West Nile Virus - available
Control ToolsDiagnostics availabilityA range of diagnostic kits are available for use in humans and animals. Not many horse IgM ELISA are available in Europe. No avian IgM ELISAs are available in Europe. Several IgM ELISA tests in the US available for use in humans and horses. GAPS:
A number of kits are available in Europe. These are generally for use in laboratories and there is no indication of pen side test availability. Most are based on ELISA often competition ELISA [competition (horses, birds) and IgM ELISA (horses)]. GAPS:
Competition ELISA validated by the EU-RL for WNV (plus other RT-PCR and ELISA kits in the future). GAP: Area to develop? See chapter 2.1.20 of the OIE Manual of Diagnostic Tests and Vaccines. Tests for use in humans are of commercial interest. Diagnostic tests in horses are currently of interest in Europe due to the recent EU outbreaks. Limited market in Europe (in particular for RT-PCR kits; serological screening most widely used). Little or no incentive to develop new diagnostic kits. GAP: Cross-reactions with Usutu virus? DIVA test in horses would be useful for monitoring the virus circulation in area with surveillance activities rather than trade purposes. GAPS:
The opportunities for development of diagnostic kits are increasing with the increase of the number of outbreaks. The possible cross reaction with other flavivirus should be referred to ELISA tests. GAP: Target antigens that are less cross reactive – prM, Domain III of E, NS1 and NS5. Vaccines availabilityA number of vaccines have been authorised in North America. In 2003 a monovalent killed West Nile virus vaccine for horses was fully licensed in the US. It requires two doses given 3 to 6 weeks apart followed by an annual booster. In 2004 a modified live canarypoxvirus vectored WNV vaccine for use in horses was licensed. In the same year an inactivated human cell line vaccine developed by Crucell NV (the Netherlands) and Kimron Veterinary Institute (Israel) obtained a market authorisation in Israel as a veterinary vaccine for geese. In July 2005, the USDA issued the first fully licensed WNV DNA vaccine for animals in the USA. The vaccine contains genes for two WNV proteins, and therefore, does not contain any whole WNV, live or killed. A chimeric vaccine, based on a yellow fever virus vector, was licensed by USDA for use in horses in 2006. These vaccines have demonstrated sufficient efficacy and safety in adequately vaccinated horses. All recombinant vaccines are produced against NY99 WNV strain (North American strain). A number of multivalent vaccines to control WNV, Eastern and Western Equine encephalomyelitis and in some cases Venezuelan encephalomyelitis are available. In November 2008, a WNV Vaccine (Duvaxyn WNV) was licensed for use in the EU (EMEA, 2008). The vaccine is an inactivated WNV strain VM-2 vaccine and is licensed for use in horses over 6 months of age. The VM-2 strain is a North American isolate (lineage 1a) with a high phylogenetic relationship to European strains circulating in EU countries, as well as Italy, and strong cross reactivity with strains isolated from France and Romania (both lineage 1a). GAP: In the recent past also lineage 2 has been identified in Central Europe and Greece. The cross protection of the VM-2 strain against those latter viruses has to be assessed. A differential diagnostic assay, such as ELISA assay against NS protein, can be used to distinguish immunity derived from vaccination vs. natural infection whether conventional, DNA or canary pox vectored vaccines are used. The DNA and canarypox vaccines do not contain non-structural protein (NS1 to NS5) and conventional killed vaccines contain only minimal amounts of NS proteins, thus will not have immune responses against those NS proteins after vaccination. GAP: Need to define better validation of the vaccines? None authorised. GAP: Need to define validation? Inactivated vaccine and CNP based vaccine have claim protection against viremia after 2 shots. Chimera vaccine has demonstrated protection against viremia and clinical manifestation of disease after one shot, however, this vaccine is currently under a voluntary recall. All 3 vaccines are likely to demonstrate good protection in the field. Effectiveness of DNA vaccine not very well known. GAPS:
Due to the recent outbreaks in EU Countries, the potential for commercial vaccines in horses has increased. GAP: this area needs attention since Europe is where more outbreaks occur and could also be the focus for dissemination. Use of the genetically modified vaccines might pose problems in some countries. GAPS: Regulatory authorities should provide a clear guideline to regulate the so called “genetically modified vaccine”. This new vaccine platform is in the verge of transforming vaccine industry in R&D and manufacture process. Animal vaccine industry can and should take the lead on this endeavour. Feasible to manufacture a range of types of vaccines. In principle if WNF becomes a problem in a country, vaccination can be used as a control measure. Antibody detection using epitope blocking (competitive) assays targeting NS1 protein have been effective for detecting WNV infection in horses and birds (Hall et al 1995; Blitvich et al. 2003a & 2003b). Competitive and indirect assays targeting NS1 should be effective and differentiating between naturally infected and vaccinated animals. GAPS: Similar specificity to neutralisation when screening out SLE and other flaviviruses in the Americas – needs further field evaluation in Europe. Also may be effective for differentiating natural infection form vaccination but need further field trials. Chimeric constructs and DNA vaccine building on the work in the US may be promising and may have a DIVA effect. Pharmaceutical availabilityHumans and horses: supportive (fluids, anti-inflammatory molecules). Some immunoglobulins are used in hamster models and humans and showed beneficial effect also in recovery and chronic lesions. Monclonals for human use are under development. Antibody product(s) conditionally licensed in USA. Anecdotal reports of efficacy. GAPS:
Possible use of antivirals (interferons, ribavirin) but unlikely in the foreseeable future. Based on current work, immunological modification (e.g., reduction in macrophage activity) is a strong future possibility as an intervention. GAPS:
None at present. GAP: No major funding available for such research since West Nile infection in human is perceived as self-limiting. None. Not applicable. GAP: No major funding available for such research since West Nile infection in human is perceived as self-limiting. Areas of interest would be in controlling the mosquito through improved methods of prevention and reduction in numbers. Novel, improved methods of surveillance recently reported (see Hall-Mendelin et al 2010 PNAS). Transgenic mosquitoes are being used as in the case for dengue infection. Based on current work, immunological modification (e.g., reduction in macrophage activity) is a strong future possibility as an intervention. New developments for diagnostic testsA major problem for WN serological assays is their high degree of cross-reactivity with antibodies produced in response to other simultaneous and/or previous flavivirus infections; and long lasting IgM (in humans). New tests and kits are being developed and there remains a need for improved sensitivity, specificity, costs, and practicality.
Some human WNV diagnostic tests are licensed. GAPS:
Time and costs depend on the nature of the test. Several years will elapse between research output and the test becoming commercially available. GAPS:
Developing diagnostic tests and kits is time consuming and labour intensive which can result in high costs. Validation has been performed by the EU-RL. GAP: It may not be cost-effective if humans experience self-limiting disease. Developing and applying new tests. Work closely with medical researchers and commercial companies to evaluate new tests developed for use in human to assess whether they could be adapted to animals. Identify alternative test methodologies and potential for rapid reliable diagnosis in the field as well as the laboratory. Tests required for the end hosts, birds and mosquitoes. GAPS:
Freedom is likely to occur following infection. As antibodies would be present it may be necessary to use RT-PCR techniques although the value of this would need to be assessed. GAPS:
New developments for vaccinesAn improved vaccine would include one shot vaccine with early onset of immunity and long duration of immunity. Current vaccines that are on the market already have good safety/efficacy profiles. Eradication of disease impossible due to extensive wild live reservoir (birds) and bird migration. DIVA test not really needed. Diagnostic tests have as main goal detecting disease for clinical purposes. Horse and human cases do not really need DIVA test. GAPS:
Time consuming 5-10 years. Depending on product profile and requirement. The currently available vaccines are offering good protection against lineage 1 strains. Expensive but may be spin off from medical research into vaccines for humans. GAPS:
Current WNV vaccines licensed in the EU have shown good safety and efficacy. Therefore, there is no immediate need for additional research and development for new vaccines. GAP: Due to the recent outbreaks in EU Countries, the potential for commercial vaccines in horses has increased. New developments for pharmaceuticalsNone. GAP: No major funding available for such research since West Nile infection in human is perceived as self-limiting. Not applicable. GAP: No major funding available for such research since West Nile infection in human is perceived as self-limiting. Not applicable. GAP: No major funding available for such research since West Nile infection in human is perceived as self-limiting. None. GAP: No major funding available for such research since West Nile infection in human is perceived as self-limiting. Disease detailsDescription and characteristics.West Nile Virus (WNV) is a single-stranded enveloped RNA virus which belongs to the genus Flavivirus in the family Flaviviridae. It is grouped within the Japanese Encephalitis virus group. GAPS:
Worldwide, two broad groupings (lineages) of WNV have been recognised: Lineage I is found in all continents except Antarctica whilst lineage II has historically been restricted to sub-Saharan Africa and Madagascar. Lineage I viruses have caused mortality in domestic geese in Israel and in Canada, although numbers are small compared to humans and horses. Lineage I viruses have also caused fatal illness in a variety of domestic and wild species of mammals as well as non-mammals such as alligators and some birds. The pathogenicity in birds appears to be related to strain genetics. The role of small mammals such as squirrels is not clear, but most likely minimal, if at all. More neuroinvasion is associated with strains from Lineage I. Lineage II viruses have recently been reported as the cause of disease in horses in Africa, as well as Hungary, Austria, and Greece. A third lineage has been recently proposed to include the Rabensburg virus, an European strain isolated in Czech Republic and a fourth independent lineage which comprises an isolate from Caucasus. GAPS:
WNV is inactivated by heat and disinfectants containing detergents or lipid solvents and is susceptible to sunlight and drying. It is also inactivated by Sodium hypochlorite and standard laboratory fixatives, such as paraformaldehyde, formalin, and glutaraldehyde. GAPS:
Species involvedMosquitoes become infected when they bite an infected bird ingesting the virus in the blood. The mosquitoes act as vectors spreading the virus from an infected bird to other birds and to other animals. There is a cycle of the virus circulating from bird to bird by way of mosquito bites, being amplified at each cycle. Equids and humans are the most sensitive mammals to WNV infection; scarce reports also indicate that sheep can develop encephalitis after WNV infection. Other mammals that can be infected are cats, bats, raccoons, chipmunks, skunks, squirrels, cervids, rabbits and dogs. Most of these mammals (except for rabbits) do not develop a sufficiently high and long-lasting viremia to be considered as WNV carriers/reservoirs. However, WNV infection has also been reported in amphibians and reptiles, and some of these species could serve as amplifying hosts. Poultry can be infected but do not usually develop disease. They have been used in the USA and Italy as "sentinels" to detect infection in areas thought to be at risk. WNV has been reported in geese flocks in Israel and Canada when many affected birds died. GAPS:
The majority of people who become infected do not suffer from any illness. Around 20 % of infected people develop a ‘flu-like disease; a small number (less than 1% of infections) suffer neurologic disease with potentially fatal meningitis, encephalitis or other neurological features. According to various reports WNV has been detected in about sixty species of mosquitoes, of which approximately 20 species have been demonstrated to be competent vectors in laboratory conditions. GAP: Difficulties in determining vector mosquito species in the field in Europe, due to very low infection rates (about 1/100,000). The reservoir of the virus is in transmission between birds and mosquitoes in warmer months and overwintering mosquitoes in colder or dry months. Many wild birds are susceptible to WNV infection and remain asymptomatic. However, birds are not persistently infected. They have a limited length (and height) of viremia. GAP: Difficulties in identifying introducing and amplifying birds in Europe (serological surveys inform about bird species in contact with WNV but not about their role, experimental infections results should be considered cautiously and in the light of local ecological data). Description of infection & disease in natural hostsThe main route of transmission of WNV is through mosquitoes. Direct transmission between birds through oral or cloacal shedding or through predation of smaller birds could occur when WNV intensely circulates and highly dense bird populations are present. GAPS:
The WN virus is maintained in nature by cycling through birds as an amplifying host, and mosquitoes which are competent biological vectors (i.e. mosquitoes of the genus Culex, among others). The virus must multiply in the mosquito and reach the salivary glands before the mosquito can pass on the infection to another vertebrate host. The vectors also act as a bridge for the transmission of the virus to other susceptible species (i.e. many species of mammals, domestic poultry, amphibians and reptiles). Numerous avian and mosquito species support virus replication, however, not all species of birds are “equal” in capability to serve as reservoir host. Duration and titer of viremia vary among all species. Humans and horses are considered dead end hosts. GAPS:
The horse seems the most susceptible to infection but most cases are sub-clinical showing no obvious signs of disease but becoming seropositive. Some develop severe neurological illness which can be fatal. Affected horses frequently demonstrate mild to severe ataxia. Signs can range from slight incoordination to recumbency. Some horses exhibit weakness, muscle fasciculation, and cranial nerve deficits. Sequelae of long duration (mild ataxia, mild cranial nerve deficits) are reported in some countries (e.g. USA). GAP: Frequency of sequelae? The incubation period is reported to range from 3-15 days. During outbreaks, 10-43% of infected horses may develop neurological signs. The reported case fatality rate in horses varies from 23% to 57%, depending on the outbreak; in the U.S., it is approximately 30-40%. GAPS:
A fleeting viraemia of low virus titre precedes clinical onset. Certainly with Lineage II WNV, lethal disease may be caused by significant immunopathology, i.e., by the immune system in response to WNV infection in the CNS. This may be modified to increase survival without altering sterilising immunity. Importantly, this is evidently in the absence of significant neuronal death, which is in any case very much less than other neurotropic (admittedly DNA) viruses such as e.g., Herpes simplex in encephalitis. GAP: Part of virus direct effects or immune-related? Zoonotic potentialHuman and horse cases have been reported from many parts of Europe, including Spain, France, Italy, Greece, Romania, Russia, Bulgaria, and Hungary. Following the emergence of WNV in the USA and Canada with associated human cases and deaths, and the severe epidemics in humans in some Mediterranean countries (Romania, Greece), there has been a raised public concern. GAPS:
Low in case of neurological signs. However, mild cases may occur unnoticed. GAPS:
Transmitted to people by mosquitoes that have fed on infected birds. There is some evidence that mosquitoes may also acquire infection from some mammals. Other methods of transmission reported include mother-to child (1.6% in the USA, 2003-2008), donated blood and organs (suspected in 0.1% of cases in the USA, 2003-2008 upon implementation of blood screening) and laboratory exposure (0.04% in the USA, 2003-2008). Does not normally spread between people except under special circumstances (e.g. blood transfusion). Transmission has been reported to occur via breast milk, and may be vertical transmitted. Aerosol inhalation should be borne in mind, since this has been reported in laboratory exposure to Japanese encephalitis virus. Risk factors for developing neuroinvasive disease include older age (>60 years old) and a history of solid organ transplantation and might also include other immunocompromising conditions, diabetes, and hypertension. GAPS:
When disease does occur, it is usually a flu-like illness with fever. A small proportion of cases (less than 1%) develop meningo-encephalitis which produces nervous signs and may be fatal. Humans, horses and other animal species are dead-end hosts, i.e. there is no natural spread from them to other people or animals. Does not normally spread between people except under special circumstances (e.g. blood transfusion, organ transplantation). Impact on animal welfare and biodiversityHigh impact on bird biodiversity in the US. Some significant suffering may be caused to affected horses but their numbers are low. Impact is likely to be low in Europe (low bird mortality). Mass fatalities have been described in passerids (corvids in particular) in the US. GAPS: In Europe the WNV circulation is sometimes associated to a contemporaneous circulation of Usutu virus. The latter may be responsible for the high mortality phenomena in black birds. Without proper diagnostic methods (neutralization assays) the two infections are not distinguishable from the serological point of view. Horses infected by WN virus develop a brief low-level viraemia that is not infectious to mosquitoes. Most horses recover from the infection, however recumbent horses are less likely to recover. Euthanasia of affected horses is usually a decision related to animal welfare and odds of recovery, horse age, value, cost of treatment, etc. Geographical distribution and spreadThe virus historically occurs in Africa, Europe, the Middle East, West and Central Asia, and a low virulence Lineage I strain is also common in Australia (Kunjin). Outbreaks have occurred in Morocco (1996, 2003, 2010), Israel (1999) Romania (1996 to date), Italy (1998, 2008 to date), Greece (2010), Bulgaria (2010) Turkey (2010), Spain (2010) Russia (1999, 2010) and the South of France (2000). However, evidence of virus circulation was obtained in several other European and Mediterranean countries. The first appearance in the USA was in 1999 since when it has spread throughout much of the country where it is now considered to be endemic. It should, however, be noted that the apparent increasing emergence of West Nile virus in some parts of the EU could be attributed to improved observation, reporting and detection methods. Speed of spread depends on a number of interdependent factors including the presence of viraemic birds and vectorial capacity, i.e. ability of the vector to transmit the infectious agent, biting rate on competent host (which is host and vector density dependent) and incubation period (which is temperature dependent). All of these are limiting factors in the ability of WNV to infect and spread through a population. Infections are dependent on mosquito transmission and are seasonal in temperate climates, peaking in the late summer/early autumn in the Northern Hemisphere. Speed of spread depends on a number of interdependent factors including the presence of viraemic birds and vectorial capacity, i.e. ability of the vector to transmit the infectious agent, biting rate on competent host (which is host and vector density dependent) and incubation period (which is temperature dependent). All of these are limiting factors in the ability of WNV to infect and spread through a population. Introduction and spread of WNV in non-affected areas is usually attributed to movement of infected wild birds or importation of infected competent vectors. Viremic periods are often considered to be short in birds (7-10 days max.), too short for migrating birds to bring WNV from Africa into Europe. Possible introduction of infected mosquitoes through vehicles and trade of goods (e.g. car tires). GAPS:
It is seasonal and related to weather and environmental conditions (including suitable bird and mosquito habitats). Climate change may result in changes in vector distribution and the ability of the virus to develop in new species of mosquito. GAP: Difficult to predict (inverse effects on mosquito number, survival and virus multiplication/transmission). Not sure that heavy rainfall is associated with increased infection (e.g. post Hurricane Katrina in USA – did not see high infection). Heavy rain may wash away mosquitoes. However, other weather conditions may influence outbreaks – e.g. hot dry summer, then rain? Vectors may be sensitive to climate change. GAPS: Clear scientific evidence of the effects of climate changes to mosquito-borne diseases are currently lacking. But, according to historical data, in the Italian areas during WNV circulation the vector population (species and abundance), did not show any significant changes compared to the previous years. Route of TransmissionMigrating birds are the most likely mechanism of the infection being introduced. WNV can be transmitted to humans and animals via the bite of infected mosquitoes. Infection of other animals (e.g. horses, and also humans) is incidental to the cycle in birds since most mammals do not develop enough viruses in the bloodstream to spread the disease. Transmission via infected blood, tissues, needle stick and organ transplantation is possible but less common, and also breast feeding. Gastrointestinal route in birds and potentially wild animals (by eating infected dead birds). Speed of spread depends on a number of interdependent factors including the presence of viraemic birds and vectorial capacity, i.e. ability of the vector to transmit the infectious agent, biting rate on competent host (which is host and vector density dependent) and incubation period (which is temperature dependent). All of these are limiting factors in the ability of WNV to infect and spread through a population. Detection and Immune response to infectionNeutralizing antibodies are generated and are protective, but cellular immunity also plays an important role. The length of detectable IgM antibodies depends on the species. In humans it seems to be 3 months whereas in horses it is about 1 month. Innate immunity may also play a role both in control and immunopathology, in particular the myeloid lineage. There is a significant infiltration of leukocytes in disease and a major microglial response to neuronal infection in the brain. GAPS: Determinants and duration of humoral and cellular immunity in horses (partly assessed) after natural infection. Few data are available about the duration of IgM response in horses. Development of antibodies to WNV. Main means of prevention, detection and controlNotification and investigation of suspect disease in horses with implementation of control measures including vector control. Infected horses do not contribute to the transmission cycle of the virus and therefore infected horses could not introduce the infection into a free country. Introduce enhanced surveillance, publicity / information campaigns to describe disease and give advice on vector reduction and avoidance. Limit exposure to the vector using a number of techniques:
GAPS:
There are a number of tests deployed to diagnose WNV. However, there does not seem to be agreement on which test and which tissues should be used in surveillance Identification of the virus:
Identification of antibodies:
Commercial IgG ELISA is available in Europe and IgG ELISA may be available in other locations. GAPS:
Worldwide. Four types of vaccines available:
Replicating, non-infectious, replicon-based WNV vaccines delivered as DNA, RNA or VLPs have also been developed and undergone preclinical trials. WNV antibody product(s) have conditional license in USA – anecdotal reports of efficacy. GAP: Research needed in this area for movements of animals internationally for sporting events. WNV has to be manipulated in BSL3 facilities. Trade and movement of horses are not affected since they are dead-end hosts. Vaccination and vector control. Statutory notification of suspected disease in horses followed by outbreak investigation. Examination of dead and ailing wild birds submitted to laboratories. Passive surveillance in horses appeared to be the earliest system in several European countries (France, Italy,...). Active surveillance, aiming at increasing the sensitivity of WNV surveillance, can be implemented : regular sampling and serological screening in domestic birds or horses, in at risk areas and during WNV season. Investigation of human neurological cases may reveal presence of WNV before cases are detected in animals. GAP: Different contexts of WNV circulation in Europe. Need for different and adapted surveillance scheme? Comparative efficiency of WNV surveillance data in more European infected countries. Variable. In the USA the virus has spread throughout the country and is now endemic. In Europe, less of a problem although endemic in Romania, Hungary and Italy. Variable pathogenicity seems to be linked to lineage and strain within the lineage. The effectiveness of mosquito control activities is variable. Even well structured mosquito control plans are thought to be able to reduce the vector abundance but not to interrupt the virus transmission chain. There is no example of successful eradication. Unspecified. Disease information from the OIEYes. http://www.oie.int/animal-health-in-the-world/oie-listed-diseases-2011/ http://www.oie.int/fileadmin/Home/eng/Media_Center/docs/pdf/Disease_cards/WNV-EN.pdf http://www.oie.int/fileadmin/Home/eng/Health_standards/tahc/2010/en_chapitre_1.8.16.pdf http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.01.20_WEST_NILE.pdf Socio-economic impactHigh impact on affected individuals. Outbreaks cause public concern but there is unlikely to be a major impact on society. Attempts to reduce mosquito populations or human exposure could be mildly disruptive. In the US approximately 1 in 150 WNV infections will result in severe neurological disease. Among those with severe illness due to West Nile virus, case-fatality rates range from 3% to 15% and are highest among the elderly. Overall deaths occur in approximately 1 in 1,000 infections. In 2008 a total of 1356 human cases confirmed in USA. No vaccine is available for use in people, and there is no specific treatment. Details of cost not available. GAPS:
Mortality in horses. Also mortality in geese in Israel and Canada. Costs of vaccination and of the implementation of surveillance systems. Low impact, however, risk perception by the public may generate perturbation on tourism and people travel. Trade implicationsInternational trade and movements of horses are not affected, since they are dead-end hosts. Possible limitation to the trade of birds, including ornamental species. Specific standards are laid down in the OIE Terrestrial Animal Health Code. Good to have a prophylactic for the horses travelling to endemic countries. GAPS:
International trade and movements of horses are not affected, since they are dead-end hosts. Possible limitation to the trade of birds, including ornamental species. Specific standards are laid down in the OIE Terrestrial Animal Health Code. Good to have a prophylactic for the horses travelling to endemic countries. GAPS:
International trade and movements of horses are not affected, since they are dead-end hosts. Possible limitation to the trade of birds, including ornamental species. Specific standards are laid down in the OIE Terrestrial Animal Health Code. Good to have a prophylactic for the horses travelling to endemic countries. GAPS:
Main perceived obstacles for effective prevention and controlDifficulties in diagnosis and in differentiating infected from vaccinated horses. Presence of a wildlife reservoir (birds). Presence of the virus in very different bird species and transmission by a large number of mosquito species. GAPS:
Main perceived facilitators for effective prevention and controlMore insight in the epidemiology of the disease and of the transmission by mosquito species and bird reservoir to develop strategies on how best to influence or monitor spread of the disease. GAPS:
RiskThe speed of spread within the US from exotic incursion in 1999 to development of a persistently endemic situation throughout the entire country and southern Canada by 2005 is of concern. The appearance of several exotic WNV strains in central and southern Europe have been documented to cause sporadic human and animal disease, as well as recent large outbreaks in Volgograd and Northern Greece. Screening of blood supplies during the Greek outbreak identified several infected blood donors. It is likely that bird migration is responsible for new introductions of WNV into Europe from Africa. The causative virological, ecological and environmental factors that predispose to outbreaks are not fully understood; however, the association with heat waves and outbreaks suggest an exacerbating influence of climate change. Routine equine vaccination may be necessary in Europe should WNV become sufficiently endemic to present a substantial and persistent seasonal risk. Outbreaks in North America and Europe are difficult to predict and the long-range epidemiologic pattern in Europe remains undefined, but in central and southern Europe may be evolving toward endemnicity punctuated by occasional large outbreaks. GAPS:
ConclusionSpecial attention should be given to further definition of the ecology, epidemiology, clinical aspects, and virology of West Nile, and evaluating factors that predispose to disease outbreaks in the EU or elsewhere. Strengthening and integrating animal and human surveillance is essential; development of preparedness plans and capacities for detection and response to outbreaks will benefit public and veterinary health. GAPS:
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