Control Tools

• AAT & HAT: Most tsetse populations show regular fluctuations which are correlated with seasonal changes in temperature and relative humidity that affect tsetse mortality and trypanosome infection.

  NTTAT: Less seasonal than tsetse-transmitted trypanosomes. Only in regions and seasons with very high temperatures and very dry climate the number of biting flies may decrease and so the risk of infection may reduce but not disappear. GAPS:

  AAT: Year on year variations are not understood.

  HAT: Year on year variations are not understood.

  NTTAT: Possible seasonality in temperate climates (tabanid season)?

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  AAT: None.

  HAT: Diagnosis in humans is well served by current tests.

  NTTAT: None: Diagnostic biological products produced from cultured parasites are available and in use for the processing of the indirect fluorescent antibody test and the indirect-ELISA (1). CATT test for T.evansi. For T.equiperdum: all ref labs make their own CFT (but issues of standardisation).

  GAPS:

  AAT: Internationally agreed standardized diagnostic.

  HAT: Much internationally funded research is underway – Foundation for Innovative New Diagnostics (FIND).

  NTTAT: Not all strains are detected by CATT; CATT sensitivity is low in pigs and variable in bovines.

• Commercial diagnostic kits available in Europe

  AAT: None.

  HAT: Diagnosis in humans.

  NTTAT: CATT / T. evansi in process of validation.

• Diagnostic kits validated by International, European or National Standards

  HAT: For diagnosis in humans.

• Diagnostic method(s) described by International, European or National standards

  AAT (including human infective trypanosomes):

  Routine methods are described in the OIE Manual of Diagnostic Tests and Vaccines.

  Identification of the agent: Several parasite detection techniques can be used, including the microscopic examination of the wet and stained thick or thin blood films. PCR is highly specific and more sensitive and can identify parasites at the genus, species or subspecies level, depending on the cases.

  Serological tests: Two trypanosomal antibody detection tests, the indirect fluorescent antibody test and the antibody-detection enzyme-linked immunosorbent assay (ELISA), are routinely used for the detection of antibodies in cattle. They have high sensitivity and specificity but can only be used for the presumptive diagnosis of trypanosomiasis.

  NTTAT: See the OIE diagnosis standards for Surra; ELISA, OPCR CATT and parasitological tests.

  GAP:

  NTTAT: For T. equiperdum: no standards, no commercial test For T. evansi: no reference test identified by OIE since no code. Will be changed.

• Commercial potential for diagnostic kits in Europe

  AAT (including human infective tryps): None.

  NTTAT: Potential for T. equipderdum: small (equine sector only). Larger potential for T. evansi.

• DIVA tests required and/or available

  No.

• Opportunities for new developments

  GAP: Standardized tests are highly expected as well as pen-side tests.

• Vaccines availability

• Commercial vaccines availability (globally)

  No.

• Commercial vaccines authorised in Europe

  No.

• Marker vaccines available worldwide

  No.

• Marker vaccines authorised in Europe

  No.

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Not applicable as no vaccines available.

• Commercial potential for vaccines in Europe

  No.

• Regulatory and/or policy challenges to approval

  Use of genetically modified vaccines might be problematic in some countries. Field trials may need specific regulation regarding the release of GMOs into the environment.

• Commercial feasibility (e.g manufacturing)

  No.

• Opportunity for barrier protection

  Could be used in Africa if there was a suitable vaccine.

• Opportunity for new developments

  GAP: NTTAT: Modified vaccines.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  NTTAT:

  Resistance is developing to the anti-trypanocidal drugs. Only four compounds available for use (pentamidine, suramin, melarsoprol, eflornithine and nifurtimox).

  GAPS:

  AAT: The quality of the existing compounds should be checked by independent laboratories

  NTTAT: Need to establish the effective doses in each of the host species of T. evansi: horse, dogs, cattle, buffalo, pig,….

• Future therapy

  AAT & HAT: Development of drugs which can be used prophylactically. Exploit public-private partnerships such as FAP/IFAH on quality control of veterinary drugs including trypanocides.

  GAPS:

  AAT:

  New veterinary drugs are needed. Chemo-sensitization of drug resistant trypanosomes should be explored. New ways for drug delivery (antibody drug conjugates) should be investigated.

  Need to develop and establish internationally agreed Quality Control/Quality Assurance protocols for drug quality testing.

• Commercial potential for pharmaceuticals in Europe

  No.

  GAP: NTTAT: no regulation adapted to French overseas department infected with T vivax and T. evansi.

• Regulatory and/or policy challenges to approval

  NTTAT: Cymelarsan not registered.

• Commercial feasibility (e.g manufacturing)

  AAT (including human infective trypanosomes): Not economic to produce drugs for sale in Europe and only a limited market in Africa although the existing drugs are relatively cheap, from a European point of view.

  NTTAT: Limited market due to the cost of production under GMP standards.

• Opportunities for new developments

  AAT (including human infective trypanosomes): See Section “Pharmaceutical availability – Commercial feasibility”.

  NTTAT: There is a great need for new trypanocidal drugs, because trypanosomes have developed resistance against the few existing drugs.

  GAP:

  AAT: Lack of new drug development will lead to inefficiency of available drugs (problem already encountered in several areas in Africa and Asia). There is a need to create a consortium (e.g. public-private sector with the participation of research institutions) for exploring new avenues (old and new chemicals, combination of chemical preparations, etc.).

• New developments for diagnostic tests

• Requirements for diagnostics development

  AAT: The development of new diagnostic tests relies on the availability of well characterized strains for the parameter to be diagnosed (drug resistance, pathogenicity/virulence).

  GAP: AAT: A public repository of characterized strains could be encouraged.

• Time to develop new or improved diagnostics

  Development of diagnostic tests is much faster and usually less expensive than developing vaccines. From development through validation to commercial availability requires time (it can take years).

  GAPS:

  AAT: See Section “Diagnostic availability – Commercial diagnostic kits available worldwide”.

  NTTAT: Epitope based tests are expected.

• Cost of developing new or improved diagnostics and their validation

  The development and validation of new tests is time consuming and labour intensive which is costly. Costs cannot be specified as they will depend on the nature of the test and the cost of producing reagents and supplying reading or processing machines if necessary. Once validated there will need to be a commercial company willing to market the test.

• Research requirements for new or improved diagnostics

  GAPS:

  AAT: As for new development of drugs, a pool (consortium) of international, regional and national institutions, with eventually the participation of the private sector, needs to be created for a concerted action addressing the problem of improved diagnostic tools.

  NTTAT: Detection of healthy carriers of T. evansi. Full genome profiles of well identified reference strains to develop more specific and differential molecular diagnostic tests.

  Differential proteome analysis, same reason but for differential Ab tests.

• Technology to determine virus freedom in animals

  Does not exist at present but could be based on serological diagnosis.

  GAP: Pathogen freedom technology required.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  Cost: Very high (ca. 200 million Euro?), but commercialisation will be very difficult due to the high cost of vaccine development.

• Time to develop new or improved vaccines

  Depending on when a candidate vaccine could be identified there will be a long timescale due to the antigenic properties of the trypanosomes. 10 years is a reasonable estimate. This will involve identification of candidate antigens, development, clinical trials and licensing. Potential vaccines need to be identified and subjected to initial trials and depending on the outcome will depend the time to commercial availability.

  GAP: Living modified vaccines should be evaluated for T. vivax and T. evansi.

• Cost of developing new or improved vaccines and their validation

  Expensive with the need to develop and undertake all the relevant tests to provide data to enable the product to be authorised. Field trial will be difficult as will evaluating the results.

• Research requirements for new or improved vaccines

  At least 100 million Euro.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  To be able to develop a new trypanocidal drug with a large spectrum of activity at European level (European registration requirements); the total cost could be c. 300 million Euro.

  NTTAT: Relatively good drugs available for surra. Yet not registered everywhere, and not validated in all species.

  GAPS:

  AAT: In vitro culture systems are an absolute prerequisite for drug screening (T. congolense, T. vivax).

  AAT: In vitro culture systems are an absolute prerequisite for drug screening (T. congolense, T. vivax).

  See also Section “Pharmaceutical availability – Opportunities for new developments” above.

• Time to develop new or improved pharmaceuticals

  Time to develop would depend on the product and the trials necessary to validate the efficacy and safety. Commercial production would then take further time. Five to 10 years seems a realistic timeframe.

  Really necessary but very little attention is given to development of new trypanocidal drugs.

  GAPS:

  AAT: See Section “Pharmaceutical availability” above.

  NTTAT: Yes but very limited research work.

• Cost of developing new or improved pharmaceuticals and their validation

  Expensive but difficult to assess as it will depend on the product and the trials necessary to validate and license.

  GAPS:

  AAT: Lack of interest of the private sector due to reduced market profits.

  AAT: Being often a chronic, endemic disease and a disease of the poor, trypanosomiasis does not attract donor, media and private sector attention. In fact, it can be classified as “neglected disease” although it is a major pathological constraint for livestock-agriculture development and, more generally, sustainable agricultural and rural development (SARD). It is no coincidence that out of the 37 tsetse-infested countries, 32 are Low-Income food Deficit Countries and 29 are Least Developed Countries. Livestock provides important contributions to livelihoods and markets in more than 20 countries where the disease occurs.

• Research requirements for new or improved pharmaceuticals

  At least 100 million Euro.

Disease details

• Description and characteristics

• Pathogen

  AAT & HAT: Trypanosomes are flagellate protozoans that inhabit the blood plasma, the lymph and various tissues of their hosts. The genus Trypanosoma belongs to the order Kinetoplastida, family Trypanosomatidae. Tsetse-transmitted trypanosomes belong to the salivarian section with subgenus Nannomonas containing T. congolense, T. simiae and T. godfreyi, Duttonella containing T. vivax, and Trypanozoon T. brucei ssp (1, 2, 3, 4, 5).

  NTTAT: Some strains of T. vivax are spread by mechanical transmission. T. equiperdum and T. evansi are phylogenetically closely related to the T. brucei ssp clade (6).

  T. equiperdum is a specific trypanosome of equines and is not found in the bloodstream but shows remarkable tropism for the mucosa of the genital organs, subcutaneous tissues and the central nervous system. GAPS:

  AAT: Clarification of the relationship between tsetse transmitted and non-tsetse transmitted T. vivax. Different clades in this species? Are tsetse and non-tsetse transmitted forms subspecies?

  NTTAT: Classification of T. evansi and T. equiperdum are currently disputed. Evidence suggests these may be subspecies of T. b. brucei (7).

• Variability of the disease

  AAT & HAT: The disease affects both people [human African trypanosomiasis (HAT) or sleeping sickness] and animals [African animal trypanosomiasis (AAT) or nagana].

  HAT or sleeping sickness, only occurs in Sub-Saharan Africa. It is caused by two human infective subspecies of Trypanosoma brucei; T. brucei gambiense responsible for gHAT and T. brucei rhodesiense which causes rHAT.

  AAT is caused by a number of trypanosome species and subspecies. The most economically important species include Trypanosoma congolense, T. vivax and T. brucei subsp. brucei. T. congolense can be classified into three types (savannah, forest and Kilifi). T. simiae and T. godfreyi can also cause AAT. The host preferences of each trypanosome species may differ, but T. congolense, T. vivax and T. brucei brucei have a wide host range among domesticated animals. T. godfreyi and T. simiae occur in pigs. Most species are biologically transmitted by tsetse although mechanical transmission by biting flies including tsetse can occur within and outwith the tsetse belt (2, 3).

  AAT and rHAT parasites have been identified in a wide range of wildlife species.

  NTTAT:

  Caused mainly by T. equiperdum in equids by sexual transmission, by T. evansi in Camelids and by T. vivax in livestock. T. evansi and T. vivax are transmited by haematophagous insects.

  T. vivax is limited to cattle, water buffalo, deer, horse (Africa and Latin America), but T. evansi in present in cattle, buffalo, horse, dogs, elephant, deer, rhinoceros, capybaras, and a large range of domestic and wild animals including rodents in Africa, Asia and Latin America

  T.vivax can be transmitted by haematophagous insects other than tsetse flies. This species of trypanosome can cause serious disease outbreaks, particularly in Latin America, with high mortality in affected animals. T. vivax also occurs in Asia. Other trypanosome species of economic importance, and non-tsetse transmitted, are T. evansi responsible for a disease caused Surra and affecting mainly bovids, including buffaloes, and camelids. T. equiperdum is distributed worldwide, sexually transmitted and causes a severe pathology, called dourine (an OIE notifiable disease) in equines. In affected animals mortality can reach 75%. Recently, mechanical transmission of T. congolense (i.e. without the intervention of tsetse flies) has been demonstrated.

  T. evansi and T. vivax are pathogenic for a very wide range of mammalians and they can both cause acute to chronic diseases.

  GAPS:

  AAT:

  Factors influencing the pathogenicity/virulence of trypanosome strains such as drug resistance, host, ecological environment. Genetic markers for virulence.

  Relationship between tsetse challenge and pathogenic consequence for all trypanosome species needs to be elucidated. It is not simply a case of numbers of infected fly bites but what those bites comprise.

  Origin of haemorrhagic strains of T. vivax?

  Evidence of pathogenesis in indigenous African cattle breeds caused by Trypanosoma brucei ssp. is limited - does Trypanosoma brucei progress to CNS in indigenous cattle breeds?

  Evidence for trypanotolerance in local cattle breeds to local strains.

  Little contemporary work looking at natural reservoirs of infection.

  Longitudinal studies are lacking examining the natural ecology of trypanosome infection in wild and domestic hosts.

  NTTAT:

  Need for identification of the vector range of NTTAT.

  Possible alternative routes of transmission of T. evansi (sexual?) and T. equiperdum (mechanical?).

  For T. vivax: Mechanisms of transmission by biting insects have to be investigated locally; is this a recent event? Can tsetse transmitted change to NTTAT?

• Stability of the agent/pathogen in the environment

  AAT & HAT: Trypanosomes do not survive for long periods outside the host. Trypanosomes survive in blood samples (cooled) for at least 12 hours.

  NTTAT: Not stable, but questionable for T. evansi in stomoxys, which once infected are able to transmit for 24-48h.

  GAP:

  AAT/rHAT: It is unknown how long parasites remain infective within an animal carcass or the risk posed by butchering meat or to wild carnivores from eating an infected carcass.

  NTTAT: Delayed transmission of T. evansi by Stomoxys?

• Species involved

• Animal infected/carrier/disease

  AAT & NTTAT:

  Trypanosomes can infect all domesticated and wild animals; clinical cases have been described in cattle, water buffalo, sheep, goats, camels, horses, donkeys, alpacas, llamas, pigs, dogs, cats and other domestic and wild animal species These diseases bear different common names such as nagana, dourine and surra (2, 3).

  In cattle, trypanosomiasis is caused by T. congolense or T. vivax and to a lesser extent T. brucei. The disease may be acute or chronic depending on the host, the fitness of the host, the pathogen and co-existence in that host with multiple pathogens. An animal is likely to be infected with multiple strains and species of trypanosome.

  In horses, extensive subcutaneous oedema is often seen in infections caused by T. brucei, T. congolense, T. evansi and T. equiperdum. T. evansi has a high rate of chronic or apparently healthy carriers.

  In the domestic pig, T. simiae produces a hyperacute, fulminating disease.

  HAT:

  Animal reservoir/human reservoir: there are several animal species which are a reservoir for rHAT (pigs, cattle, sheep, goats, dogs and wild ruminants) but in which rHAT does not cause disease. rHAT causes acute disease in exotic breeds of cattle, progressing to the CNS. A wide range of wildlife can be infected by T. brucei.

  Primates and other monkeys can also be carriers of gHAT and in these species gHAT may result in disease.

  GAPS:

  AAT:

  Most animals infected with AAT do not carry high parasitaemias. Most infections in indigenous species do not migrate to the CNS. Most infections in peripheral blood are low level.

  Infections in exotic animals by contrast are acute and cause death. Role of this ‘carrier state’ in the global immune response of the host to new infections needs to be elucidated.

  NTTAT:

  Host range for NTTAT and TTAT; detection of healthy carriers. Host specificity of T. equiperdum - only equines?

• Human infected/disease

  HAT: Trypanosoma brucei gambiense (T.b.g) is found in west and central Africa. Trypanosoma brucei rhodesiense (T.b.r) is found in eastern and southern Africa (3). The two forms of HAT are focal diseases. Uganda has HAT foci for both forms of the diseases but the diseases do not currently overlap.

  AAT: AAT is normally not infective for humans, although there have been cases of T. evansi diagnosed recently in India and Vietnam (9) and several cases of trypanosomiasis caused by T. lewisi in Asia (and a single case in Africa) (10).

  GAPS:

  HAT: Factors underpinning the separation of the two forms of disease and the likelihood that they will merge.

  HAT: Characterisation of the human immune response to challenge with AAT parasites.

  HAT: The role of silent carries of infection – PCR positive but no visible trypanosomes (8).

  NTTAT: Proportion of human carriers of T. evansi and T. lewisi?

• Vector cyclical/non-cyclical

  HAT & AAT:

  Tsetse flies genus Glossina are found only in sub-Saharan Africa.

  Glossina have been caught in Saudi Arabia, near Yemen but their role in the transmission of trypanosomes in the Arabian Peninsula is unknown (11).

  Different species of tsetse fly occupy different habitats. They require humidity, and are found in vegetation near rivers and lakes, in forest-galleries and in wooded savannah. Some 29 to 32 species and sub-species (depending on classification) have been identified. All species are potential vectors of AAT and/or HAT but only 6 are recognized as main vectors of HAT (3).

  T. vivax can be transmitted by tsetse flies (cyclical) or by biting flies (non-cyclical)

  NTTAT:

  T. vivax and T. evansi only transmitted by biting flies (Tabanidae, Stomoxyinae and Hippoboscidae). T. equiperdum only venerealy from stallion to mare.

  Particular case of T. evansi in Latin America with a biological vector (vampire bat).

  Transmission of T. evansi may result from butchering an infected bovine.

  GAPS:

  AAT & HAT:

  Role of non-tsetse vectors, especially outside sub-Saharan Africa. Role and importance of different tsetse species in various agro-ecological zones.

  The recent move towards molecular analysis of tsetse flies trapped in the wild, artificially inflates calculation of infection rates due to amplification of non-active/ and in some cases dead infections in the tsetse gut material. This needs to be quantified since data are needed for modelling.

  The role of tsetse flies in T. b. gambiense epidemics requires further investigation. The infection rate (ie mature salivary gland infections) in tsetse in gHAT foci is unknown (12).

  NTTAT:

  Vector identification. Exact role of Stomoxyinae in the transmission of T. evansi remains to be elucidated. Is there evidence for immediate and delayed transmission?

  Existence of other mechanical or biological vectors not yet identified or other forms of transmission (e.g. butchering)?

• Reservoir (animal, environment)

  AAT & NTTAT: Wild and domestic animals can host these pathogenic trypanosomes and under particular conditions they may represent an important reservoir (especially wildlife) of infection for their vectors.

  HAT: A large range of wild and domestic animals can act as reservoirs of the human-infective parasites especially T. b. rhodesiense. Although animals can be infected with T. b. gambiense, the epidemiological significance of a non-human reservoir is unknown (1, 3).

  GAPS:

  HAT:

  Role of animal reservoir in T. b. gambiense remains unquantified. Role of wildlife reservoir for rHAT has been examined only in limited foci.

  NTTAT:

  Role of wild host as reservoir for livestock infection?

  Reservoirs of T. evansi, role of small ruminants. No pathology yet possible reservoir?

• Description of infection & disease in natural hosts

• Transmissibility

  AAT & HAT: Transmission of trypanosomes involves three interacting organisms: the host (human or animal [livestock or wildlife]), the insect vector and the pathogenic parasite (3). Trypanosomiasis is transmitted to man and animals by a blood sucking insect, the tsetse fly. Although in recent years vertical transmission of T. b. gambiense has been suggested as a transmission route (14).

  Direct infection, through contaminated blood and other body fluids is possible.

  Per oral and trans-placental transmission for T brucei; iatrogenic for all.

  NTTAT: Mechanical transmission depends on the fly picking up trypanosomes, interrupting the meal and then recommencing feeding on a different host.

  GAPS:

  AAT:

  Effect of trypanocidal drug resistance on transmissibility.

  HAT:

  A significant role for vertical transmission of T. b. gambiense has recently been proposed (11).

  Sexual transmission has been reported for T. b. gambiense (13).

  AAT & HAT:

  Transmission efficiencies, effect of fly age, genetic susceptibility and physiological condition (fly’s immune system). Effect of environment on susceptibility of the tsetse fly. Role of trypanosome genotype on transmissibility. Current role of biting flies in epidemiology HAT and AAT.

  NTTAT:

  Role of intermediary and temporary hosts of biting arthropods in perorale infection? Could be a link between wild and domestic reservoirs.

  Mechanical and tsetse-transmitted T. vivax.

• Pathogenic life cycle stages

  HAT & AAT: When a tsetse feeds on the blood of a parasitized host it also ingests blood-stream forms of the trypanosome. These bloodstream forms multiply within the fly and then migrate to the mouthparts (T. congolense) or the salivary glands (T. brucei). Development of T. vivax takes place in the mouthparts only. This process takes 5-13 days for Trypanosoma vivax, 15-23 days for T. congolense and 12-23 days for T. brucei. After this period, trypanosomes will be injected into a host as the fly feeds. Once infected, the fly remains infective for the remainder of its life.

  NTTAT: Mechanical transmission.

  GAPS:

  NTTAT:

  Biological basis of the shift between NTTAT and tsetse-transmitted T. vivax (speed of induction, reversibility, synchrony of both ways of transmission.

  Variability of T. vivax species unknown.

• Signs/Morbidity

  AAT: Tsetse-transmitted trypanosomiasis (T. congolense, T. vivax and T. b. brucei) is a classically acute or chronic disease that causes intermittent fever and is accompanied by anaemia, oedema, lacrimation, enlarged lymph nodes, abortion, decreased fertility, delayed sexual maturity, loss of appetite and weight, leading to early death in acute forms or to digestive and/or nervous signs with emaciation and eventually death in chronic forms. The severity of symptoms is related to the gradient of susceptibility to trypanosome infections and pathogenicity of species and strain of the infective trypanosome. Morbidity and mortality rates are high, Generally, wild mammals and some humpless Bos taurus African cattle (the N'Dama and the various West African Shorthorn breeds) and small ruminant (Djallonk sheep, Dwarf West African goats) breeds posses a certain degree of tolerance to the infection and appear to be able to control the anaemia it causes. This trypanotolerance also extends to crossbred cattle breeds (Bos indicus x Bos taurus) such as the Méré (1,2).

  HAT: T. b. gambiense (chronic form of HSS) and T. b. rhodesiense (acute form of HSS). Usually not very pathogenic in livestock.

  NTTAT: T. evansi (see AAT above): mainly in cattle, horses, camels and in dogs; without treatment the disease is fatal.

  T. equiperdum: fever, swellings and local oedema of the genital organs and mammary glands, oedematous eruptions of the skin, anaemia, emaciation, ocular lesions, lack of coordination in the limbs, facial paralysis and continuing appetite. Pregnant mares may abort or foal normally.

  T. evansi/T. equiperdum very difficult to distinguish. T. vivax and T. evansi have often mild or unapparent infections; classical sign of trypanosomiases are not specific. GAPS:

  AAT:

  Effect of TDR on associated morbidity.

  Factors affecting to the virulence of a trypanosomal infection in livestock.

  NTTAT:Pathognomonic “plaques” for dourine T. equiperdum not often observed - artefact?

• Incubation period

  AAT: (including human infective species): In cattle, small ruminants and equines the disease becomes apparent about seven to ten days after the bite of a trypanosome infected fly with a range of the incubation period from 4 days to approximately 8 weeks. Infections with more virulent isolates have a shorter incubation period when the disease can become apparent in 7 to 10 days in cattle and small ruminants after an infective tsetse bite (2).

  NTTAT: T. equiperdum: from 3 to 3 or more months. T. evansi: very difficult to know, from days to years depending of the age of the animal, health status, stress.

  GAP:

  NTTAT: Needs to be studied in NTTAT.

• Mortality

  AAT (including human infective species): Mortality varies with the breed of the animal, as well as the strain of the infecting organisms. In untreated cattle and equines infected with some strains, the mortality rate can reach 50-100% within months after exposure, particularly when poor nutrition or other factors contribute to debilitation. More generally, field studies in many endemic areas indicate that AAT increases death rates in exposed cattle populations by about 2 percentage points.

  NTTAT: T. evansi is responsible of very high rates of death in newly affected area in horses. Without treatment, T. evansi infections are almost always fatal. Mortality rates due to T. equiperdum depend of the clinical form (mild to very severe depending of the pathogenicity of the trypanosome and general condition of the host). The infection persists for one or two years generally and about half of the animals die during that time. Some animals may remain infected for 3 to 5 years.

  GAPS:

  AAT: The factors contributing to endemic trypanosomiasis (high morbidity but low mortality) in livestock are not fully understood.

  NTTAT: Only little studies on socio-economic impact of NTTAT performed. Nearly all in SE Asia. Neglected in Africa. No idea of possible impact on Europe by NTTAT.

• Shedding kinetic patterns

  AAT & HAT: Blood-borne and not shed. Depends on mechanical transmission by biting flies or cyclical transmission by tsetse.

  NTTAT: Sexual transmission T. equiperdum.

• Mechanism of pathogenicity

  The mechanisms of pathogenesis are poorly understood.

  Immunosuppressive effects of T. evansi are responsible for disease outbreak and vaccination failure.

  GAPS:

  • AAT: Genetic markers of pathogenicity/virulence would improve control of the disease.
  • NTTAT: Genetic markers of pathogenicity/virulence would improve control of the disease. Immunosuppressive effects of T. evansi need to be studied extensively

• Zoonotic potential

• Reported incidence in humans

  HAT: In 2000, WHO estimated 50 to 60 million people in Africa were at risk of HAT, with 300 000 affected by the disease, a figure which was much larger than the 27 000 cases diagnosed and treated that year. Since that date wide-ranging control programmes have been undertaken and the population under surveillance was substantially increased. In 2014, the number of new cases was reported as 3796, although high levels of underreporting mean the true figure is much higher. Ongoing mapping of HAT foci (5) has helped to estimate the population at risk and active screening facilitates the estimation of case incidence.

  NTTAT: Rare atypical cases (T. evansi, T vivax, T. lewisi).

  GAP:

  HAT: Accurate estimates of incidence depend on ongoing surveillance work supported by other information, such as mapping.

• Risk of occurence in humans, populations at risk, specific risk factors

  HAT: The disease affects mostly poor populations living in remote rural areas of Africa. Travellers visiting the sub-Saharan part of the continent may also become infected when they travel through tsetse infested zones. There is no risk of sleeping sickness transmission in urban areas; however, peri-urban transmission has been recently described in Kinshasa and Luanda.

  GAP:

  NTTAT: Evaluation of contact human-parasite in exposed human population (veterinaries, farmers, slaughter house technicians, rural population / ingestion of row meat and blood etc).

• Symptoms described in humans

  HAT: Human African trypanosomiasis typically takes two forms, depending on the parasite involved:

  • Trypanosoma brucei gambiense (T.b.g.) represents more than 90% of reported cases of sleeping sickness and causes a chronic infection. A person can be infected for months/years without major signs or symptoms of the disease. When symptoms do emerge, the patient is often already in an advanced disease stage when the central nervous system is affected.
  • Trypanosoma brucei rhodesiense (T.b.r.) represents less than 10% of reported cases and causes acute infection. First signs and symptoms are observed after a few months or weeks. The disease develops rapidly and invades the central nervous system (3).
  • Both forms of the disease, if left untreated, lead to death in humans.

  NTTAT: Fever, oedema, anaemia (T. evansi or T. lewisi).

  GAP:

  NTTAT: Need to identify human cases in rural population.

• Estimated level of under-reporting in humans

  HAT: Difficult to assess the current situation in a number of endemic countries because of a lack of surveillance and diagnostic expertise. Because the symptoms are shared with a number of other more common illnesses, under-reporting is common. Studies indicated that for T. b. rhodesiense approximately 60% of cases are reported in areas with a good health infrastructure and awareness of the disease. For T. b. gambiense, diagnostic limitations and levels of uptake of screening programmes can also result in about 40% of cases not being diagnosed in an initial survey. Elsewhere, in the absence of active surveillance and/or awareness of the disease, under-reporting rates may be higher.

  NTTAT: Unknown.

  GAPS:

  HAT: More site-specific studies of under-reporting for both forms of the disease are needed.

  NTTAT: Underreporting suspected.

• Likelihood of spread in humans

  HAT: Mother-to-child infection: the trypanosome can cross the placenta and infect the foetus (12). Otherwise, spread from human to human is only via the vector, but several family members, especially mothers and young children, can be thus affected. Evidence of sexual transmission for T. b. gambiense.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  AAT & HAT: Animal disease poses a welfare problem. This is most often a chronic disease, and trypanocides are both costly and sometimes unobtainable so that animals may be ill and suffering for considerable periods.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  AAT (including human infective species): Most wild animals are known to be susceptible to infection. However, as the natural hosts of tsetse, wild animals are trypanotolerant if not stressed. The disease is not thought to be implicated in threatening the survival of any endangered species.

  NTTAT: T. evansi grows in all mammals with gross pathology in deer, ocelot, howler monkeys, tapir, tiger, orang-utan, lion, elephant.

  GAP: NTTAT: Prevalence in wild hosts.

• Slaughter necessity according to EU rules or other regions

  AAT (including human infective species): No.

  NTTAT: T. equiperdum normally in all cases; T. evansi in case of highly chemo-resistant strains.

  GAP: NTTAT: Is it necessary or not to slaughter the animals to eliminate the parasite?

• Geographical distribution and spread

  Sub-Saharan countries, South and Central America and the Caribbean, The Indian sub-continent, Asia, southern Europe, Spain very recently, Eastern Europe, some former Russian republics and Africa.

• Current occurence/distribution

  AAT & HAT: Occurs in 37 sub-Saharan countries covering about 9 million km2 (2,3) an area which corresponds approximately to one-third of Africa's total land area and includes Africa’s rain forests. The infection threatens an estimated 50 million head of cattle. Trypanosomes, particularly T. vivax, may spread beyond the ‘tsetse fly belt’ by mechanical transmission.

  NTTAT: T. vivax, T. evansi and T. equiperdum is also found in South and Central America and the Caribbean, areas free of the tsetse fly (2,6). T. evansi is also found in the Indian sub-continent, Asia, southern Europe (Canary Islands, some cases in camels and horses in Spain very recently). T. equiperdum in Eastern Europe, some former Russian republics and Africa. It is a real threat for the horse population of any country in the world. Its distribution inside these infested areas may change.

  GAPS:

  NTTAT: Currently for T. equiperdum eradication strategy following OIE Code ‘The status of T. equiperdum is very unclear’. T. equiperdum: new drugs seem to work (16); revision of strategy necessary? Towards treatment of T. equiperdum?’

  Seven countries have reported to OIE dourine being present from 2013 through 2015 although number of infected countries likely higher, need additional studies.

  Eighteen countries have reported to OIE Surra being present or suspected to be present from 2013 through 2015, likely higher, need additional studies.

  Occasional foci in Spain and France, but status unknown in Turkey, Greece and Italy.

• Epizootic/endemic- if epidemic frequency of outbreaks

  AAT:

  In Africa, where the parasites are transmitted by tsetse flies, trypanosomiasis appears as a persistent endemic disease (2).

  HAT:

  The disease in humans is associated with periodic massive outbreaks, with low prevalence of 0.1%, increasing to over 1% and, if unchecked, leading to the infection of virtually all members of affected communities. Historically, these epidemics have been devastating leading to the depopulation of some affected areas (14).

  NTTAT:

  In South America, where T. vivax is transmitted strictly mechanically, trypanosomiasis occurs in cattle as epizootics separated by a few years when the disease appears to be silent and subclinical. After a series of outbreaks, animals tend to be immune and maintain the parasites in very low numbers. Once the susceptible population increases the disease returns.

  T. evansi transmitted by biting flies is a persistent endemic disease.

  GAPS:

  AAT:

  What is the role of trypanocidal drug resistance? Is this increasing over time?

  Studies of AAT morbidity and impact of infection on indigenous breeds (health and productivity) are needed.

  HAT:

  The role of non tsetse transmission during epidemics needs to be investigated. The role ‘silent human carriers’ of infection needs urgent consideration (11).

  NTTAT:

  Economical impact of such periodic outbreaks?

  Currently endemic in northern Africa, very recent two outbreaks in mainland Europe due to importation of camels from Gran Canaria. Urgent follow-up needed. Risk assessment needed for importation of T. evansi into EU.

  Risk assessment of importation of T. equiperdum from Asia into EU (through import from Russia via e.g. Poland) needed.

• Speed of spatial spread during an outbreak

  AAT: Can spread rapidly within an area. Dependant on the vector range, tsetse population density, susceptibility of tsetse to infection, susceptibility of infected hosts, movement of hosts, virulence of parasite and drug resistance.

  HAT: Focal nature and potential for spread (e.g in Uganda). HAT occurs in recognised geographical foci that have changed little over time. The exception is the focus for T. b. rhodesiense that has rapidly expanded due to importation of infected cattle to previously unaffected districts bringing outbreaks of rHAT and a risk of overlap with gHAT focus. The epidemic nature of the disease has been noted in Section “epizootic/endemic” above.

  NTTAT: Linked with healthy carrier movements. Could potentially spread rapidly within an area but dependant on the vector range, number of biting flies and the infection rate.

  GAPS:

  AAT: Epidemiological models of disease transmission are required.

  HAT: The focal nature of HAT offers options for sustainable control. The alarming expansion of rHAT focus in Uganda is cause for concern. If gHAT and rHAT overlap, diagnosis and treatment protocols will be severely compromised.

  NTTAT: Unknown.

• Transboundary potential of the disease

  AAT: Most trypanosomes are transmitted by tsetse flies, and can only become established in areas where these vectors exist. T. vivax does not require tsetse flies and can become endemic in other areas as it has in parts of South America (2). Tsetse fly control often needs to be transboundary involving several countries within a region.

  HAT: Risk of spread of rHAT from Uganda to neighbouring countries.

  NTTAT:

  Highly important especially in the case of T. evansi in Asia with important animal movements from India and China to South East Asia, and interference with Foot and Mouth Disease vaccination.

  NTTAT can become endemic in any country with a mild to tropical climate i.e. everywhere where biting flies can survive.

  GAPS:

  AAT:

  Risk of cross-border movement is not understood.

  HAT:

  Factors underpinning the separation of the gHAT and rHAT is not well understood.

  NTTAT:

  Risk assessment for the spread of T. vivax in Mediterranean countries.

  Surra could compromise vaccination campaigns against FMD and Haemorrhagic septicaemia.

  T. evansi is a transboundary risk, especially in absence of proper legislation (importation of camelids, transport of (race) horses from endemic regions.

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  AAT: African trypanosomiasis is mainly cyclically transmitted through the bite of tsetse flies.

  HAT: rHAT is cyclically transmitted through the bite of the tsetse fly; gHAT can also be vertically and sexually transmitted.

  NTTAT: T. evansi and T. vivax transmitted by biting flies to herbivores, T. evansi perorale to carnivores and T. equiperdum sexual (equidae).

  GAPS:

  AAT: Role of mechanical transmission in tsetse-infested areas.

  HAT: Evidence of cyclical transmission of gHAT by tsetse flies is limited. The role of vertical transmission and silent reservoirs of infection needs examination.

  NTTAT: T. evansi: dynamic of transmission by biting insects.

• Occasional mode of transmission

  AAT & HAT:

  Carnivores can be infected by ingesting meat or organs from infected animals. Infection occurs through the mucosa of the mouth in which bone splinters make wounds through which the parasites penetrate (17).

  Mechanical transmission possible but importance not known.

  NTTAT: T. evansi by ingestion of meat and organs of infected animals and iatrogenic transmission. Transplacental transmission in T. evansi and T. vivax.

  GAPS:

  AAT: Infection increases with age for AAT as expected if no acquired immunity.

  HAT: Infection does not increase with age for T. brucei, suggesting that high exposure to parasite infection can offer immune protection.

  NTTAT: Role of other vectors (biting arthropods or other hematophagous invertebrates).

• Conditions that favour spread

  AAT (including human infective species): Density and distribution of cattle and tsetse flies and factors which increase contact between the vector and the host (e.g. watering points). Presence of parasite species (HAT).

  NTTAT: Animal movements, density of biting flies, animal population density.

  GAPS:

  AAT & HAT: Factors driving the population dynamics of tsetse populations is not understood.

  NTTAT: Factors driving the population dynamics of Tabanidae (or biting flies in general) populations is not understood. Transfrontier movements with uncontrolled animal movements. International regulations and quarantine rules need refined as well as proper diagnostic schedules.

• Detection and Immune response to infection

• Mechanism of host response

  AAT (including human infective trypanosome species): The immune response is unable to completely eliminate trypanosomes, and animals can become unapparent carriers. These unapparent infections can be reactivated if the animal is stressed (2).

  NTTAT: Immune control possible for T. vivax and T. evansi after some time and after trypanocidal treatments.

  Stress will cause increased pathology.

  GAPS:

  AAT: Immunology of animal trypanosomiasis not well understood. Requires further investigation.

  NTTAT: Immunization with modified parasites.

• Immunological basis of diagnosis

  AAT & HAT: Several antibody detection techniques have been developed to detect trypanosomal antibodies for the diagnosis of trypanosomiasis, with variable sensitivity and specificity (e.g. CATT, ELISA).

  NTTAT: Semi-commercial kits exist for T. evansi.

  GAP: Need for proficiency testing and validation of serological tools in view of their “fitness for purpose”.

• Main means of prevention, detection and control

• Sanitary measures

  AAT:

  Protecting animals from trypanosomiasis is difficult in endemic areas, as bites from tsetse flies and a variety of other insects must be prevented.

  T. vivax does not require tsetse flies to become endemic in other areas.

  NTTAT:

  T. evansi: Efficacy of treatment in various host species is variable.

  T. equiperdum: All affected or suspected and serological positive animals have to be slaughtered. Treatment is not allowed in most countries.

  GAP:

  NTTAT: Evaluation of sterilizing treatments (e.g. melarsomine) to eliminate T. evansi and T. equiperdum. Establishment of effective doses in various host species (e.g. horse, buffalo, cattle, pigs).

• Mechanical and biological control

  AAT & HAT:

  The integration and adaptation of the various control measures to the local prevailing environmental and agro-ecological conditions is essential to give optimum results:

  1. Use of prophylactic trypanocidal (animal form of the disease) and curative (both human and animal forms) drugs, although drug resistance is a problem

  2. Exploitation of trypanotolerant livestock breeds

  3. Reduce or eliminate tsetse fly population density in a given area with traps, insecticide-impregnated targets, insecticides applied from aircraft and other means

  4. Protection of individual animals by using insecticide-impregnated netting or fencing, which will also reduce fly density in the locality

  5. Use of insecticides on animals, usually cattle, (applied by spraying or pour-ons) to reduce the population of tsetse in an area; the insecticides used usually and, usefully, also kill ticks (1).

  6. If and where fly populations are isolated, an area-wide integrated intervention approach can be envisaged to create sustainable tsetse-free zone - particularly attractive, as it permits the definite elimination of the vector from the targeted area (2,3).

  7. Where the creation of tsetse-free zones is the objective, the use of the sterile insect technique (SIT) is advocated where residual tsetse fly populations persist after their numbers have been reduced using other means.

  NTTAT: Use of curative trypanocidal drugs, use of insecticidal drugs. No large-scale vector control, almost no prophylactic use of drugs.

  GAPS:

  AAT: None of the currently used methods guarantees 100% success or is equally efficient on the various tsetse species and/or transmitted species of trypanosome. A similar situation applies to those insects other than tsetse flies and those trypanosome species mechanically or sexually transmitted (e.g. T.vivax, T.evansi, T. equiperdum).

  AAT: Optimal intervention strategies are not understood for all vectors and agro-ecological settings.

  HAT: Optimal intervention strategies are not used for all vectors and agro-ecological settings.

  NTTAT: Optimal intervention strategies are not understood for all vectors and agro-ecological settings.

• Diagnostic tools

  AAT (including human infective species):

  Parasitological methods: These methods aim at detecting the parasite itself mainly in blood through microscopical examination of thick or thin blood stained smears. Another parasitological method is through concentration of trypanosomes through blood centrifugation and microscopic examination of the interface (buffy coat) between the white and red blood cell, where trypanosomes are concentrated. From live animals, the parasite can be isolated from blood and lymph collected from lymph node. A blood or lymph sample of suspected infected animals can be injected in one or more laboratory animals (mouse, rat or rabbit).

  Serology: The detection of antibodies indicates that there has been an infection but as antibodies persist for some time (weeks or months) after all trypanosomes have disappeared from the animal (e.g. following drug treatment) a positive result is no proof of active infection.

  Molecular tests: Sequences of nucleotides specific for the various species of trypanosomes can be detected in fluids (mainly blood) of mammalian host. These tests can only be carried out reliably in well-equipped laboratories by specifically trained staff, and are still mainly research tools (7).

  NTTAT: See for AAT.

  GAPS:

  AAT:

  A sensitive penside test for differentiation within the brucei clade.

  None of currently and commonly used diagnostic methods (parasite isolation, parasitological methods, serology) provides an absolute certain and definite answer, as false positive and/or false negative cases occur. This situation is intrinsically linked to the low sensitivity or low specificity (or both) of used method(s); also low level(s) of parasitaemia below the detection threshold are often encountered in field conditions. In addition, parasite isolation and serological diagnostic tests require a well equipped laboratory and skilled personnel. Cost of diagnosis is also a gap for mass diagnostic campaign necessary to evaluate the impact of the disease and to set up intervention campaign.

  HAT:

  A sensitive bedside test for the differentiation within the brucei clade.

  There is a need for sensitive and specific point-of-care diagnostic tools that can identify silent carriers of gHAT.

  NTTAT:

  Serological tool: T. evansi: is there an extravascular focus which does not stimulate the immune system; if so, how can we detect such infections?

  Molecular test to distinguish T. brucei / evansi / equiperdum.

  Need for test uniformity, validation and PT not only for NTTAT but also AAT and HAT.

• Vaccines

  AAT (including human infective species) & NTTAT:

  No vaccines are available at the present time and prospects for a vaccine in the short-medium term are poor.

  GAPS:

  AAT:

  DNA vaccinations against secreted proteins responsible for virulence.

  Up to now, the immunogenic variability of the parasite has prevented the development of an effective and mass field applicable vaccine. Research on specific and stable immunodominant antigen(s) or recombinant immunoprotein(s) may help in progressing towards the development of a vaccine.

  NTTAT:

  To be investigated for T. evansi (and T vivax) – live or modified vaccine.

• Therapeutics

  AAT (including human infective species):

  Trypanocidal drugs for use in cattle are limited to the salts of just three compounds:

  1. diminazene aceturate (Berenil®, Hoechst; Veriben®, Sanofi; and other various generic formulations).

  2. homidium bromide (Ethidium®, Laprovet) and homidium chloride (Novidium®, Mérial) and;

  3. isometamidium chloride (Samorin® /Trypamidium®, Mérial; Veridium®, Sanofi)

  Drugs may be used therapeutically for the treatment of an ongoing trypanosome infections or to prevent infection. Some drugs may be used for either purpose, while those which are eliminated rapidly are limited to therapeutic use (2).

  NTTAT: Melarsomine, quinapyramine. Isometamidium based drugs - not very effective in Africa against T. evansi, but still effective in Asia; diminazene based drugs and melarsomine. cymelarsan for use in camelids

  T. equiperdum: cymelarsan seems to be effective but not at present allowed by OIE (15).

  GAPS:

  AAT: New veterinary drugs or new drug combinations are needed.

  AAT: No new chemical agents have been developed in the past 30 years. Chemoresistance in various trypanosome species to the commonly used trypanocides is a wide spread phenomenon. Additionally, counterfeit, fake and/or poor quality of trypanocides is a worldwide problem which entails a reduction in efficacy and safety profiles and has a direct role in the development of drug resistance. The use of counterfeit drugs has severe implications for both animal health and food safety as it causes problems with unspecified, unwanted chemicals and their residues in the food chain, a public health concern. No internationally agreed quality control/quality assurance methods/protocols are established for trypanocides.

  NTTAT: Need for validation of efficacy of cymelarsan in dourine cases. New veterinary drugs or new drug combinations are needed for T. vivax and T. evansi.

• Biosecurity measures effective as a preventive measure

  None: (i) Some trypanocides (e.g. homidium) are considered potentially carcinogenic and active on animal genetic material. (ii) The application of the sterile insect technique (SIT) implies the use of a nuclear radio-active source for insect sterilization.

  Trypanosome infections compromise the immunosystem and animals may become more susceptible to disease agents of relevant biosecurity importance.

  GAPS:

  AAT: Lack of information on mis-use of therapeutic measures and complexity of the SIT application.

  NTTAT: As with AAT for the use of trypanocides.

• Border/trade/movement control sufficient for control

  AAT (including human infective species):

  No specific rules laid down in the OIE Animal Health Code although trypanosomiasis due to T. congolense in bovines was included in the former List B of OIE. It is essential that livestock are treated with trypanocides before being moved to new areas in order to prevent the spread of HAT in T. b. rhodesiense areas. Treatment of all cattle in markets should therefore be recommended.

  NTTAT:

  Regulation to be established for T. evansi

  T. equiperdum: OIE animal health code.

  GAPS:

  AAT: No regulation is available for most of the trypanosome infections as far as border/trade/movement control of domestic or wild animals are concerned (exception is T. equiperdum in equines). Climatic changes and changes in the agro-ecological conditions, together with international or regional animal movements could provide the requisites for trypanosome species to establish, expand and become endemic in new areas or livestock-agricultural systems.

  HAT: Legislation to ensure that livestock are given trypanocides prior to movement and at markets is essential to stop spread HAT within and from T. b. rhodesiense endemic areas to uninfected areas.

  NTTAT: Urgent need for code for Surra.

• Prevention tools

  AAT (including human infective species): Prophylactic use of trypanocidal drugs to prevent the disease in animals protects people as well as animals from illness since in many rhodesiense HAT areas domestic cattle are now the main reservoir of the human infective T. b. rhodesiense.

  (See also Section “Main means of prevention, detection and control - Vaccines and –Therapeutics”).

  NTTAT: Regular use of insecticidal drugs on the animal and its direct environment, animal movement and quarantine rules.

  GAPS:

  AAT: See Section “Main means of prevention, detection and control – Vaccines and – Therapeutics”.

  NTTAT: As per AAT.

• Surveillance

  AAT (including human infective species): The antibody ELISA is a very useful test for large-scale surveys to determine the distribution of tsetse-transmitted trypanosomiasis. Sample collection and storage is made easy through the use of filter papers (7).

  NTTAT: Idem for T. vivax and T. evansi. T. equiperdum: Regular clinical control of horses and donkeys. CFT testing of all equines for export.

  GAPS:

  AAT: See Section “Main means of prevention, detection and control –Diagnostic tools”.

  NTTAT: As in AAT.

  NTTAT: Need for standardisation and validation of CFT test. Alternative tests exist but need validated to replace CFT (est. 1915).

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  AAT & HAT:

  1. It has been demonstrated over the past 50 years that eliminating tsetse from an area is not only exceedingly difficult but even if this is achieved, the area remains susceptible to re-infestation from neighbouring areas. Tsetse populations are highly resilient; they can persist at very low densities, the 29 species and subspecies are widely dispersed and they are highly mobile. The various methods are listed in Section “Main means of prevention, detection and control – mechanical and biological control” above.

  2. Tsetse control by applying insecticide to cattle (insecticide-treated cattle or ITC) has been shown to greatly reduce the numbers of tsetse in an area which in turn means fewer cattle will be bitten. The insecticides used are usually ones which also affect ticks, thus having the added benefit of reducing damage from ticks and the incidence of tick-borne diseases. The use of insecticide-impregnated fencing or netting is effective in protecting stock from bites. These low-cost methods can be applied on a small or a large scale and can be affordable by livestock keepers in Africa – they do however rely on cattle being present and evenly distributed.

  3. Permanent eradication of tsetse over large areas has been achieved in Nigeria and Zimbabwe in the past, using residual insecticides applied from knapsack sprayers by teams on the ground and in South Africa using airplanes. Although highly effective and used at dosages which are not environmentally damaging, the use of residual insecticides is no longer advocated for tsetse control. Tsetse were eventually eliminated from Zanzibar using a variety of techniques, culminating in the release of sterile male tsetse (sterile insect technique – SIT).

  Targets and traps are also very effective in reducing or eliminating tsetse populations and do not rely on the presence of cattle. They have been widely used in programmes to control HAT as well as AAT.

  Aerial spraying using several sequential applications of non-residual insecticides has been effective and appears to have achieved permanent elimination in the Okavanago Delta of Botswana. Aerial spraying has also been successful in a wide range of situations throughout Africa, achieving a rapid reduction or local elimination of tsetse, although gradual fly reinvasion has usually eventually occurred.

  NTTAT:

  Historical temporary infection in the French West Indies (T. vivax) and in Australia (T. evansi); recent temporary outbreak in France (currently under surveillance)

  Eradication of biting flies for T. evansi and T. vivax is impossible.

  Eradication of T. equiperdum is possible by slaughter of all affected, suspected and serological positive animals (USA, Canada, several European countries). Dourine was eradicated in EU after WWII through treatment, castration and slaughtering.

  GAPS:

  AAT & HAT:

  A review of past efforts to control tsetse and analysis of their strengths and weaknesses, with particular emphasis on cost, sustainability and issues of reinvasion by tsetse is urgently needed to inform present policy.

  NTTAT:

  Possible eradication by treatment?

  Current trial to eradicate T. evansi from Gran Canaria needs attention.

  Follow-up of continental outbreaks need follow-up. Lessons to be learnt? (Diagnosis, rules and regulations, quarantine, treatment before transport)?

• Costs of above measures

  AAT: Infection treatment costs are high (more than US$1/treatment/animal and higher for prevention treatment). Elimination of tsetse is also expensive (for instance use of sequential aerosol technique (SAT) can cost between US$250 and US$400 per km2) (1, 17, 18).

  HAT: Treatment costs vary greatly according to which drug regime is used, the duration of hospital stay and whether patients are diagnosed in the first or second stage of the disease (when the central nervous system has become involved); costs are estimated to range between US$ 100 and US$ 800 per patient, most often between $100 and $250. Currently, new drug regimes and shorter hospital stays are being introduced for the second stage of the disease (3).

  AAT: To end-users the cost of trypanocides generally varies between $0.6 and $2 a dose. The cost of administration ranges from the cost of needles and syringes, where livestock keepers inject their animals themselves to over US$20. Typical fees are in the US$2 - $4 bracket. See also Section “Socio-economic impact – direct impact costs of private and public control measures”, below.

  Vector control: The cost of controlling tsetse varies greatly depending on the method used (see section 9.2) and whether the objective is to maintain tsetse control over a number of years or to create tsetse free zones and protect them from reinvasion. To cite some examples, very rough orders of magnitude indicate that creating tsetse free zones using aerial spraying is likely to cost US$ 600 per sq km excluding the substantial ongoing costs of preventing reinvasion. Ongoing suppression of tsetse numbers to very low levels, using insecticide-treated cattle is likely to cost between US$ 25 and US$ 100 per km2, depending on how much insecticide is used, how it is applied and the costs to livestock keepers in time and money (1, 17, 18).

  GAPS:

  AAT:

  No simple, cheap and ready field applicable diagnostic test is available, particularly for mass screening. Trypanocidal drugs are becoming more and more expensive and their efficacy is reduced by the appearance of chemoresistance. No internationally agreed quality control standards are available and no new and cheap animal trypanocides are being developed. Integration and comparative advantages of tsetse control methods need to be tested.

  Critical and quantitative analyses of socio-economic costs and benefits of control are scant.

  HAT:

  Critical and quantitative analyses of socio-economic costs and benefits of control are scant.

  NTTAT:

  As per AAT but adapted to biting insects and concerned trypanosome species.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes. Trypanosomosis (tsetse-transmitted) is a OIE listed disease.

  NTTAT: Disease suspected in 4 countries, infection present with no clinical disease in 1, clinical disease confirmed in 21 countries, and restricted to certain zones in 3 countries. Based on the distribution of positive reports which included China, India, Vietnam, Pakistan, Colombia and Venezuela it is not clear which type of trypanosomiasis is being recorded.

  GAPS:

  AAT: Tsetse-transmitted trypanosomes only notifiable in bovines while also occurring on other species; need to be on multispecies list – e.g. T. evansi was transferred from equine to multispecies in 2008.

  NTTAT: Reporting is messy. Often wrongly identified or classified.

• WOAH disease card available

  Trypanosoma evansi (including Surra): http://www.oie.int/fileadmin/Home/eng/Animal_Health_in_the_World/docs/pdf/Disease_cards/TRYPANO_EVANSI.pdf

  Trypanosomosis (tse-tse transmitted): http://www.oie.int/fileadmin/Home/eng/Animal_Health_in_the_World/docs/pdf/Disease_cards/TRYPANO_TSETSE.pdf

• WOAH Terrestrial Animal Health Code

  Not available.

• WOAH Terrestrial Manual

  Trypanosoma evansi infections (including Surra):

  http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.01.21_TRYPANO_SURRA.pdf

  Trypanosomosis (tse-tse transmitted):

  http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.04.17_TRYPANOSOMOSIS.pdf

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  HAT:

  Untreated, the disease is always fatal in humans and devastating epidemics have occurred over the last century, leading to depopulation of whole settlements. The disease tends to affect the active adult population and sick individuals need a great deal of care. Many are not diagnosed as HAT patients and die as a result. The labour burden on affected households is thus considerable. The financial burden per treated patient is also considerable, variously estimated at the equivalent to 2 to 10 months of an average rural wage. The average DALYs per untreated patient have been estimated at 24 for T. b. rhodesiense and between 27 and 33 for T. b. gambiense. Global annual DALY estimates range from 1.5 – 2 million; this figure understates the impact of the disease, as it is highly focalised so that very heavy burdens are imposed in affected communities. For example, one study showed that, comparing HAT to malaria, there were 133 times as many cases of malaria reported, but these only caused 3 times as high a DALY burden (20).

  With respect to geographic impact, Gambian and Rhodesian forms of the disease occur only in Africa south of the Sahara, where poverty, social instability, insecurity and weak health systems are widespread; The disease is rural, occurring mostly in remote, difficult to access areas, distributed over wide areas of land and affecting a population with poor or no access to health services. As stated in Section “Geographical distribution and spread - speed of spatial spread during an outbreak”, the geographical foci of the two forms are well known and delimited and relatively constant. The high rate of under-reporting and the fact that most diagnosed patients are initially treated for other illnesses, often several times, before being recognised as suffering from HAT reflects both the inherent difficulty in diagnosing the disease and the limitations of under-resourced health services (14).

  GAPS:

  HAT:

  Under-reporting is the major unknown. A methodology has been developed for estimating this for T. b. rhodesiense. For T. b. gambiense, the effectiveness of surveillance gives some indications, but more work on this is needed. Associated with its GIS work, WHO is developing tools for the early detection of outbreaks.

  More studies on disease burden need to be added to the handful of studies which have estimated DALYs and financial and labour burden to affected households.

  Critical and quantitative analyses of socio-economic costs and benefits of control are scant.

• Zoonosis: cost of treatment and control of the disease in humans

  HAT: Treatment is expensive, normally ranging from US$150 to US$800 per person, and in the later stages of the disease treatment itself involves some 5% mortality (3).

  GAP:

  HAT: Critical and quantitative analyses of socio-economic costs and benefits of control are scant.

• Direct impact (a) on production

  Where tsetse flies are present, trypanosomiasis in livestock acts as a constant drain on livestock productivity and livestock keepers’ time and money. It also acts as a brake on rural development, since it affects human health, particularly in the working population and both agricultural and livestock productivity (see also11.7). These impacts are felt to a greater or lesser extent throughout the tsetse-infested parts of Africa, being particularly high in the areas on the fringes of tsetse infestation (where higher numbers of cattle are present), in parts of eastern Africa, especially Ethiopia; conversely losses are very much lower in areas of Africa with low cattle populations, or covered with rainforest.

  All AAT diseases have an economic impact on the development of agriculture in Africa. Those affecting cattle are undoubtedly the most important economically since they are a major cause of reduced meat and milk production and limit the use of draught power for agricultural production. The economic losses due to reduced meat and milk from cattle production alone are estimated to be in the range of US$ 1.0 - 1.2 billion. The impacts of the disease on mortality have been summarised in Section 3.5 above. Trypanosomiasis is also thought to reduce calving rates by 5 to 20 percentage points, kidding and lambing rates by 20 to 30 percentage points and milk yields by 2-25% (18, 19).

  NTTAT: Very high due to very high mortality rate, production losses, abortion; weak animals are not available for traction. T. vivax high impact in South America and increasing in central America; T. evansi high impact in horses in Latin America and in bovidae in Asia. High in recent outbreak and mild in enzootic situation; surra: model of impact of subclinical infection developed in the Philippines.

  GAPS:

  AAT:

  The information on which calculations of the economic costs of tryps in livestock is based is limited to some twenty to thirty studies, in specific locations and production systems and there have been few studies in the last 10 years. The existing studies are reviewed in 17 and 18. There is no detailed study looking explicitly at the effect on draught power. Much work has been done on collecting prevalence, PCV and weight data, but this is difficult to translate into economic terms in Africa’s production systems. Critical and quantitative analyses of socio-economic costs and benefits of control are scant at national and sub-national level.

  Impact on newly emerging semi-intensive and intensive production system(s) (e.g. small milk production units) is unknown. Limited information is also available on the impact of newly developed tsetse control methods, like the insecticide-mosquito fencing technique.

  Need for evaluation of factors (host and parasite associated!) affecting the impact of the disease in livestock.

  Need to update tsetse distribution maps and refine maps’ accuracy. Critical and quantitative analyses of socio-economic costs and benefits of control are scant. Evaluating factors affecting the impact of the disease on livestock.

  NTTAT:

  Surra: impact of subclinical infection to be evaluated in Asian countries. Need for socio-economic impact studies of NTTAT.

  What is the impact of surra in Asia: including general medical impact and immunosuppressive impact (interference with intercurrent diseases and with vaccinations campaigns).

• Direct impact (b) cost of private and public control measures

  AAT:

  Approximately 35 million doses of trypanocidal drugs are administered annually (1, 2) with a cost estimated at more than US$40 million for purchasing drugs alone.

  Taking this figure of 35 million doses per annum (see 9.11 above) it is likely that Africa’s livestock keepers are spending some US$90 - US$140 million per annum on drugs to prevent or treat trypanosomiasis. A proportion of this cost is borne by the public purse, where the cost of administering trypanocides is paid for or subsidized by veterinary services.

  Tsetse control: Current expenditure on tsetse control is unknown. Farmers are spending substantial sums on pour-ons and spraying their cattle, which also helps to control ticks. Public projects’ costs can be found out on a case by case basis. Funding is very sporadic, with almost all African countries closing down or merging their specialist tsetse control units, so that public investment relies on occasional projects. Cost of the different tsetse control techniques are outlined in Section “Main means of prevention, detection and control – costs of above measures”.

  NTTAT: see AAT

  GAPS:

  AAT:

  An updated estimate of the number of doses of trypanocides currently used per annum in Africa is needed (An estimate of annual sales could be obtained from their manufacturers).

  Tsetse Control:

  An inventory of ongoing tsetse control activities, both private and public and their estimated cost is needed.

  Critical and quantitative analyses of socio-economic costs and benefits of control are scant at national and sub-national level.

  Rather limited information is available on the spread, on local markets, and use of poor quality, fake and counterfeit trypanocides.

• Indirect impact

  AAT: Trypanosomiasis in livestock has a severe impact on agriculture in sub-Saharan Africa. Trypanosomiasis limits the use of work oxen and hence the acreages cultivated and, together with tick-borne diseases, constrains the upgrading of livestock, for example using grade dairy cattle.

  In tsetse-infested countries, half of the population suffers from food insecurity. The overall impact extends to restricted access to fertile and cultivable areas, imbalances of land use and exploitation of natural resources and compromised growth and diversification of crop-livestock production systems, including use of upgraded, more productive animal breeds (meat and milk production).

  GAPS:

  AAT:

  Evaluation of the exact impact on production parameters of cattle infected by drug resistant trypanosomes and treated with trypanocides.

  Livelihood vulnerability and food security level are negatively affected by the presence of tsetse and trypanosomiasis. However, the economic magnitude of the problems posed by the presence of tsetse and trypanosomiasis to food insecurity and rural socio-economy is less discernible.

  Critical and quantitative analyses of socio-economic costs and benefits of control are scant at national and sub-national level.

• Trade implications

• Impact on international trade/exports from the EU

  AAT (including human infective tryps species): None.

  NTTAT: T. equiperdum is notifiable, may cause export problems. So far no rules for T. evansi but risk is there.

  GAPS:

  NTTAT:

  A real gap exists in the regulation and prevention of introduction of T. evansi into Europe.

• Impact on EU intra-community trade

  AAT (including human infective tryps species): None.

  NTTAT: T. evansi: no regulation.

  GAP:

  NTTAT: Regulation to be established.

• Impact on national trade

  AAT (including human infective tryps species): None.

  NTTAT: T. equiperdum?

• Main perceived obstacles for effective prevention and control

  AAT:

  1. Control or elimination of the tsetse fly in affected areas and regions is complex and costly.

  2. Where control or elimination of tsetse has been achieved, preventing of reinvasion is difficult. The technology for creating barriers to reinvasion exists, but barriers are notoriously difficult to maintain over long periods, primarily because of the labour and financial inputs required.

  3. Development of resistance to currently used drugs in trypanosomes for the treatment and prophylaxis of trypanosomiasis.

  4. Lack of new drugs for dealing with the disease (Section “Pharmaceutical availability – commercial feasibility”). The market for these is too small for pharmaceutical companies to develop new drugs on a commercial basis.

  5. Absence of vaccines: The complex antigenic structures of trypanosomes will make the development of a vaccine for animals or humans extremely difficult.

  6. Need for sustained long term measures which are difficult to maintain and pay for.

  7. Supply chain for trypanocides – livestock keepers in remote rural areas still have problems in obtaining veterinary pharmaceuticals and in finding a qualified person to inject their stock.

  8. Quality of trypanocidal drugs often questionable. Need for national/international quality control system.

  HAT:

  1. Ongoing surveillance is essential for control, particularly of T. b. gambiense, so as to prevent resurgence and future epidemics. However, funding is costly and difficult to justify once the incidence of the disease has fallen to low levels.

  2. For T. b. rhodesiense (where applicable), control of the livestock reservoir is effective, by initially by treating domestic cattle with trypanocides to remove the parasite, then by maintaining low cost tsetse control, for example by spraying cattle with insecticides.

  3. Public private partnerships have succeeded in making existing drugs available and trialling and introducing some new drugs.

  4. Diagnosis is still a major constraint.

  NTTAT:

  Standardisation and validation of tests for dourine/ absence of rules and regulations for T. evansi (tests exist but are not compulsory).

  Difficult detection of healthy carriers; absence of protocol to identify healthy farms for exportation of camelidae (surra).

  GAPS:

  AAT:

  Need full and effective commitment of national and local authorities and participation of local communities. Up to know, absence of integration of different control methods and synergistic exploitation of comparative advantages of various control techniques. No vaccine available. Reduced efficacy of trypanocides due to poor quality and drug resistance in trypanosome populations. Need for quality control in trypanocides. Limited financial and human resources of national veterinary services and NARS.

  HAT:

  Is detection and treatment adequate in all circumstances; Role of reservoir hosts.

  Effective integration of different control strategies.

  Safe and effective drugs

  Cheap and practicable diagnostic tests

  How to maintain adequate surveillance and treatment between outbreaks

  NTTAT:

  Need for a highly sensitive test AND that can distinguish T. equiperdum (trading of infected animals forbidden) from T. evansi.

• Main perceived facilitators for effective prevention and control

  AAT: The greater availability of animal health workers and private veterinarians has, to some extent, helped to make both trypanocides and their administration more accessible to livestock keepers – although probably not sufficiently to compensate for the massive reduction in government veterinary services in the last two decades.

  HAT: Country level, WHO, bilateral and NGO HAT control programmes have brought the recent resurgence of the disease under control. There are more trained individuals and the basic infrastructure for ongoing surveillance now exists.

  Tsetse control: Efforts to control tsetse continue at two levels:

  1. Private/Farmer level: farmers can apply insecticide to their cattle, use impregnated netting or fencing, or sometimes traps and targets. The cost of insecticide-treated cattle, nets and fencing is low, and there is much recent experience to show their effectiveness as well as support for their use (21). The extra benefit of controlling ticks is an added incentive for using insecticide treated cattle.

  2. Public level: projects and programmes exist for undertaking larger scale projects, and particularly through high level support by the African Union and the efforts of FAO and WHO there is good awareness of this problem.

  NTTAT: Diagnosis and treatment.

  GAPS:

  AAT: See Section “Main perceived obstacles for effective prevention and control above”.

  NTTAT: Need for more surveillance.

• Links to climate

  Seasonal cycle linked to climate

  AAT: Associated with the seasonal change as to the extent of the tsetse belt and the density of flies and movements of hosts.

  HAT: HAT epidemics linked to displacement of populations.

  NTTAT: Linked to seasonal activity of biting insects.

  GAPS:

  AAT: Large scale predictive modelling needed.

  HAT: Climate and starvation links need examination.

• Distribution of disease or vector linked to climate

  AAT & HAT: Tsetse distribution is influenced by climate.

  NTTAT: Possible increases of biting insect density.

• Outbreaks linked to extreme weather

  AAT & HAT: Climate can impact on tsetse populations, susceptibility of vector to infection. Disease, outbreaks indirectly linked to host condition/ fitness.

  NTTAT: Possible influences on biting insect density. Host fitness.

  GAPS:

  AAT/HAT/NTTAT: Impact of extreme weather unknown. Modelling needed.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  AAT & HAT: Climate change may result in a change in the vector geographical range (13).

  NTTAT: Biting insects such as Stomoxys may proliferate or reduce. Biting flies may expand their habitat and become a danger for milder climate regions or contract in areas too hot.

  GAPS:

  AAT & HAT: Impact of climate change on AAT and HAT largely unknown.

  NTTAT: Role of haematobia species as vectors of surra in Europe?

Risk

• AAT (including human infective trypanosomes):

  Sustained tsetse control on various scales is feasible (in large parts of sub-Saharan Africa) and low-cost effective options exist. Creation of tsetse free zones is also possible, but preventing reinvasion is in important issue in all but a limited number of isolated populations. The development of drug resistant trypanosomes will lead to potential increased levels of disease in animals and humans. Whilst the use of insecticides to kill tsetse, applied from aircraft, to cattle (so as to control both tsetse and ticks) or to stationary targets and traps, is effective there is the possibility of development of insecticide resistant tsetse flies (risk is probably low but behavioural resistance could become an issue).

  NTTAT: Indirect risk for surra is the immunosuppressive effects which can enhance inter-current diseases and interfere with vaccination campaigns. Eradication is impossible.

  T. evansi: possible risk for introduction into EU.

  T. equipderum: idem, need for more vigilance.

  GAPS:

  NTTAT: CODE, test validation, rules and regulations on EU level for Surra.

Main critical gaps

Conclusion

• The prospects of developing a vaccine are very poor as trypanosomes have evolved a system to evade the host’s immune system by varying the structure of their surface coating. This change is controlled genetically and each parasite has a huge so-called ‘repertoire’ of variable antigenic type (VATs). As the host’s immune system responds to one VAT, the parasite switches to another and thereby evades destruction. Within any particular geographical area, there will be several species, subspecies, types and strains of trypanosome, each with its own repertoire of VATs. Consequently, livestock cannot develop an effective immunity to the disease. However, lions in the wild do exhibit evidence of immunity to T. brucei (not observed for T. congolense and T. vivax) and this may offer an avenue for exploration (16).

  The prospects of developing a vaccine are very poor as trypanosomes have evolved a system to evade the host’s immune system by varying the structure of their surface coating. This change is controlled genetically and each parasite has a huge so-called ‘repertoire’ of variable antigenic type (VATs). As the host’s immune system responds to one VAT, the parasite switches to another and thereby evades destruction. Within any particular geographical area, there will be several species, subspecies, types and strains of trypanosome, each with its own repertoire of VATs. Consequently, livestock cannot develop an effective immunity to the disease. However, lions in the wild do exhibit evidence of immunity to T. brucei (not observed for T. congolense and T. vivax) and this may offer an avenue for exploration (16).

  GAPS:

  AAT:

  In livestock, is there a decrease in humoral immunity linked to trypanosomiasis (potential of vaccines against secreted proteins causing anaemia).

  HAT:

  Immunity observed in lions to T.brucei caused by extraordinary exposure (challenge) by trypanosomes suggests immunity to T.brucei s.l. may be possible.

  Due to its biological nature and its links with agro-ecological settings, the disease constitutes a complex and vast sub-Saharan problem to be solved. Investments have to be spread over five main areas: (i) human resource development; (ii) improved technology for diagnosis and treatment of AAT and HAT; (iii) improved methods for disease prevention, including vector control; (iv) increased exchange of information and (v) regional, national and international support.

  Due to the high level of complexity, a consortium of coordinated and concerted actions is needed.

Sources of information

• Expert group composition

  Names of expert group participants have been included where permission has been received to do so.

  Sue Welburn, University of Edinburgh, UK - [Leader]

• Reviewed by

  Project Management Board.

• Date of submission by expert group

  September 2016

• References

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  2. FAO: http://www.fao.org/AG/AGAInfo/programmes/en/paat/disease.html

  3. WHO: http://www.who.int/trypanosomiasis_african/en/ and http://www.who.int/mediacentre/factsheets/fs259/en/

  4. CDC: http://www.cdc.gov/parasites/sleepingsickness/index.html

  5. Cecchi et al., (2009) Towards the Atlas of human African trypanosomiasis. Int J Health Geogr. 8:15.

  6. Desquesnes et al. (2013) Trypanosoma evansi and surra: a review and perspectives on transmission, epidemiology and control, impact, and zoonotic aspects. Biomed Res Int. Epub 2013 Sep 18.

  7. Wen et al., (2016) Further evidence from SSCP and ITS DNA sequencing support Trypanosoma evansi and Trypanosoma equiperdum as subspecies or even strains of Trypanosoma brucei. Infect Genet Evol. Epub 2016 Mar 23.

  8. Wastling, S.L. and Welburn, S.C. (2011) Diagnosis of human sleeping sickness: sense and sensitivity. Trends Parasitol. 27:394-402

  9. Van Vinh Chau et al. (2016) A Clinical and Epidemiological Investigation of the first reported human infection with the zoonotic parasite Trypanosoma evansi in Southeast Asia. Clin Infect Dis. 62:1002-1008

  10. Desquesnes et al. (2016) Zoonotic trypanosomes in South East Asia: Attempts to control Trypanosoma lewisi using veterinary drugs. Exp Parasitol. 165:35-42.

  11. Elsen et al. (1990) First record of Glossina fuscipes fuscipes Newstead 1910 and Glossina morsitans morsitans Newstead in south western Saudi Arabia. Ann Soc Belge Med Trop. 70: 281-287.

  12. Welburn et al. (2016) Beyond Tsetse - Implications for Research and Control of Human African Trypanosomiasis Epidemics. Trends Parasitol. 32:230-241.

  13. Lindner, A.K. and Priotto, G. (2010) The unknown risk of vertical transmission in sleeping sickness – a literature review. PLoS Negl.Trop. Dis. 4, e783

  14. Rocha et al. (2004) Possible cases of sexual and congenital transmission of sleeping sickness. Lancet 363, 247.

  15. Simarro et al. (2015) Monitoring the progress towards the elimination of Gambiense human African trypanosomiasis. PLoS Negl. Trop. Dis. 9, e0003785