to a peri-urban/urban focus over the last several decades. Because these endemic areas have a high population density, larger human and canine populations are now at increased risk. Limited outbreaks in fox hounds have been reported in several states of theUS, but the mode of transmission is unclear.GAP: An understanding of the importance of infection and clinical expression in cats and horses remains minimal at this stage. Multivariate environmental and climatic features that significantly affect the geographical spread of sand flies and canine transmission are still poorly understood.
Zoonotic VL is endemic in dogs with a sporadic pattern in humans (no epidemics reported in the past decades). In humans, epidemic modes are only described for anthroponotic VL in Indian subcontinent and East Africa (outbreaks apparently occurring at around 10-year intervals) and for Old World zoonotic CL in northern Africa and Middle East, mostly associated to land reclamation in biotopes where infected rodents live.GAP: The mechanisms underlying the persistence of the infection in between epidemic outbreaks of anthroponotic VL in Indian subcontinent andEast Africa has received limited investigation at this stage. Mathematical models that capture the epidemiological patterns are needed.
Although in the Mediterranean basin exposure to infected sand flies occurs only during the warm months, there is little evidence for seasonal variation in the prevalence of the disease in dogs and humans. In much of endemic Brazil, transmission to dogs appears to be year round.
In dogs the epidemiology is essentially endemic. Human outbreaks of anthroponotic VL and zoonotic CL may involve new infections across large regions and territories within relatively short time frames.
Traditionally, cooler temperatures and reduced vector activity season have limited infection/disease spread northward of the canine disease in the EU. Global warming is likely to have an impact at this level (see above). Geographical spreading could also be related to vector dissemination linked to human activities (transport, travel) although long range (inter-continental) dispersion is unlikely because sand flies are not as robust as some mosquitoes and are not known to be wind-dispersed (as for instance Culicoides). There is direct evidence for the introduction to Northern EU of L. infantum in dogs taken to Southern EU on holidays or rescued from there as strays. Importation of non-endemic Leishmania species is frequent among immigrants or tourists. Of special concern are those anthroponotic species (L. donovani and L. tropica) which may find suitable vectors (specific or permissive) in southern EU (f.i. L. donovani transmitted by Larroussius sand flies in Cyprus; L. tropica by P. sergenti in Sicily). L. infantum is thought to have been introduced originally into the New World by dogs infected in the Old World.
In the Mediterranean basin exposure to infected sand flies is higher during the summer months, but due to the variable and lengthy pre-patent period, seasonal variation in the prevalence (cf. incidence) of the disease in dogs and humans may not be apparent. By contrast, in warmer regions such as much of endemic Brazil, sand fly activity and human and canine transmission of zoonotic VL is year round. There are no reliable historical data to test the effects of climate change on leishmaniasis cycles.GAP: The affects of climate and climate change on transmission dynamics over longer timescales requires systematic and standardized longitudinal monitoring.
Temperature affects the development time and overwintering of sand flies and the extrinsic incubation period which is likely to be reflected in their duration of infectiousness.GAP: Investigation of the vectorial capacity of traditionally non-vectorial sand flies in new foci or under different climatic conditions e.g. in Northern EU.
Vector survival is limited in extreme weather.
Climate change might impact zoonotic VL distribution directly (shortening of larval development or the extrinsic incubation periods) or indirectly (effect on the range and seasonal abundances of sand flies, extension of the breeding season increasing the risk of exposure for susceptible hosts).GAP: Historical data are scarce to provide compelling evidence of the impact of climate changes on sand flies and disease distribution in the EU.
Natural transmission of Leishmania occurs exclusively by the bite of infected phlebotomine sand flies. In zoonotic VL e.g. in US fox hounds it has been suggested that dog-to-dog transmission may occur in some circumstances.
Sporadic reports of congenital transmission of VL in humans are consistent with some confirmation in experimental puppies. Additional transmission routes include blood transfusions, organ transplantations, and sexual transmission in humans. Transmission through shared infected syringes has been reported amongst IV-drug users inSouthwest Europe.
In some dogs (fox hounds) occasional transmission through bites is considered to play a role (essentially in theUS).
Outdoor activity of hosts during peak sand fly biting times (particularly at dusk and sunrise). Increased travelling of dogs to southern EU (holidays, second homes) also increases infection spread. In humans, immunosuppression is clearly a risk factor. In Brazil, most transmission appears to be peri-domestic and potentially also inside houses. Migration and crowding are typical conditions favouring spread of anthroponotic agents (L. tropica and L. donovani). Generally, factors affecting increased densities of vectors and mammalian reservoir hosts.
The large number of refugees in EU from countries with different Leishmania species are likely to spread the pathogen especially in Mediterranean countries where vectors of Leishmania are abundant.The role of stray dogs must be investigated mainly in endemic areas.
Immune responses in dogs and humans are highly variable. In asymptomatic carriers of VL forms or in self-resolving CL forms, cellular responses are predominant. Cellular anergy and strong humoral responses are typical of acute forms of human VL or progressive stages of CanL.GAP: Precise immunopathological mechanisms underlying the disease evolution in hosts are only partially understood.
In dogs and humans affected by zoonotic VL, and in humans affected by anthroponotic VL, disease progression is usually associated with detectable high titre anti-Leishmania humoral responses while resistance appears to be associated with cellular immunity, measured by a leishmania-specific skin test or by quantification of one or more surrogate cytokine markers. In human CL, humoral responses are very limited unless mucosal tissues are involved (e.g. in MCL).GAP: Immunological based diagnostic tools, particularly rapid tests, commonly show high sensitivities to detect symptomatic infections but not asymptomatic infections. Improved sensitivities can be variably achieved using molecular based methods (PCR). Need to develop specific analytical tools to unravel cellular immunopathology mechanisms both in canines and in humans. Diagnostic methods to differentiate exposed, infected and infectious hosts are highly desirable e.g. to better target control.
Sanitary measures are largely diverse depending on the nosogeographical entity of leishmaniasis. As regards zoonotic VL, massive destruction of dogs had been practiced in endemic foci ofChina in the past, with some results. Culling of seropositive dogs has been implemented in Brazil but has had very limited efficacy to reduce the prevalence of either canine or human diseases, likely because of low owner compliance, insensitive diagnostic tests, long delays to dog removal, and high replacement rates with susceptible dogs. Active case detection and drug treatment of infected individuals are the recommended measures in both zoonotic and anthroponotic forms of leishmaniasis (e.g. VL elimination programme in the Indian subcontinent).GAP: Need for controlled, replicated and appropriately powered intervention trials to test different dog removal strategies. Logistics, ethical and animal welfare aspects are serious limitations to dog culling programs.
Fine mesh nets are the most effective mechanical measure to prevent sand fly bites on humans indoors, but are not expected to impact on zoonotic transmission cycles where humans are not a reservoir. Also, large scale control of vectors by spraying insecticides is only expected to be effective when sand flies are accessible (i.e. when transmission occurs peridomestically) and blood-fed flies rest indoor (endophilic behaviour). Therefore, in endemic EU epidemiological conditions, insecticide spraying is expected to be of low cost-effectiveness. In this context, insecticide-impregnated bednets are not considered a practical option to control zoonotic VL but have demonstrated some (variable) efficacy against anthroponotic CL and VL.
In dogs, individual transient protection is possible using topical insecticides (3-4 weeks efficacy) or insecticide-impregnated collars (6-month efficacy).GAP: Need for controlled, replicated and appropriately powered intervention trials to test different spraying strategies and formulations. Transient protection of individual dogs is possible using topical insecticides or repellent-impregnated collars but a longer-term solution with much broader applicability is required for disease prevention/control of larger dog populations to impact on the zoonotic VL transmission cycles. Compliance in the developing world will largely depend on the availability of low cost products.
Demonstration of parasites in smears/imprints of infected tissues or culture from the same material still represents the golden standard for leishmaniasis diagnosis worldwide, but is of low sensitivity. Different serology based diagnostic tests are available with good performance to assess clinical disease. However, sensitivity is not always sufficient to detect some asymptomatic (pre-patent and pre-progressive disease) stages that may have an important role in transmission. Molecular diagnostics (PCR) are also available but remain of limited sensitivity when performed on blood samples, and require relatively high levels of technical skill.GAP: Easy to use sensitive and specific diagnostic tools to detect pre-patent and pre-progressive stages of disease.
Vaccination is the most rational strategy to control the disease in dogs and could also be of interest to control anthroponotic forms of leishmaniasis in humans. A conventional vaccine (“leishmanization”) based on live attenuated parasites was in use for humans to prevent some forms of the cutaneous disease in Middle East and Central Asia, but is no longer recommended. A recombinant protein-based vaccine has demonstrated some protective potential in humans when combined with chemotherapy. A canine vaccine licensed only for use in Brazil has shown efficacy but is not widely adopted. In Europe there are two canine vaccines commercialized.GAP: No vaccine for human leishmaniases is available anywhere in the world as of today.
Several therapeutic options exist for both humans and dogs including pentavalent antimonials, amphotericin B deoxycholate, liposomal formulations of amphotericin B, miltefosine and paromomycin. In general, human cases of VL or CL are successfully treated with cure rates exceeding 95% with some exceptions e.g. in the Indian subcontinent where 35% of VL patients are unresponsive to antimonials. Potential long-term improvements in cost and effectiveness are expected with the use of combined drug treatments. In contrast to the general trend in humans, dogs with patent and progressive disease are mostly unresponsive to, or relapse after, treatment. Despite the poor parasitological responses, anti-Leishmania therapy is commonly practiced in dogs in EU countries, which may lead to the spread of drug resistance.
Need for new canine and human pharmaceutical options, and clinical trials of combined therapies.In EU these pharmaceutical options have to be different for dogs and humans in order to protect Public Health from drug resistant Leishmania species.
Due to the absence of airborne transmission and the need for a vector sand fly, biosafety requirements for Leishmania research are minimal.
Leishmania immunology status is required in some administrative regions of EU as a prerequisite to trade dogs to other EU countries.
GAP: After the wide use of vaccines in southern European countries it is useless to test for the immunological status of dogs, travelling either into EU or to other continents, since we cannot differentiate infected from vaccinated ones.
Insecticide residual spraying of houses and animal sheds against peridomestic vectors. Mechanical tools (fine mesh nets to prevent sand fly bites indoor), insecticide treated bed nets (ITNs) and topical insecticides to protect humans. In dogs, individual protection is also possible using topical insecticides (3-4 weeks duration) and/or insecticide-impregnated collars (6-month duration).
Insecticide-based products provide individual protection; community-wide application to dogs has been shown to impact on human and canine zoonotic VL infection incidence, whereas community-level provision of ITNs to protect humans is not expected to impact on zoonotic transmission cycles, whereas they have shown some success against anthroponotic Leishmania species.GAP: Need for controlled, replicated and appropriately powered intervention trials. Large scale and sustainable prevention based on canine topical insecticides currently face multiple logistic and socio-economic challenges (e.g. owner compliance, current costs, and short inter-intervention intervals). Sustainable long-acting compounds and formulations should be developed in conjunction with studies on effective delivery/public health education.
Research on CanL spatial distribution in EU and the Mediterranean region is increasing and made accessible online by the EC FP6 EDEN project. Another EU-funded project, LeishRisk (with WHO support) produced a compilation of peer-reviewed epidemiological literature.
Seasonal dynamics of phlebotomine sand fly species proven vectors of Mediterranean leishmaniasis caused by L. infantum has been carried out between 2011-2013 under the frame of EU FP7 EDENext project.GAP: Public health and veterinary surveillance data remain fragmentary. More surveillance is necessary inEurope including better coordination of existing surveillance and linking human health, veterinary data, sand fly distributions and climate patterns. The monitoring of dog travel should continue to be improved and standardized. The existing notification systems provide only limited information and rarely differentiate between the zoonotic and anthroponotic forms of VL which may be particularly relevant where migration is prevalent. This is another factor that limits the ability to estimate the true importance of each form of the disease.
Insecticide residual spraying of houses and animal sheds, and culling seropositive dogs inBrazil appears to have had limited impact on VL incidence. The latter practice is also questioned on ethical grounds. Reasons for failure include low owner compliance, insensitive diagnostic tests, long delays to dog removal, and high susceptible dog replacement rates. Setting up an effective control strategy for anthroponotic visceral leishmaniasis remains a challenge in endemic areas, as these are largely in the poorest countries of the world, in remote places and/or in complex settings (e.g. civil war inSomalia). In many endemic regions access to health care is logistically complex and treatment is not subsidised. Insecticide-impregnated bed nets have been used with some success against anthroponotic infections.GAPS:
The cost-effectiveness of culling dogs is low as culling requires house-to-house visits to screen dogs, expensive diagnostic kits and laboratories, and a revisit to remove positive dogs. Additional tests (and delay) may be required where owners dispute the initial results. Although the costs of insecticides to re-dip insecticide-impregnated bednets to prevent human leishmaniasis are low, investment on community education programs to sustain coverage are relatively high. Re-impregnation logistical issues have been partially overcome with the development of nets with long-lasting insecticide impregnation. Insecticide residual spraying is labour intensive and municipalities in developing countries have limited funds for regular blanket application. Current costs of the canine vaccine inBrazil are prohibitively expensive, as are costs of impregnated dog collars, thus neither are widely adopted for personal canine protection, particularly in poorer communities. Some municipalities have purchased collars for public distribution but without follow-up to monitor efficacy.
The leishmaniasis burden (all entities) is calculated at 2 090 000 disability adjusted life years (1 249 000 in men and 840 000 in women).
Dogs are found infected with L. infantum in all countries endemic for zoonotic VL reported above: Southern Europe including Balkans, Afghanistan, Algeria, Egypt, Iran, Iraq, Israel, Jordan, Lebanon, Libya, Morocco, Pakistan, Palestinian Authority, Saudi Arabia, Syria, Tunisia, Yemen, Georgia, Uzbekistan Western China, and in Latin America from Mexico to Argentina, but mainly in Brazil.
First-line treatment for VL in humans (antimonial drugs) is expensive and needs to be administered parenterally by trained personnel. Treatment-cycle costs range from US$ 30 (for generic sodium stibogluconate) to US$ 120 (for meglumine antimonate) or US$ 150 (for sodium stibogluconate). In the case of relapse, patients need to be treated with a far more toxic second-line medicine, such as conventional amphotericin B (US$ 60) or pentamidine (US$ 70). Liposomal amphotericin B, currently the first-line choice in EU and the USA, requires short treatments by i.v. route, is highly effective and almost not toxic but is unaffordable in developing countries (US$ 1500 or more). Injectable paromomycin costs US$ 10. The first oral treatment, miltefosine, costs US$ 150 or more. There are no established treatments for CL or MCL; the most common are intralesional injection of antimonials, local cryo- or heat therapy, or parenteral administration of drugs used for VL, depending on the number and site of lesions. Costs can be extremely variable.GAP: There is the need for controlled studies designed to test treatment efficacy for tegumentary leishmaniasis worldwide.
There is no estimation of the impact on livestock. The clinical expression of the disease is restricted to dogs and humans, the impact - if any - can only be indirect.GAP: Need to better understand the economic consequences of L. donovani infections in ruminants in endemic settings of anthroponotic VL.
In endemic countries that implemented specific programs for the control of leishmaniasis, public budget is allocated for human diagnosis and treatment, and insecticides and bednets for vector control. In most of the endemic countries, however, measures are integrated with those of other transmissible diseases, and free treatment of human patients is usually available at health centres or hospitals. Where treatment is not provided for free, private loans (with/without disproportionate interest charges) are sought with immeasurable impact on case families.
In some countries endemic for zoonotic VL diagnosis of dogs is encouraged at public reference centres with reduced costs for the owners. No country endemic for zoonotic VL provides for free tools for the prevention of leishmaniasis in dogs (topical insecticides, collars), nor therapies.GAP: Need for actions to facilitate diagnosis, treatment and prevention access of the poor to reduce direct and indirect impacts.
Human VL is essentially a disease affecting the poorest population, for whom the infection contributes to the further propagation of poverty, because treatment is expensive and hence either unaffordable or imposing a substantial economic burden, including loss of wages. Loss of labour (due to leishmaniasis), and the need of workforce replacement may also represent an economic impact.GAP: Human patients in developing countries have to overcome major logistic problems in order to access treatment: long distances to the treatment centre, lack of transport, treatment is unaffordable, or its costs pose a serious financial burden. For these reasons, patients may not comply with treatment (if they began) and drug resistance may emerge. There is a shortage of information on the actual cost of leishmaniasis, although it is known that in some parts of Asia, a family in which there is a case of leishmaniasis is three times more likely than an unaffected family to have sold its cow or rice field, plunging it into a vicious circle of disease-poverty-malnutrition-disease.
No existing information.
No existing information.
No existing information.
Lack of an effective, safe and affordable vaccine is the main obstacle for controlling the disease in dogs but also in humans. It is anticipated that large scale canine vaccination would be instrumental to control the disease in dogs and hence eliminate the primary reservoir of zoonotic VL. An integrative approach including insecticides based-vector control program could also be considered. In developing countries there are insurmountable logistic difficulties in delivery of efficacious insecticide residual spraying and dog test and removal regimes. Lack of education programs to encourage sustainable community-run interventions.GAPS: Regarding vaccines, two canine vaccines are licensedin the EU. None of the vaccines prevent infection, only decreases the development of disease and severity of clinical signs. In addition, infected LiESP/QA-21 vaccine vaccinated dogs are able to transmit the parasites to the vectors (although in a significant lower number). No data regarding the infectiousness of infected Recombinant Protein Q from Leishmania infantum MON-1vaccinated dogs in available. Several gaps interfere with further development of these vaccine candidates, including the lack of fully reliable experimental models to test vaccine candidate efficacy and safety at an acceptable cost and the lack of definitive understanding of immune surrogate markers in dogs. Regarding the experimental model, the lack of a laboratory challenge model including natural transmission of the parasite from infected sandflies to the target species (the dog) is a severe limitation to validate and rank potential vaccination strategies.
Translational collaborative research encompassing complementary expertise is required for vaccine development. It is critical to ensure that expertise covering all stages of the vaccine development program (from early antigen discovery to registration, including also manufacturing design and industrialisation, and delivery) are fully integrated.GAPS: Regarding intervention delivery, levels of coverage leading to sustained control or elimination are currently only theoretical. Superior level training of facilitators in endemic (developing) countries is essential.
About 2 million new cases of human visceral leishmaniasis are considered to occur every year in the endemic zones of Latin America, Africa, the Indian subcontinent, the Middle East, Central Asia, China, and the Mediterranean region. Public health and veterinary surveillance data remain fragmentary and these statistics are expected to be underestimates due to significant under-reporting.
In humans, risk factors include famine, malnutrition, mass migration, civil disturbance, poor economic conditions, and crowding. Proximity to infected dogs is a risk factor for both human and canine zoonotic VL infection. Cooler temperatures and a reduced vector activity season have limited the spread of infection northwards in the EU but global warming is likely to affect the distribution of zoonotic VL.
Vector control is difficult and insecticide spraying and the use of insecticide-impregnated bednets are not considered practical options to control zoonotic VL. In dogs, transient protection is possible using topical insecticides or insecticide-impregnated collars and community-wide application to dogs has been shown to impact on human and canine zoonotic VL incidence. Active case detection and drug treatment of infected individuals are recommended measures in both zoonotic and anthroponotic forms of leishmaniasis.
The lack of an effective, safe and affordable vaccine is the main obstacle for controlling the disease in dogs but also in humans. It is anticipated that large scale canine vaccination could be instrumental in control the disease in dogs and hence eliminating the primary reservoir of zoonotic VL. Current approaches to the detection and control of disease are expensive and difficult to implement particularly in developing countries.
Leishmania spp. are globally widespread but the number of species and the diverse epidemiology of infection leads to a complex spectrum of diseases. The lack of an effective, safe and affordable vaccine is the main obstacle for controlling the disease in dogs but also in humans. It is anticipated that large scale canine vaccination could be instrumental in control the disease in dogs and hence eliminating the primary reservoir of zoonotic VL. Current approaches to the detection and control of disease are expensive and difficult to implement particularly in developing countries.
Expert group members are included where permission has been given.
Fabrizio VITALE (OIE Reference Laboratory, IZS Sicily, Italy) - [Leader]
Oliva GAETANO (Università degli Studi di Napoli Federico II, Italy)
Carla MAIA (Institute of Hygiene and Tropical Medicine, University Lisbon, Portugal)
Laia Solano CALLEGO ( Universitat Autonoma de Barcellona, Spain)
Jose DE LA FUENTE (Univesity of Castilla-La Mancha, Ciudad Real, Spain)
Sofia BOUTSINI (Ministry of Rural Development and Food, Athens, Greece)
31 December 2017.
Project Management Board.