Rapid immunodiagnostic test (RIDT) kits (lateral flow devices – LFDs) provide a simple and rapid method for rabies detection. They neither need cold chain maintenance for transportation nor complicated training for personnel. Their use should be considered in the absence of a diagnostic laboratory or any gold standard test.
List of commercially available kits (Diagnostics for Animals)
The quality of available RIDTs shows great differences. It would be of great advantage if the different commercial available LFD products would be tested (validated) by an international panel of rabies reference laboratories and, if deemed suitable, receive an international approval. Hence, people would know which product is acceptable.
See “Commercial diagnostic kits available worldwide.
A commercially available ELISA kit (Platelia Rabies II ELISA) for the determination of immune status post-vaccination in individual dogs or cats, and in fox populations is currently mentioned in the OIE Manual of Diagnostic Tests (version 2018) as a suitable test for post-vaccination immunity evaluation and not for international movement of animals.
Continuing educational training on the kit for professional laboratories. Improved quality assurance programmes need to be put in place.This specific kit does not seem to be particularly suitable for routine use, and more generally, the ELISA technique appears to be inappropriate for the evaluation of individual immunity.A new kit has been developed and has provided more accurate results in several collaborative studies.
Identification of the agent: To date, fluorescent antibody test (FAT) is the gold standard recommended technique for the agent identification. It provides a fast and reliable diagnosis in 98–100% of cases for all lyssavirus species if a potent and broad-spectrum conjugate is used. Recently, both the dRIT and molecular techniques (rRT-PCR and RT-PCR) have been recommended as alternative methods to diagnose rabies infection in animals in absence of FAT. For a large number of samples, as in an epidemiological survey, PCR or enzyme-linked immunosorbent assays (ELISA) can provide rapid results. Furthermore, the RTCIT (virus isolation in cell culture) can be used in case other assays give inconclusive results.Identification of postvaccinal antibodies: Virus neutralisation (VN) assays in cell cultures are the recommended tests by OIE (for international trade). Results are expressed in International Units.Alternatively, use may be made of a test that is known to correlate with these, notably an ELISA using antibody to the G protein. The latter cannot be used for international trade, because the international regulations require neutralizing antibody determination; on the opposite, ELISA results are therefore expressed as negative or positive.
dRIT: a biotinylated polyclonal antibody cocktail is distributed through the NGO The Global Alliance for Rabies Control (GARC)-South Africa. The biotinylated polyclonal antibody preparation can be supplied on its own, or as part of a DRIT training kit that contains sufficient DRIT-specific reagents to diagnose about 300 samples. However, multiple commercial sources are still missing and therefore consistent provision might not be guaranteed. For monitoring oral rabies vaccination campaigns there is no need to determine an absolute value for the immune response; a simple ‘positive’ or ‘negative’ would suffice. Hence, ELISA kits offer a suitable alternative to VN-assays and eliminate the use of live virus and expensive equipment such as a fluorescence microscope.
There may be a market to improve LFDs or to provide a dRIT (ideally under a kit format) for resource poor countries.
In the framework of post oral vaccination campaigns in Europe, all rabies positive cases within the vaccination area need to be investigated in order to rule out the occurrence of vaccine-associated field infections. This is not a DIVA-approach but the assays (PCR) used need to be able to differentiate between field and vaccine strains distributed during the vaccination campaigns. A high-throughput test has been standardised based on Pyrosequencing technology.
The approach needs to be extensively adopted and other tests possibly standardised.
There is currently no possibility of diagnosing rabies in the incubating animal. A special PCR-based kit to determine the presence of rabies virus in saliva has been developed Thailand and is commercially available there. However, full validation is still needed, especially in terms of clinical sensitivity of the test.
There is an increasing need for ensuring the truthfulness of international trade certificates using a shared block chain secure technology.
For Europe, there may not be an immediate need for new developments. However, in other settings, field tests (i.e. accurate LFDs or small PCR-kits) to be used directly in the field where logistical constraints severely hinder submission of samples to the laboratory could increase rabies surveillance in these remote areas considerably.
Furthermore, using mobile phone techniques (apps) for data collection and – reporting could increase real time data evaluation tremendously.
Development of a diagnostic test in an animal incubating rabies would reduce the need to establish quarantine facilities. Within this context, the use of non-invasive samples to develop intra-vitam diagnostic tests would be paramount.
More and more rapid tests (mainly LFDs, ELISA) are available on the market but not validated according to international standards by independent laboratories prior to use. Urgent need to define a validation process scheme following ICH guidelines for the validation and further OIE approval of these kits.
A wide range of vaccines authorised globally. There are human, cat, ferret, horse, sheep, cattle, and dog rabies vaccines, all of them based on inactivated viruses. As well, a recombinant rabies vaccine based on canarypox virus is now available for cats.
All vaccines currently used in wildlife for oral vaccination programmes are either modified live-virus vaccines or live recombinant vaccines.
Although, there is evidence that current vaccines are extremely potent, there is a need for longer lasting (perhaps lifelong) vaccines.
Additionally, in dogs a combination of rabies vaccine and contraceptive vaccines would provide a valuable tool in the fight against rabies. Lifelong immunity in animals, especially dogs, would be hugely beneficial to achieving dog rabies elimination globally.
Pets & Livestock: A range of vaccines are authorised in Europe. Inactivated rabies virus vaccines are licensed for use in pets and livestock. As well, a recombinant vaccine based on canarypox virus is available for cats.
Wildlife: All vaccines currently used for oral vaccination programmes are based on replication-competent viruses, either modified live-virus vaccines or live recombinant vaccines.
Fox-mediated rabies has almost disappeared from the EU. However, the risk of re-emergence cannot be ignored, in particular in Southeast Europe bordering countries with endemic rabies. In several of these countries, large populations of free-roaming unvaccinated dogs are present. The need of a licensed product for oral vaccination of dogs in case of a rabies outbreak should be assessed.
Vaccination is the favoured method for rabies control in reservoir populations of dogs and wildlife. It is also a method for rabies prevention in human beings.
For animals, live rabies virus and recombinant vaccines are effective by the oral route and can be distributed in baits in order to immunise wild (or domestic) animals.
Pets & livestock: Although rare, feline injection-site sarcomas (FISS) are cancerous tumours that can arise following vaccine injections. Adjuvants are often blamed for these adverse reactions, but it could also be caused by inflammation. For cats, a live recombinant canarypox virus vaccine is now commercially available. In Latin America losses in cattle can be attributed to inadequate use of the vaccines, and to failure of the vaccine to adequately immunize the animals.
Wildlife: For oral rabies vaccines, presently only live replication-competent viruses based on human pathogens are available. The development of oral vaccines has enabled the eradication of rabies from the red fox population in most of Europe. In addition, programmes for oral vaccination of wildlife such as raccoons, coyotes, foxes, and skunks are being undertaken in North America using oral baits in areas where rabid wildlife is frequently found. For oral vaccination, either attenuated rabies strains or live-recombinant vaccines may be used. The vaccine should not induce any adverse signs in target and non-target species
Considering that rabies, with the exception of bat rabies, has almost been eliminated in EU countries, the demand for rabies vaccination is bound to decrease as, there will be no commercial or limited potential for new vaccines.
The risk of bat rabies spill-over infections is extremely limited, thus the incentive to develop a commercial pan-lyssavirus vaccine will be rather scarce.
Genetically Engineered vaccines (not expressing a foreign gene) and GMO vaccines, where the vector expresses a foreign gene, are currently both considered as recombinant vaccines in the EU, but this may not be acceptable in some countries. In the EU, recombinant vaccines must go through central EMA authorization.
Need to revise the efficacy standards for oral vaccines. In fact, a sharp distinction between vaccine efficacy and vaccine bait efficacy needs to be made as the latter is also influenced by bait handling of the animal.
Development costs for human and animal vaccines are extremely high, hence unless the market potential lies also outside Europe, new products are not commercial feasible.
Vaccination could be used for barrier protection around outbreaks in new regions.Rabies is still endemic in several countries bordering the EU, hence a vaccination belt (cordon sanitaire) is currently in use along these borders to prevent the re-introduction of wildlife-mediated rabies.
The most effective protocol for a vaccination belt (within the EU MS or along neighbouring countries) is still to be defined.
WHO and, more recently, OIE stimulated studies on oral vaccination of dogs (OVD) and the development of safer and effective vaccines/baits and overall bait delivery methods for OVD. OVD offers new approaches and promises a significant increase in the dog vaccination coverage (especially of free-roaming and poorly supervised dogs), especially when applied as an alternative method within a wider frame of parental vaccination campaigns.
A number of requirements regarding safety of candidate vaccines and safety, efficacy and actual cost of bait delivery, remain to be fulfilled. This is especially important in dogs, based on the domestic nature of this species. Although promising, OVD needs to be adapted to local conditions to limit the risks of human exposure to the vaccine, thus reducing the possible applications in the field compared to wildlife.
Stringent efficacy requirements listed by OIE might also prevent a straightforward application of OVD considering the level of incertitude linked to bait handling by the animals not under control during these studies. WHO-coordinated laboratory and field research on OVD carried out over the years has however been fruitful and allowed to set up the proper conditions for launching field trials in places where dog accessibility to parenteral vaccination has been identified as the obstacle to rabies elimination.
Oral or parenteral contraceptive vaccines for dogs, in combination with rabies vaccines may be a valuable option.Longer lasting rabies vaccines – perhaps even lifelong immunity.
No therapy for animals has been developed.
Development of an appropriate animal model that could be used to improve human treatment regimens.
The identification of the agent can be supplemented by identifying any variant virus strains using the PCR followed by DNA sequencing of genomic areas or by full genome sequencing. Such techniques can distinguish between field and vaccine strains, and allow to identify the geographical origin and epidemiology of the field strains.Although target sequencing of amplicons as well as full genome sequencing can be outsourced, result interpretation requires previous training of the personnel.
In general, the time for development of new tests depends on the nature of the test. The transfer of a new test from the development to an available diagnostic tool will take time, possibly years. However, development of in house diagnostic tests can be rapid.
The collaboration between the industry and at least one international reference laboratory for independent validation during the development phase is strongly recommended; such collaboration is not feasible in certain countries (impossibility for governmental laboratories to work with the industry to avoid any conflict of interests).
Developing new tests, particularly rapid tests, will be costly. Validation of new tests will be both time and labour intensive, meaning they will also be costly.
ICH-guidelines give detailed information on validation of assays. Unfortunately, several national and international rabies reference laboratories do not have rabies diagnostic assays in use in their laboratories which have been validated according to these guidelines. Hence, the results obtained by these laboratories are often questioned by regulatory authorities when their data are used for the registration of new products (assays, vaccines, biologicals).
Develop tests to identify incubating animals. Tests to identify infection in live animals if considered to be carriers.
Freedom of virus in animals is impossible to determine at present due to the lack of host antibody response and to the restriction of the virus to the neural tissues and salivary gland.
There is currently no diagnostic test to identify rabies infection prior to an animal showing clinical signs, neither a protocol for intra vitam diagnosis of rabies.
Current vaccines are effective and give a solid immunity. Before newly developed vaccines can be licensed, the duration of immunity resulting from their use should be determined in vaccinated animals of the target species. Parental vaccines should confer protective immunity for at least 1 year; 6 months is an acceptable time-span for oral vaccines. For live virus vaccines, the minimum virus content that will elicit an adequate immune response must be established.For live vaccines that are prepared for oral vaccination of wild (or domestic) animals, safety and efficacy in target animals and safety in non-target species must be demonstrated.The development of combination vaccines to include a rabies element as well as other diseases has some merit and such vaccines are in production.
New vaccines for lyssaviruses not covered by current vaccines (including phylogroups II, III and putative IV). Longer lasting vaccines that could provide lifelong protection to animals.Need to develop universally accepted criteria for vaccine potency testing. The current in vivo assay (NIH) requires the use of thousands of mice annually. The test is highly variable and urgently needs to be replaced by a combination of in-vitro testing (e.g. Trimeric glycoprotein quantification) and consistency monitoring.
As there is an enormous amount of data gathered concerning immune response and protection, the possibility to refrain from performing rabies challenge studies including control animals i.e. esp. under MUMS conditions) need to be investigated.
A long period of 5-10 years is always anticipated for development of new vaccines
Very expensive and little probability of a much larger market in Europe, which is close to eradicate the disease in its major reservoir species, the red fox.Vaccine banks have been implemented for endemic countries and targeting both human and animal vaccines.
Need to better exploit vaccine banks, i.e. in European member countries in case of rabies resurgence. More specifically, a vaccine bank for oral vaccines in Europe has still to be developed.
As rabies is a neglected tropical disease and predominantly a problem in developing countries with limited financial resources, vaccines targeted for country-specific problems (reservoirs/host species) as well as financial support to develop such products (including tech-transfer for local manufacturing) are strongly needed.
Need to improve financial support to develop these new vaccines and perhaps to provide tech transfer to countries that could produce the vaccines themselves.
None.The provision of Rabies Immunoglobulins (RIGs) for human post exposure prophylaxis is becoming an extremely rare (and expensive), alternative, as monoclonal antibodies (mAb), are needed. To date, a single mAb product against rabies, which was licensed in India in 2017, has been demonstrated to be safe and effective in clinical trials.There is currently no therapy.
Several attempts to introduce mAbs as an alternative for RIGs has been halted or aborted due to the extreme high costs associated with their development, in particular clinical phase III trials. These high costs will potentially lead to an increased price on the market.
In case of alternatives to RIG, it must be shown that they offer protection, preferably against all lyssaviruses known.
Rabies is caused by viruses belonging to Lyssavirus genus. Apart from rabies virus, which is largely circulating in non-flying mammals and responsible of most human deaths, other 16 species have been accepted by the International Committee on Taxonomy of Viruses (ICTV) and even more are expected to be discovered.
Lack of knowledge on the pathogenesis of disease;New viruses that are not covered by current vaccines.
There are several variants and genetic clusters of the classic rabies virus (RABV), each of them generally maintained in particular reservoir host(s) and distributed in specific geographic areas.The negative sense RNA genome encodes a small leader sequence followed by the N (nucleocapsid), P, M (membrane), G (envelope glycoprotein) and L (replicase) proteins which are translated from five capped and polyadenylated monocistronic mRNAs, each encoding one of the five viral proteins.
Lack of data on variability of disease in various species; lack of epidemiological data on rabies-related lyssaviruses; lack of research on why some animals shed virus for longer periods of time and why some animals may survive the disease while others succumb.
Lyssaviruses can be inactivated by lipid solvents (soap solutions, ether, chloroform, acetone); 1% sodium hypochlorite, 2% glutaraldehyde, 45-75% ethanol, iodine preparations, quaternary ammonium compounds, formaldehyde or a low pH. Β-propiolactone and binary ethyleneimine (BEI) are generally used to inactivate the virus in industries. This virus is also susceptible to ultraviolet radiation or heat of 1 hour at 50° C. It is rapidly inactivated in sunlight, and does not survive for long periods in the environment except in a cool dark area.
Lack of data on the efficacy of various substances used to eliminate or degrade the virus after a bite wound. What is the value of ‘washing the wound’? Can washing the wound with specific substances improve survivability after a bite exposure if the patient cannot receive RIG or in case post-exposure prophylaxis (PEP) is delayed.
Lyssaviruses are transmissible to all mammals. The animal hosts that maintain rabies virus in nature are mesocarnivores (RABIES VIRUS) and bats (RABIES VIRUS and most other lyssaviruses). Other animals do not play a role in the maintenance of the disease, but are victims of the disease.
What bat species are involved? Why are some species more susceptible than others? Why does there appear to be a species barrier for some bat lyssaviruses? Why are there limited spill-over infections even when bats co-roost with other species of bats or animals? Are specific receptor molecule or virus load threshold involved? Identification of new lyssaviruses. Rabies virus can mutate to be better adapted to a new animal species (i.e. dog to fox in Europe, bats to skunks in Arizona); more research on why this occurs is needed.
Lyssaviruses are transmissible to humans by inoculation. Inhalation of rabies virus is an extremely rare event. Human cases have occurred in the US and Germany via transplantation of infected organs from an undiagnosed donor. Atypical infection route has been also shown through slaughtering and meat consumption of infected dogs.
Why do some animals, including humans, sometimes survive after exposure without contracting the disease (some humans and bats have been reported to have antibody titres without having been vaccinated)?
Important animal primary hosts include chiroptera and carnivores (i.e. dogs, different fox species, raccoons, skunks, vampire and several species of insectivorous bats).
What causes rabies to adapt to a new species?
While the domestic dog is the primary reservoir of RABIES VIRUS through urban cycles in Africa, Asia, South East Asia, and in certain residual foci of Central and Latin America, other reservoir hosts are important in maintaining sylvatic RABIES VIRUS cycles in various regions of the world, including mainly bats and mesocarnivores. In particular, different species of bats are involved across the Americas, including insectivorous bats in the whole continent and vampire bats (Desmodus rotondus) in Latin America only. Among the mesocarnivores, rabies is maintained in skunks (primarily the striped skunk Mephitis mephitis) in the Americas, in raccoons (Procyon lotor) in North America and in alien populations established in Northeastern Europe, in the raccoon dog (Nyctereutes procyonoides), in the coyote (Canis latrans) in Central America (Mexico and southern US) and in foxes, with specific strains detected in the red fox (Vulpes vulpes) in North America, continental Europe and the former Soviet Union, the grey fox (Urocyon cinereoargenteus) in the US and in the arctic fox (Vulpes lagopus) in the Arctic. In addition, rabies strains circulate among different species of jackals in parts of Africa and Asia, in the Middle East and emerging in Europe and in different species of mongooses in South Africa and the Caribbean. The cycle of sylvatic rabies in the grater kudu (Tragelaphus strepsiceros) reported since the 1970s in Namibia is unique, as the circulation in this livestock species seem to be unrelated to local circulation in carnivores. In addition, bats serve as reservoirs for most of the lyssaviruses beside RABIES VIRUS; indeed, all known species but Mokola and Ikoma lyssaviruses have been identified in bats.
The epidemiology of various animal species is not well documented. The dog population size estimates and animal movements are poorly understood worldwide.
Infection is usually spread by the bite of an infected animal because the virus is present in the saliva. The virus is shed intermittently in saliva. Little is known about the quantity of a particular virus in the saliva, which would affect a successful exposure (threshold or specificity). Very few quantitative analyses are performed on human or animal saliva during or prior to the clinical phase of the disease.
Understanding the difference in transmissibility of various rabies virus variants and animal species.
Clinical signs of rabies in humans and animals are well documented. At first, affected individuals show changes in their behaviour. Typical signs include sudden behavioural changes and progressive paralysis leading to death. In some cases, however, an animal may die rapidly without demonstrating significant clinical signs.
Care should be taken when diagnosing rabies based on clinical signs only; there is no unambiguous sign for rabies and therefore individuals (humans and animals) with rabies can be misdiagnosed.
The incubation period varies with the amount of virus transmitted, virus strain, site of inoculation (bites closer to the head have a shorter incubation period), host immunity and nature of the wound. In dogs and cats, the incubation period varies from 10 days to six months; most cases become apparent in a time span of two weeks- two months. Little is known about the incubation period of rabies and other lyssaviruses in bats.
What is the specific correlation between the incubation period and site of bite; is there a difference in length of incubation period and virus variant.
Once symptoms appear, rabies is almost always fatal in humans and terrestrial animals.
There have been several documented survival cases. Why were these individuals able to survive whereas others died? Data also indicate that some animals, bats in particular, survive rabies after challenge. A scientific investigation into the specific reasons is needed.
As well as affecting the central nervous system, rabies virus can also colonise the salivary glands, which allows the transmission of infection by infected saliva through bite wounds – the most common route. Animals may excrete virus by this route before the development of clinical signs, for up to 13 days in dogs. Duration of virus excretion before the onset of clinical signs differs among animals.
Investigation into the difference in shedding period according to the virus variant and animal species involved. Such investigations are highly dependent on the understanding of the infective dose of native virus in saliva required to initiate an infection, which mimics a field case. Experimental studies are hampered by the need to amplify strains in tissue culture to ensure a sufficient standardised volume to inoculate a statistically significant number of animals. The virus may thus be attenuated and inoculated at sub-optimal levels to reflect a natural exposure.
The virus will generally remain at the entry site for a while before travelling along the nerves to the brain, where it multiplies quickly and manifests itself through clinical signs. The virus then moves from the brain along the nerves to the salivary glands (and other peripheral organs).
Why does the virus sometimes stay in an ‘eclipse’ phase for weeks, months or even years? Which is the role of interferon and the origin of neuronal dysfunction determining fatality?Better understanding could help to understand the pathogenesis and better treatment after infection.
Rabies is widely distributed across the globe. More than an estimated 59 000 people die of rabies each year. About 95% of human deaths occur in Asia and Africa. Most human deaths are the consequence of a bite from an infected dog. A large proportion of the victims of dog-bites are children under the age of 15.
There is no accurate surveillance system for the number of rabies deaths globally. Most go unreported. New models need to be developed on incidence of disease.
Systems need to be developed whereby local-level surveillance data can be easily aggregated to the national-level for improved disease resolution so that the burden estimates can be revised with accurate information.
Once the signs and symptoms of rabies start to appear, there is no treatment and the disease is almost always fatal. Human rabies is a disease of the underprivileged who do not have access to PEP. As regards dog-mediated rabies, children in these settings are more at risk than adults as they often have close contacts with the main reservoir species, the domestic dog. Most times the wounds inflicted by rabid dogs on children have more severe consequences than in adults.Besides dogs, vampire bats are the most frequently reported source of human infection. In absence of livestock to bleed, humans become victims of vampire attacks, particularly when sleeping outdoors or in structures providing no physical barriers to bats. Bites are inflicted to exposed areas of the skin such as the toes and the face.
More research is needed to determine effective treatment protocols.
As the infection progresses, someone infected with rabies may develop any of these symptoms: irritability, excessive movements or agitation, confusion, hallucinations, aggressiveness, bizarre or abnormal thoughts, muscle spasms, abnormal postures, paralysis, coma.
Deaths and symptoms caused by rabies might be misidentified as cerebral malaria, in those areas in which the two diseases are both present. In Malawi, up to 10% of pediatric cerebral malaria deaths are actually caused by undiagnosed rabies. Better data collection is needed. The use of decentralised diagnostic tools would be most useful in helping to provide better diagnostic tests for developing endemic areas.
In developed countries, widespread vaccination and animal control programmes have reduced to low levels the incidence of the disease in man. Dog-mediated human cases are now rare in the Northern hemisphere. African and Asian countries are particularly affected by rabies because the virus is maintained in animal reservoirs and there often is inadequate healthcare and lack of control measures.Underreporting of human rabies differs among countries; some have established a very good surveillance system while others lack any system.
Better assessment is needed to establish how the risk of rabies in humans is related to lack of access to vaccines due to cost, travel time, unavailability of RIG etc.
Dogs continue to be the main carrier of rabies in Africa and Asia and are responsible for most of the human rabies deaths worldwide. Humans most often become infected with rabies through the bite or scratch of an infected dog or cat.
Vaccination, responsible dog ownership and effective control of the dog population, the main animal causing human exposure and death, are crucial. As for dog population control, contraception along with awareness, owner-education and effective management of waste need to be fully addressed.Culling alone has been shown to be ineffective in reducing the population and disease prevalence.
The disease is distressing for the affected animals. Attacks by rabid carnivores compromise the welfare of other animals.
Rabies is not only an almost 100% fatal disease but is often associated with gruesome symptoms. In the past, dog rabies control measures focused on culling of dogs, for example by distributing poisoned baits, which induced severe suffering of the affected animals. The most cost-effective way of dog rabies control is mass dog vaccination. Unfortunately, in many countries a large proportion of dogs in not accessible for parenteral vaccination and these animals are caught using catching poles – or nets. Some of these catching techniques also have an impact on animal welfare.
In wildlife, a rabies epidemic could cause high mortality among the reservoir species but also in species living in close proximity of the affected reservoir; a large proportion of the badger population could also fall victim during a fox rabies outbreak in Central Europe.For wildlife rabies control in the past, the targeted reservoir species was also culled by shooting, trapping and poisoning, especially through the distribution of baits containing poison would kill many non-target animals, included endangered and protected species.
Some culling practices used for the control of bat rabies in Latin America, such as burning and sealing caves, which result in the killing of multiple species indiscriminately, are ethically and ecologically unacceptable.Similarly, culling of wildlife (in case of human exposure to guarantee rapid diagnosis) might have unforeseen consequences in forest health and agriculture due to the loss of ecosystem services provided by affected species.
In addition, the pollution of vaccine baits distributed in the environment should be not underestimated, considering tetracycline as well as the plastic component of the baits.
Increased and improved educational programmes that are culturally sensitive and effective and that focus on animal welfare and rabies prevention need to be established and disseminated. This improves the relationship between animals and humans and generates a direct impact on animal welfare.
Fortunately, nowadays, there is a general consent that irrespective killing of the reservoir species is not an effective control method; actually it is most likely counterproductive and enhances the spread of the disease. In Latin America the inefficacy of culling for the control of rabies has also been shown for vampire bats, which are responsible for the transmission of the disease to humans and livestock. Despite several studies showed that reduction of the population likely determines critical changes in the equilibria of bat population inducing the dispersal of individuals with the consequent spread of the disease, there are currently no vaccines available for this species.New delivery techniques for the vaccine in these animals deserve further investigation (i.e. taking advantage of the grooming behaviour of the vampire bat).
All the impacts described above are of particular concern for endangered species, especially for small populations, which are susceptible to local extinction, as shown by the abrupt decline of the Ethiopian wolf and African wild dogs.In Europe, susceptible species include the Iberian lynx (Lynx pardinus), the world’s most threatened felid listed as critically endangered by the IUCN, but also species listed as endangered, such as the European mink (Mustela lutreola). But the behavioural ecology of these species would limit a spillover to just a few individuals, in contrast to social carnivores, such as Ethiopian wolves and African hunting dogs.It is also assumed that rabies might favour the spread of other infectious diseases such as distemper, also due to aberrant behaviour of affected animals.
Decreasing the exposure rate between wild life species and the rabies vectors is essential to prevent rabies transmission at this interface, especially if critically endangered species are involved. In this context, securing mass dog vaccination around these populations is usually more effective than management of wildlife population, as shown by the control of rabies in the Serengeti park.
In the meantime, it is important to evaluate the actual safety and efficacy of available vaccines in non-target wildlife species. Modelling studies are important to foresee patterns of disease transmission and to test in silico the effect of different control strategies. Finally, interactions with other dangerous infectious diseases should be better explored, also in terms of multi-pathogen vaccination campaigns, covering, for example, rabies and distemper.
Affected animals will die. Early slaughter of individuals may be necessary for diagnosis and to alleviate pain and suffering.
The actual risk of exposure during slaughtering, meat preparation and consumption of affected animals, dogs included, still needs to be evaluated.The actual disease transmission and incidence in animals (either dogs or bats) taken to the market to be sold for meat is still underrated in several endemic areas.In addition, the burden of rabies in domestic ungulates should be further investigated. Indeed, both diagnosis and report of rabies cases in these animals are rare in endemic countries other than Latin America.
Rabies is widely distributed throughout the world and is present in all continents. The number and size of rabies-free countries, territories, or areas is small compared to those of rabies-affected areas. Many rabies-free countries and territories are islands. In addition, large parts of Europe and Latin America (e.g., Uruguay and Chile) are also free of rabies (except bat rabies).
The occurrence and distribution of bat rabies has not been investigated in many parts of the Old World.
Rabies is maintained in different ecosystems thus recognising different hosts. In wildlife, epidemiological cycles are linked to bats or non-flying terrestrial mammals. Among domestic animals, dogs remain the main host. Among domestic animals, dogs serve as a major reservoir of rabies virus and cause the greatest number of human deaths. More than one variant or virus species can circulate in the same geographic area, in association with different hosts.
More data are needed on the lowest incidence of vaccination coverage required to be effective as it relates to population data.
Many different species are involved and also geographical, climatic and, in case of dogs, cultural settings have a profound influence on the occurrence of the disease. For example, fox rabies showed a clear seasonal pattern, with the lowest incidence reported during late Spring.
Is there a seasonality in bats or other species? More needs to be understood about the disease mechanisms, which allow the virus to be maintained for long periods during hibernation e.g. bats, raccoon dogs and so on.
Variable and depends on the distributio, density as well as home range size of the hosts and susceptible species.
Models need to be developed on the spatial spread of rabies in an outbreak situation. This would help to provide a cost estimate on how to halt the spread as well as strategic plans for implementation.
In free countries the main risk is the import of infected animals.Rabid animals imported from enzootic areas are reported every year in rabies-free areas. This threatens the rabies-free status of terrestrial animals achieved in European countries and challenges the public health surveillance system and the health structures alike. Where wildlife hosts exist the potential for spread is high if the reservoir species move freely across boundaries. Recent outbreaks in Indonesian islands seem to be linked with the transportation of infected dogs via fishing boats.
More research is needed on how to develop regional plans to implement effective rabies prevention measures on a large scale and how to more effectively provide monitoring systems to prevent rabies from re-entering, what to do if and when it is reintroduced.
Yes, see below.
Further data are required to understand the effect on rabies cycles within species effected either directly or indirectly by climate change/seasonality.
The distribution of the reservoir species is linked to climate. For example, the occurrence of the vampire bat has been linked to the 10°C minimal isotherm (January). Hence, vampire rabies and vampire-transmitted rabies can only occur in certain areas. As a result of climate change, the distribution area of the vampire bat can shift and potentially southern US can become a suitable habitat for these animals.
Extreme cold weather in the arctic with large areas covered by sea ice can facilitate the spread of arctic fox rabies, as these animals are known to travel extensively over large distances.
There is anecdotal evidence that climate change can affect the rodent populations in Northern Europe, which in turn can affect the populations of rodent eating arctic foxes. Similarly, climate change may affect the distribution patterns of artic fox rabies, through a progressive northward colonisation of the red fox. This species may compete with the artic fox fighting for the same food or by killing the competitor species (intraguild predation).There is a consensus that spread of vampire bat population carrying rabies and spills-over of infection (i.e. bovines, dogs, humans) are strongly affected by deforestation and changes in agriculture in Latin America.
This virus is usually transmitted through the saliva of an infected animal. Infection occurs primarily via bite wounds or infectious saliva entering an open cut or wound. Less often, it is spread by infection entering mucous membrane, such as those in the mouth, nasal cavity or eyes. The rabies virus is not transmitted through intact skin.
There are gaps in understanding the transmission rate of specific rabies viral variants.
There are rare reports of transmission by other routes.There has been some evidence for transmission of virus from saliva via abrasions in the mouth of kudu as they feed on thorny acacia trees.Aerosol transmission has been documented in special circumstances for example, in the environment of a densely populated bat cave.There is also some speculation that ingestion could play a role in wild animals, although exposure is more likely to occur during eating rather than digestion (gastric juices are likely to kill the virus).In humans, rare cases of rabies infection have been linked to slaughtering (and eating) rabid dogs. Moreover, a few cases have been reported after organ donor.
Research on the ingestion route as a means of transmission needs to be investigated as it could play a role in maintaining rabies in a specific area, being also a public health issue.Research into better and easier diagnostic tests that are developed for organs being transplanted. This has to be coupled with specific epidemiological and clinical investigations in the donor.
High population density of reservoir hosts and susceptible species. Poor controls, lack of education and awareness, lack of vaccination.
Population density and transmission of rabies need to be further investigated as they relate to the primary host species.
Pathological changes in the brain. Limited immunological response.
There are gaps in understanding how to stimulate a more effective immunological response to rabies as it is transmitted along the nerves after exposure.
The absence of specific antibodies cannot be useful to rule out a suspect case, as the host might die before developing a recognisable immune response. However, the detection of antibodies in a previously unvaccinated host is predictive of active or abortive rabies infection.
Assays need to be developed for earlier diagnosis of rabies in humans. This could provide more time to save lives through treatment and by preventing further exposures.
In free countries the strategy is to prevent the introduction of the disease by the application of import controls, quarantine and post import checks. A rabies contingency plan to stamp out the disease if it occurs should be in place. Depending on the circumstances, this could involve controls on domestic pets, vaccination, restrictions on animal gatherings, detention of stray animals and vaccination or destruction of wildlife in limited areas.
In countries where the disease is endemic, measures are implemented to address and reduce the risk of infection in susceptible populations (wildlife, stray and domestic animals) and create a buffer between the animal source of the disease and humans.• Surveillance and reporting of suspected cases of rabies in animals.• Vaccination programmes for domestic animals.• Wildlife rabies control programmes including vaccination (trap/vaccinate/release or delivery of oral vaccines).• Population control and vaccination programmes for stray animal populations.
In Latin America, where rabies is a major problem to the cattle industry, the only effective means of rabies control in herbivores is preventive vaccination of domestic spills-over instead of control of the primary host vampire bat (Desmodus rotundus) populations.
Cost-benefit analyses need to be developed to determine the effectiveness and long range financial savings of developing and implementing strategic rabies plans. Looking at the cost savings of rabies in health strategies could be convincing evidence to improve the governmental support of prevention programmes.
Determining the best overall strategy for implementing oral and parenteral rabies vaccination in dogs – when and how to use each strategy. Assessing the cost effectiveness to either reduce or not reduce the dog population jointly with rabies vaccination programmes.
As no clinical signs nor gross post-mortem lesion can be considered pathognomonic in domestic or wild animals, the diagnosis of rabies has to rely on laboratory testing. Rabies is diagnosed using the direct fluorescent antibody (DFA) test, which looks for the presence of rabies virus antigens in brain tissue. The test requires that the animal be euthanized.
a. Identification of the agent.
b Antibody detection techniquesSerological evidence of infection is not useful because of late seroconversion and the high mortality rate of host species although such data may be used in some epidemiological surveys. Antibody detection is used as a demonstration of rabies vaccine efficacy.
Modern diagnostic methods, using molecular techniques, are able to characterise rabies viruses to identify their geographical origin and host species.
Introduction of field tests into areas and regions where there is a lack of diagnostic facilities needs to be investigated. There are huge gaps in availability of diagnostic laboratories in resource poor regions of the world. Expensive and labour intensive diagnostic tests are not likely to be the strategy to increase the number of laboratory facilities. New, less expensive and even field tests, such as LFDs, need to be tested and made available to those that need them.Gaps in training of personnel in diagnostic laboratories in resource poor countries. Lack of continuing education and ongoing quality assurance programmes.
Rabies vaccines for use in animals contain either (i) live virus attenuated for the target species (such as Flury low egg passage, Flury high egg passage, Street- Alabama-Dufferin or Kelev), (ii) virus inactivated by chemical or physical means or (iii) recombinant live vaccines.The virus is cultivated in embryonated eggs, or in cell cultures. Rabies vaccines are usually lyophilised, but inactivated virus vaccines, preferably with an adjuvant, may be stored in liquid form just like oral rabies vaccines.
Development of longer lasting rabies vaccines for animals. Replacement of all nervous tissue vaccines with more modern and less reactogenic vaccines.
Rabies vaccines for use in animals contain either (i) live virus attenuated for the target species (such as Flury low egg passage, Flury high egg passage, Street- Alabama-Dufferin or Kelev), (ii) virus inactivated by chemical or physical means or (iii) recombinant live vaccines.
The virus is cultivated in embryonated eggs, or in cell cultures. Rabies vaccines are usually lyophilised, but inactivated virus vaccines, preferably with an adjuvant, may be stored in liquid form just like oral rabies vaccines.
While treatment of clinically infected animals and man is of no avail, post exposure prophylaxis of man with vaccine and hyperimmune serum is used successfully. This remedial treatment is only partially successful in dogs and other animals and is therefore not recommended.
In humans, part of PEP-treatment are the administration of immunoglobulins (ERIG/HRIG). Especially, HRIG is becoming extremely rare (and expensive). As alternative, monoclonal antibodies (MAb) have been developed and such a MAb has recently been licensed in India.Antiviral agents, interferon and massive doses of rabies immunoglobulin have been used to treat human cases, but seem only to prolong the clinical course without affecting fatality.There have been several human rabies survival cases, as recently reported. More research into modifying treatments and determining the most effective anti-viral is needed.
Rabies vaccines available determine protection against rabies virus only; whilst some cross-protections against other lyssaviruses are not guaranteed. Humans working with suspect material must be vaccinated against rabies that may be present in diagnostic samples. The laboratory must comply with national bio containment and biosafety regulations to protect staff from contact with pathogens.
There are gaps in the number of laboratories that can conduct testing using live rabies viruses. At least one national laboratory in every country for manipulation of rabies virus should be in place.
Based on history, clinical freedom, identification and effective vaccination prior to movement. However, border/trade/ movement control is hardly feasible for wildlife.
More effective border controls need to be put in place. There is lack of education on the importance of keeping unvaccinated dogs out of rabies free countries.
Prophylactic vaccination of dogs and vaccination campaigns for wildlife reservoirs.
Notifying and reporting suspect cases of disease with effective laboratory facilities to confirm outbreaks is important to assess the level of the problem.
More effective surveillance systems need to be established using modern technologies when appropriate, i.e. mobile phone technology.
Great progress in dog rabies control has been made in Latin America by implementing mass dog vaccination campaigns.In many parts of Asia and Africa, the vaccination coverage established in the dog population (30% to 50%) is not high enough to break the transmission cycle of the disease.Where high levels of coverage can be achieved the incidence of rabies in dogs will decline.
A trend toward a decline in the number of cases in animals has been reported in European countries and EU is almost free from terrestrial rabies. This improvement followed the massive use of the oral immunization technique for foxes and the dispersal over wide areas since 1989 remarkable decreases have also been noted in Canada and Texas (USA), where oral vaccination projects targeting coyotes and foxes, respectively, have been conducted.
Cooperation between many different ministries needs to be established. Governments need to be supportive if programmes are to be sustainable. Thus, programmes should be developed in a holistic manner. There is a need to determine what sustainability factors should be in place to make a programme not only successful but sustainable in the future. Also, cross-border cooperation between neighbouring countries is essential for sustained rabies elimination.
Costs of vaccine and disease control measure application can be high. Baiting to control rabies in wildlife can be costly. Although costs of rabies control programmes in the reservoir species are high, it is still the most cost-effective approach to reduce the burden of rabies.
Rabies kills at least 59,000 (95% Confidence Intervals: 25-159,000) people each year, half of whom are children under the age of 15, even though effective vaccines for post exposure prophylaxis (PEP) are available and almost 16 million individuals actually receive rabies PEP each year. It is also believed that this figure is a serious underestimate as there are almost 25 million doses of rabies vaccine produced in China alone.Rabies is primarily a disease of children, who are particularly at risk due to their close contact with dogs. Conclusions drawn are that deaths due to rabies are responsible for 3.7 (1.6–10.4) million disability-adjusted life years (DALYs) lost each year.
Education can save lives, but many countries lack culturally sensitive education materials.
The disease is of significant economic importance in areas where rabies is endemic. Treatment of people who are bitten is unpleasant and expensive. Vaccination of animals rather than of humans is the best approach to control the disease. However, pre-exposure vaccination of certain parts of the human population, e.g. children, people in remote areas with no access to PEP may be needed to prevent rabies cases.As the costs of rabies prophylaxis differ significantly among countries, it is not possible to present a fixed number. As rabies is almost 100% fatal, in countries with limited resources, patients with confirmed rabies are often sent home.Anderson & Shwiff (2015) estimated that the global burden of canine rabies is approximately $124 billion annually.
There is a need to develop and encourage health professionals to work together in a more coordinated fashion. Much of the focus has therefore been on using PEP in humans. Development of a more integrated sustainable strategy between relevant ministries is required.
At present, the disease still causes remarkable economic damage through loss of animals destined for production, mainly in Latin America. In Brazil, bovine and equine herds are severely affected by the disease. In Africa, rabies in Kudus in Namibia causes severe financial losses to the agricultural sector.
The economic impact of rabies on livestock has not been fully elucidated and is grossly underestimated.
Can be high but depends on the situation in a specific country.According to the US Centers for Disease Control, the estimated costs associated to rabies prevention and control have risen to more than $300 million annually and include vaccination of companion animals, animal control programmes, maintenance of rabies laboratories, and medical costs, such as those incurred for rabies post-exposure prophylaxis.
There is an urgent need to re-evaluate the economic burden of rabies globally and to evaluate the cost-effectiveness of intervention strategies.
The impact of lost income whilst seeking PEP for individuals exposed should not be underestimated (Hampson et al., 2015). Also the loss of livestock in certain settings can have a profound impact on the quality of life; for example, a whole household may depend heavily on a single cow (milk, meat, hide, etc.); the family existence and survival may be severely jeopardized when this animal succumbs to rabies or has to be sold for the purchase of PEP after exposure.
Assurances on rabies status are required for trade in live animals and products.
Assurances on rabies status are required for trade in live animals and products.
Illegal importation of dogs poses a threat to the reintroduction of rabies into previously rabies free zones.
While knowledge and tools are available to eliminate the threat of canine rabies, the disease remains a public health threat in many parts of the world. Lack of motivation by governments, cultural issues and inadequate funding remain barriers, despite the number of human rabies deaths worldwide is greater than that from polio, meningococcal meningitis, Japanese encephalitis, yellow fever, SARS, bird flu and other scourges that attract more attention. For sylvatic rabies, multi-species reservoirs represent a challenge to disease control using oral rabies vaccines. Also, the vast areas in Eurasia and the Americas affected by wildlife-mediated rabies make its control a financially demanding challenging.Rabies control in bats does not seem a feasible option in the near future, although it has been shown that vampire bats can be vaccinated by the oral route as well.
Lack of educational awareness on all levels of society as to the rabies prevention. Agriculture and human health often do not work together or share information. Lack of financial support from international funding agencies. Dogs are not normally considered ‘food animals’ and are not valued highly, even though they do serve a valuable role in societies.No cost-effective vaccination strategies for elimination of wildlife-mediated rabies for vast territories are available yet.
Dog-mediated human rabies accounts for more than 99% of all human cases. Hence, the elimination of dog-mediated human rabies would be a great accomplishment.Safe and effective vaccines for dogs are now widely available. It is the need to control rabies in dogs that must occupy most attention. The tools are available, but attitudes must change before they can be applied.
The over-population of dogs makes it seem impossible to implement rabies control programmes in many resource poor countries. The role of animal welfare in removing dogs, even humanely, is often contentious.Education is critical to improve support. Understanding the cost-effectiveness of rabies prevention is critical to convince governments to support national strategies.
Failure to control rabies in dogs in developing countries will result in continued high mortality each year and will create possibilities for spill-overs into wildlife. Targeted surveillance (indicator animals) should be established in all countries. Other reservoir hosts including chiroptera should be included, as there is a potential of spill-over into new hosts and/or reservoirs. In general, better surveillance and diagnostic facilities are required.
Need for cost-benefit analyses of the implementation of rabies prevention programmes.
Cheap and safe vaccines for animals as well as humans have been developed. Oral vaccination of wildlife has been successful in Europe and is beginning to reduce the incidence of rabies among foxes and raccoons in the US. Although not practiced until now, oral vaccination of stray dogs could lead to the eradication of rabies in small areas where dog rabies parental vaccination is unsuccessful. Cost of both vaccination methods along with in-field efficacy should be carefully evaluated.
Paola De Benedictis, IZS Venezie, Italy - [Leader]
Thomas Müller, FLI, Germany
Conrad Freuling, FLI, Germany
Hervé Bourhy, Institut Pasteur, France
Florence Cliquet, ANSES, France
Louis H. Nel, University of Pretoria and Global Alliance for Rabies Control, South-Africa
Sergio Recuenco, Department of Preventive Medicine and Public Health, Universidad Nacional Mayor de San Marcos, Peru
Ad Vos, IDT Biologika
Christian Kaiser, IDT Biologika
Programme Management Board.
2 October 2019