Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  IgG and IgM ELISAs are available from ID-VET, Ingenasa and BDSL.GAP: DIVA ELISAs should be the subject of further developments.

• Commercial diagnostic kits available in Europe

  Multi-species IgG and IgM ELISAs are available from ID-VET (ID-Screen competitive RVF ELISA Kit, ID-Screen IgM RVF ELISA kit), Ingenasa (Ingezym-FVR competition) and BDSL recombinant ELISA kit.

  GAPS:

  Additional commercial diagnostic kits ELISAs should be validated for testing human serum samples.

  Testing performance of current ELISAs with human sera.

• Diagnostic kits validated by International, European or National Standards

  None officially.

  Validation of the ID-VET kits is continuing. They are very easy to use, but sensitivity is lower than virus neutralization tests (VNTs), which therefore remain the gold standard. GAP: OIE reference laboratories should be able to provide standardized tools for VNTs, including at least the protocol, virus, cells and positive and negative control sera.

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

  Details of diagnostic tests are described in the OIE Manual of Diagnostic Tests and Vaccines Chapter 2.1.18 (http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.01.18_RVF.pdf): Identification of the agent • Virus isolation: o inoculation of mice or hamsters - preferred method o inoculation of 1-2-day-old lambs o inoculation of embryonated chicken eggs o tissue culture inoculation (Vero, CER, BHK-21, mosquito line cells or primary calf, lamb and goat kidney and testis cells) in combination with immunofluorescence • Viral antigen identification by immunofluorescence in cryostat sections or in impression smears of liver, spleen and brain. Also by complement fixation and immunodiffusion on tissue suspensions • Antigen detection in blood: immunodiffusion, enzyme immunoassay Serological tests • Enyzme-linked immunosorbent assay - IgG and IgM • Virus neutralisation • Fluorescent antibody test • Haemagglutination inhibition • Plaque reduction neutralisation • Complement fixation • Immunodiffusion

• Commercial potential for diagnostic kits in Europe

  High in Southern Europe for surveillance purposes.

• DIVA tests required and/or available

  None available, but would be important in non-endemic-at risk countries performing routine RVF surveillance.

  These would be useful for epidemiological studies and vaccine field studies, but not essential for trade in Africa for several reasons. First, RVFV is not a contagious disease and infection does not result in persistence of the virus. Animals that are infected with RVFV, whether vaccinated or not, will develop antibodies that are protective (strong correlation of neutralizing antibodies with protection). Therefore, a seropositive animal can safely be transported. Specifically, use of a DIVA vaccine is not needed if animals are kept in quarantine for 3 weeks before export to free countries. Preferably, the animals are vaccinated before going into quarantine. Recommending DIVA vaccines could prevent transport of animals with protective antibodies and thereby not improve, but reduce free trade. Finally, it should be noted that DIVA diagnostics, when done properly, is very costly (much more costly than vaccination and almost certainly too costly for most African countries). However, in the event of an introduction of RVF in Europe these tests would be desirable if vaccination campaigns or emergency vaccination are implemented.

  GAP: Development of a cheap diagnostic test that identify unequivocally whether animals have been vaccinated or infected, irrespective of the type of vaccine used. Looking for either unique infection signatures or unique vaccination signatures.

• Opportunities for new developments

  Improved tests for screening and surveillance.

  GAP: Development of a Quick RVF antigen/antibody detection diagnostic test that could be used by the farmer.

• Vaccines availability

• Commercial vaccines availability (globally)

  Live attenuated RVF virus vaccines Clone 13

  and Smithburn vaccine. Available in Africa.

• Commercial vaccines authorised in Europe

  None.

• Marker vaccines available worldwide

  None.

• Marker vaccines authorised in Europe

  None. Recent developments in RVF vaccine research support the possibility of licensing animal vaccines in Europe.

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Both the live-attenuated and the inactivated vaccines have had extensive field use. Lifelong immunity against clinical disease is probable when using the live vaccine. Inactivated vaccines are used in areas where RVF is not endemic and as a consequence the knowledge of their efficacy is limited as natural field challenge does not occur.

  The inactivated vaccine failed to protect animals against abortion, following two vaccinations in more recent epizootics. The lack of efficacy in pregnant ewes of the inactivated vaccine has been shown previously [10]. A booster dose is recommended 3–6 months after the initial vaccination with the inactivated vaccine and this should be repeated annually.

  GAP: Lack of data on efficacy of these vaccines or vaccination campaigns in African countries.

• Commercial potential for vaccines in Europe

  None at present. But very high in the event of a single RVF case being reported within Europe.

• Regulatory and/or policy challenges to approval

  None apart from the process of obtaining a marketing authorisation.

• Commercial feasibility (e.g manufacturing)

  Low.

• Opportunity for barrier protection

  Yes, especially if climate models show an increase probability of an epizootic in a specific year.

• Opportunity for new developments

  High.

  GAP: Development of multivalent vaccines against RVF and other important ruminant diseases.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None.

  GAP: Exploring efficacy of antiviral drugs approved for human use.

• Future therapy

  None anticipated at present.

• Commercial potential for pharmaceuticals in Europe

  None.

• Regulatory and/or policy challenges to approval

  None.

• Commercial feasibility (e.g manufacturing)

  Low.

• Opportunities for new developments

  Low.

• New developments for diagnostic tests

• Requirements for diagnostics development

  Need improved tests.

  GAP: Quick rapid test to detect specific RVF antibodies as well as the detection of the virus itself (within 2 hours).

• Time to develop new or improved diagnostics

  Quick RVF test prototypes being developed by some companies and labs.

• Cost of developing new or improved diagnostics and their validation

  Affordable.

• Research requirements for new or improved diagnostics

  Current commercial diagnostic kits cannot differentiate animals vaccinated with attenuated or inactivated RVFV vaccines.

• Technology to determine virus freedom in animals

  Conventional technologies (virus isolation, molecular detection) available.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  In case of introduction of the disease into Europe or the US, vaccination would be needed. Novel and safer candidate vaccines have been developed and tested but these are not available commercially.

  Since the erratic cycle of RVF outbreaks means that annual vaccination is unlikely to be adopted by farmers in Africa, development of combined vaccines may ease to include RVF in annual vaccination of livestock.

  GAP: If RVF outbreaks occur in Europe, no vaccine will be available for a quick intervention against disease spread.

• Time to develop new or improved vaccines

  Currently available candidate vaccines could be licensed within 3 years if funds are available.

• Cost of developing new or improved vaccines and their validation

  ~10m€ for a new vaccine. Probably not needed since highly promising candidates are available.

• Research requirements for new or improved vaccines

  Need to register at least one of the newly developed vaccines for use in Europe as a contingency plan.

  GAP: Involvement of vaccine industry. Public-private partnership desirable.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  No for animals. Yes for humans.

• Time to develop new or improved pharmaceuticals

  Unknown.

• Cost of developing new or improved pharmaceuticals and their validation

  High.

• Research requirements for new or improved pharmaceuticals

  Assessing effectiveness of current antivirals against RVFV.

  GAP: Testing efficacy of current antivirals against RVFV.

Disease details

• Description and characteristics

• Pathogen

  RVFV is a member of the family Bunyaviridae, genus Phlebovirus. The virus comprises a three-segmented negative-strand RNA genome. Progress in molecular biology of RVFV has been made during the last decades. Like other bunyaviruses, RVFV produces non-structural proteins: NSs, NSm and P78. The role of the NSs nuclear protein is best characterized. NSs is a major virulence factor that suppress host general transcription counteracting both the antiviral interferon (IFN)-β response and the double-stranded RNA (dsRNA)-dependent protein kinase (PKR) activity (reviewed in [1]).

  The role of NSm has been related with apoptosis inhibition in mammalian host cell and, together with P78, may have some role in insect host cells.

  GAPS:

  To get more insights into variability of genes involved in RVF strains virulence, particularly in countries where the presence of inter-epizootic periods has been clearly defined without causing any major clinical outbreaks.

  To investigate further the role of other factors (accessory viral proteins, P78, NSm) in mosquitoes and in mammals.

• Variability of the disease

  All isolates belong to a single serotype. Isolates can be classified into 7 genetic lineages. A re-assortant strain has been described in the last 2010 South African outbreak [2].

  Host range includes

  • Cattle, sheep, goats, camels
  • Wild ruminants, buffaloes, antelopes, wildebeest, etc.
  • Humans
  GAP: The susceptibility of deer (and other free-range European ungulates) should be evaluated.

• Stability of the agent/pathogen in the environment

  The virus in cell culture supernatants can survive for several months at 4 °C without significant loss of titer [3]. Heat and pH affect virus viability but according to early reports the virus retains infectivity for several months at room temperature or even in dried preparations (reviewed in [4]).

• Species involved

• Animal infected/carrier/disease

  RVF is able to infect many species of animals causing severe disease in domesticated animals including cattle, sheep, camels and goats. Sheep (particularly newborn lambs and pregnant ewes) are most susceptible to disease. An important role for camels in the RVF epidemiological cycle has been described[5]. Camelids can now be fully considered as a susceptible host with fatal cases and abortions.

  GAP: Since camels are a susceptible host for the virus, vaccine efficacy studies in these animals may be needed.

• Human infected/disease

  Humans are susceptible with flu-like symptoms prevailing. GAP: The pathogenesis of the variable disease progression observed between different RVFV-infected human subjects is still poorly known. Why are most infected patients exhibiting low-grade fever while other patients suffer fatal haemorrhagic fever and/or encephalitis?

• Vector cyclical/non-cyclical

  The virus has been isolated from more than 30 different species of mosquito (Aedes, Anopheles, Culex, Eretmapodites, Mansonia etc.). The biological cycle of mosquito vectors conditions the enzootic/epizootic virus cycle.

  GAP: There is still insufficient knowledge about the vector competence of European mosquito species. Particularly Aedes vexans is relevant to study. Identification of the minimum viral load for a vector to play its role of competent vector (amplification/spread) and impact on the environmental factors on the vector competence.

• Reservoir (animal, environment)

  In specific species of Aedes mosquitoes, the virus can transmit to the eggs. These mosquitoes can therefore be considered as reservoir hosts, although a role for other wild small mammal reservoirs cannot be ruled out. Serological and virological analyses in Madagascar indicated seroconversions in animals that did not move from their village, suggesting an RVFV local circulation when mosquitoes are rare or inactive [6]. Three hypothesis were formulated to explain these seroconversions: 1) Direct transmission mechanisms, 2) virus overwintering in vectors (residual active mosquito population during the dry and cold season and ticks), or 3) the existence of a wild reservoir other than wild terrestrial small mammals [7].

  GAP:

  Identify wild reservoir other than small mammals.

  Transovarial transmission was only demonstrated once and should be confirmed, at least with Aedes mcintoshi mosquitoes.

• Description of infection & disease in natural hosts

• Transmissibility

  RVF is transmitted among ruminants via bites from infected mosquitoes and possibly other biting insects that have virus-contaminated mouthparts. Although humans can also be infected via mosquito bite, most human infections are attributed to contact with contaminated animal products during the slaughtering of diseased animals. RVFV can be infectious and virulent when inhaled by humans [8] or experimental animals (rats) [9].

  GAP:

  Horizontal transmission of RVFV was previously reported [10, 11]. More recently, it was found that co-housing of RVFV-infected lambs with immunocompetent or immunosuppressed lambs does not result in virus transmission [12]. This discrepancy warrants further investigations. The risk of unpasteurised milk consumption is still unclear. Up to now, there are no specific studies demonstrating the RVF viral transmission though raw milk. In many countries, drinking raw milk is a basic and needs to be considered in terms of pathogens transmission risk.

  The risk of RVF semen transmission needs to be further analysed.

• Pathogenic life cycle stages

  Female mosquitoes which feed on infected animals can become infected with RVFV. Transovarian transmission can occur in at least one Aedes species (Aedes mcintoshi). The eggs of these mosquitoes can survive for several years in dry conditions. During periods of heavy rainfall, flooding will often occur which enables the eggs to hatch with the consequent rapid increase in the mosquito population. After floodwater Aedes mosquitoes have infected the first ruminants, also other mosquito species may contribute to further spread.GAP: Transovarial transmission was only demonstrated once and should be confirmed, at least with Aedes mcintoshi mosquitoes. The survival of eggs containing the virus could also be investigated in other European-range mosquito species.

• Signs/Morbidity

  The disease is characterised by high mortality among young animals and high rate of abortion in ruminants. Among pregnant infected ewes, abortion rates may reach almost 100%. The start of an epidemic may be indicated by a wave of unexplained abortions among livestock. Sheep are the most severely affected. The course of the disease in different animal species including humans and domesticated ruminant was reviewed by Easterday [4].

  Cattle

  Calves: fever (40-41°C), depression.

  Adults: fever (40-41°C), excessive salivation, anorexia, weakness, fetid diarrhoea, fall in milk yield. Abortion may reach 85% in the herd. Mortality rate is usually less than 10%

  Sheep, goats

  Lambs: fever (40-42°C), anorexia, weakness, death within 36 hours after inoculation.

  Adults: fever (40-41°C), mucopurulent nasal discharge, vomiting; in pregnant ewes, abortion may reach 100%.

  Unapparent infections are quite frequent in other species than sheep.

  GAP: It is not known what triggers ocular alterations (corneal opacity in sheep, retinopathy in humans). The mechanisms of late onset neurological disease often observed in rodent models are not fully understood.

• Incubation period

  The incubation period varies from 1 to 3 days in sheep, cattle, goats. In newborn lambs, it is 12 to 36 hours. Experimental infections usually become evident after 12 hours in newborn lambs, calves and kids.

• Mortality

  Cattle: Mortality rate: 10%, mortality can be up to 70% in young calves.

  Lamb: Mortality rate: for animals under 1 week of age - up to 90%; for animals over 1 week of age - up to 70%.

  Adult sheep, goats: mortality may reach 20-30%.

• Shedding kinetic patterns

  Viraemic animals pose a risk as mosquitoes feeding on these animals can become infected. GAP: The infectious period of sheep and cattle should be investigated (the period of viremia sufficiently high to result in infection of mosquitoes). Such data can be used to improve epidemiological models.

• Mechanism of pathogenicity

  Related to liver and brain tropism of the virus as well as immunopathogenic effects. Although there has been great advances in characterizing clinical, pathological, and virological features of RVFV infection (reviewed in [13] and [14] the exact mechanisms of pathogenicity are unknown and may vary between species.

  GAPS:

  Mechanism that triggers haemorrhagic fever, entry to the brain, or retinal complication are unknown [15].

  Despite efforts to characterize the immune response in natural hosts [16-19] including humans [20, 21], or experimental animals [22-27] little is known about how the host immune response influences clinical outcome during the primary RVFV infection.

• Zoonotic potential

• Reported incidence in humans

  Humans are highly susceptible to RVF. During outbreaks in animals, mosquitoes may spread the virus to humans and cause epidemics. However, most human infections are attributed to contact with animal products during the slaughtering of diseased animals. The role of mosquitoes in epidemics obviously depends on the presence of mosquitoes that feed on both humans and ruminants. The major source of human infection is aerosols transported from sick infected animals to healthy humans, not mosquitoes.

  GAP: The real involvement of mosquitoes in human to human transmission needs to be studied.

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

  Most cases develop in veterinarians, abattoir workers and others who come into contact with blood and tissue samples from animals.

  Genetic host factors have been established as a key element in RVF disease in rodent models [28-30]. Association between immune related genes and severe symptoms suspected in humans [31].

  GAP: Genes associated with RVF clinical disease in high-risk populations remain to be identified in experimental animals, livestock, and humans.

• Symptoms described in humans

  Most people with RVF recover spontaneously within a week. Ocular disease is seen in approximately 0.5% to 2% of cases, and encephalitis or haemorrhagic fever in less than 1%. The case fatality rate for haemorrhagic fever is approximately 50%. Deaths rarely occur in people with eye disease or meningoencephalitis, but 1% to 10% of patients with ocular disease have some permanent visual impairment [13].

  GAP:

  The symptoms are well described in humans. However, the physiopathological mechanisms are poorly understood, as for examples:

  - The mechanism of entry of the virus in the central nervous system.

  - The physiopathology of the encephalitis.

  - The mechanisms of clearance of the virus.

• Estimated level of under-reporting in humans

  Unknown but probably high in non-developed countries. In many cases patients suffering from hyperthermia, headache, dengue like syndromes are not initially diagnosed of RVF since the clinical signs fall under “dengue-like syndromes” but further laboratory testing identified these patients as RVF cases [32].

• Likelihood of spread in humans

  No human to human spread has been reported. Nasal discharge, blood, vaginal secretions after abortion in animals, mosquitoes, contaminated fresh meat and raw milk are potential sources.

  Nosocomial transmission risks evaluated as low [33].

  GAP: The risk of consumption of raw milk and transmission through semen (as Zika virus) should be assessed.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  Quarantine.

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

  Wild ruminants (buffalo, antelope and wildebeest) are susceptible. GAP: Incidence of abortions in these species not known.

• Slaughter necessity according to EU rules or other regions

  No.

• Geographical distribution and spread

• Current occurence/distribution

  RVF has been recognised exclusively in African countries with some incursions into the Middle East.

  RVF usually occurs in epizootics in Africa, which may involve several countries at the same time. The first reported occurrence of disease outside Africa occurred in 2000 when cases were confirmed in Saudi Arabia and Yemen. There remains a concern that RVF could spread to other regions, particularly Europe and Asia.

  Serological evidence of exposure suggests active circulation of RVFV in Tunisia in 2014 [34]. Absence of RVFV in domestic and wild ruminants from southern Spain has been reported [35].

  GAP: In the Northern part of Africa and particularly in Tunisia, RVF has been reported to be present [34]. No data are available for Morocco and Algeria which are countries closely linked together and to Europe.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Epizootics follow the periodic cycles of exceptionally heavy rain, which may occur very rarely in semi-arid zones (25–35-year cycles), or more frequently (5–15-year cycles) in higher rainfall savannah grasslands. During the inter epizootic period low level RVFV activity may occur.

  Outbreaks are generally associated with above normal rainfall and explosions of mosquito populations.

• Seasonality

  The periodic RVF outbreaks have been associated with variability in rainfall patterns in most of Eastern Africa. RVF is most commonly associated with mosquito-borne epidemics during years of unusually heavy rainfall.

• Speed of spatial spread during an outbreak

  Variable.

• Transboundary potential of the disease

  Yes. The movement of clinically normal viraemic animals into unaffected areas where vectors are present has the potential to cause epidemics and epizootics. This could explain some outbreaks in the Horn of Africa (sequence data). GAP: Perform risk analysis studies linked to animal mobility in order to develop adequate surveillance plans based on risk of introduction and settlement of the infection.

• Route of Transmission

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

  The virus is transmitted by mosquitoes. Transovarial transmission can occur in at least one Aedes species (Aedes mcintoshi), which may, at least partially, explain the survival of the virus during inter-epidemic periods.

  GAPS:

  Competence of mosquitoes from Southern Europe (Greece, Spain, Italy) should be assessed including transovarial transmission.

  Competence of ticks, phlebotomus, and culicoides from Southern Europe should be evaluated.

• Occasional mode of transmission

  Transmission of RVF virus by mechanical means via biting flies is also possible.

  During parturition, necropsy or slaughter, viruses in the tissues can become aerosolized or enter the skin through abrasions (direct contact). The RVF virus has also been found in raw milk and may be present in semen [36].GAPS:

  The biology of the virus in mosquitoes is poorly documented. Could this knowledge be used to block the transmission?

  The role of biting insects and perhaps even ticks should be investigated. This does not seem to play a major role in Africa, but this may be different in Europe.

  The presence of RVFV genomic RNA in semen raises the possibility of sporadic sexual transmission.

• Conditions that favour spread

  Heavy rainfall and movement of infected animals into free areas.

• Detection and Immune response to infection

• Mechanism of host response

  Natural infection results in a high neutralizing antibody response which correlates with protection. GAP: Late onset neurologic disease may be related with inappropriate/uncontrolled immune responses. The exact mechanisms are unknown and should be the matter for future research.

• Immunological basis of diagnosis

  Detection of antibodies. GAP: Identification of the host immune response (humoral and cellular) elicited during a natural RVF infection.

• Main means of prevention, detection and control

• Sanitary measures

  Vector control may be beneficial.

• Mechanical and biological control

  Interference with the mosquito life-cycle may be beneficial. GAP: Identification of the risk areas based on environmental factors (rainfalls, wind, waterpoints) favouring the abundance and distribution of the competent mosquito species.

• Diagnostic tools

  Classic virological as well as both molecular and serological tests are developed (listed in OIE’s Manual Chapter 2.1.14). Commercial antibody detection test fully available. Virus neutralization remains a gold-standard.

  GAPS:

  Development of sensitive specific rapid bench tests

  Perform RVF diagnostic ring trials among European and northern African countries.

• Vaccines

  Both live-attenuated virus and inactivated virus vaccines have been developed for veterinary use. Only one dose of the live vaccine is required to provide long-term immunity but the vaccine that is currently in use may result in spontaneous abortion if given to pregnant animals. The inactivated virus vaccine does not have this side effect, but multiple doses are required in order to provide protection. The Clone 13 vaccine was marketed by Onderstepoort Biological Products in 2010 and was extensively used in the field. This vaccine provides solid protection after a single vaccination and is safe for young lambs. However, a recent safety study that was performed according to the regulations and guidelines from the OIE and European Pharmacopeia demonstrated that the Clone 13 virus can transmit to the ovine fetus, which was associated with stillbirths and fetal malformation when administered during the first trimester of gestation. [37]. MP12 is another alternative vaccine with extensive data on field and clinical trials. An adenovirus-based vaccine has shown full protection against viremia in several livestock species [38]. Protein Subunit and DNA vaccines based on recombinant RVFV glycoproteins are able to elicit protective immune responses, but not after a single immunization.

  GAPS:

  Several candidate vaccines were developed that have shown great promise in target animals (sterile immunity after a single vaccination). The safety and efficacy of these vaccines should be evaluated in sheep and cattle (at least) according to the guidelines and regulations of the OIE and European Pharmacopeia so that these vaccines can be used in Europe in emergency situations. It is strongly preferred that these vaccines are evaluated in close collaboration with pharmaceutical companies.

  Developments towards human vaccines must be addressed, particularly those based on approaches already proved safe for human use (subunit/ DNA/adenovirus and/or MVA platforms)

  Efficacy of adenovirus vaccine against RVFV should be tested in pregnant animals.

  Develop methods ensuring protective efficacy of subunit vaccines after a single dose.

  Develop methods to enhance the efficacy of DNA vaccines.

• Therapeutics

  No specific treatment. Supportive treatment in severe human cases. However several molecules with anti-RVFV activity have been demonstrated in laboratory animal models:

  - Combined administration of Ribavirin and Favipiravir reported to be beneficial post infection in Golden Hamsters [39]. Not tested in human patients;

  - Screenings for compounds with antiviral activities are currently performed in cell cultures [40-43].

  GAPS:

  Antiviral products for human patients (should be discussed with the experts)

  Vaccine manufacturers have little incentive to develop vaccines against human RVF owing to a perceived non-credit worthy market in Africa Protection of human populations, will rather depend on the development of specific anti-viral compounds to control the infection and/or its clinical corollaries. The success of this strategy is critically dependent on the identification of new antiviral targets. The use of drugs tested in humans against other infectious diseases could be an alternative for RVFV (Favipiravir against flu, ebola etc).

• Biosecurity measures effective as a preventive measure

  1. Restrict or stop all animal movement to prevent introduction into unaffected areas.

  2. Observe, detect and report any disease or unusual signs as quickly as possible.

  3. Removal of mosquito breeding sites (stock tanks, ponds, old tires etc.) helps to prevent spread of the disease.

  4. Protect humans against mosquito bites and use personal protective equipment (respirator, gloves, eye protection etc.) when handling tissues from animals that have aborted and during slaughter of diseased animals (which should be prevented when possible).

  Information from Biosecure (biosecure.eu)

  There exists significant EU legislation and trade restrictions designed to prevent the introduction of RVF into Europe. All countries exporting livestock to the EU must be officially certified as RVF free, monitored by national veterinary services, and there is a prohibition against trans-shipment through endemic regions. (Chevalier et al., 2010). However, cattle trade does occur with Egypt, which has potential for emerging endemicity of RVFV (Rolin et al., 2013), with the most recent outbreak occurring in 2003 (Kenawy et al., 2018). Another potential route for spread into Europe could be through West Asia and Türkiye into South Eastern Europe and the Balkans, however, for the time being this is not likely, as RVFV is only currently endemic in Saudi Arabia and Yemen. It is however, potentially possible and ecologically feasible for further spread, as similar arboviruses, such as West Nile Virus (WNV) have spread to Iran (Rolin et al., 2013). Another potential route of introduction could be via imported wildlife or zoo animals, however, stringent quarantine regulations exist to prevent this from occurring (Chevalier et al., 2010).

• Border/trade/movement control sufficient for control

  Restricting or banning the movement of livestock may be effective in slowing the expansion of the virus from infected to uninfected areas. However, after found seropositive and a quarantine period animals could be transported safely to free countries. Of note, DIVA is only useful for epidemiological studies. It would greatly facilitate trade if seropositive animals are deemed safe for transport. GAP: To support the notion that seropositive animals can indeed be transported safely, the duration of immunity after infection or vaccination with a given vaccine should be carefully determined. This would include demonstration that organs from these animals do not pose a risk for risk groups (slaughterhouse workers) after a given period.

• Prevention tools

  Vaccines.

  Additional, less commonly used, preventative measures include vector control, movement of stock to mosquito-free areas (e.g. higher altitudes), and the confinement of stock in insect-proof stables. All these control methods are often impractical, or are ineffective because they are instituted too late. The movement of animals from endemic areas to RVF-free regions might result in epidemics. Alternatively, animals can be kept in quarantine for a period of 2-3 weeks and subsequently transported to free areas. Preferably, these animals are vaccinated before being placed in quarantine.

  GAPS:

  European countries should be able to show their contingency plans

  Could Wolbachia and other bacteria be used to fight RVFV transmission in Culex pipiens and Aedes vexans?

  All trade animals from endemic to free areas should be vaccinated before movement. In this case a DIVA vaccine is advantageous.

  Estimate the minimum time needed for effective quarantine.

• Surveillance

  Animal health surveillance is critical to detect new cases and to identify the initial stages of an epidemic. This act as an early warning system for both the veterinary and public health authorities. RVF should be suspected when abortions and deaths among newborns occur following unusually heavy rains along with reports of influenza-like illness among humans.

  GAP: Develop Control strategies in non-endemic areas (routine monitoring of sentinel animals, monitoring virus circulation in mosquito species in wetland areas in Southern Europe.

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

  Although there is very little doubt that vaccination has contributed significantly to control RVF outbreaks, there is no quantitative data about the effect of vaccination campaigns. The difficulty with RVF outbreaks is that they tend to occur after many years of apparent absence of the disease. As risk perception dismisses farmers have no incentive to vaccinate their livestock. When outbreaks suddenly occur, vaccine manufacturers do not have sufficient time to produce the vaccine and even if they have, it is extremely challenging to deploy the vaccine in the field in a timely manner. Therefore, either emergency stockpiles have to be prepared or combination vaccines should become available that protect not only against RVF but also against another, preferably endemic disease that affects the same species. As it is unclear who will pay for the maintenance of a vaccine stockpile, the second option is probably the most realistic.

  GAPS:

  Vaccines should be developed that protect against RVF and another, preferably endemic, disease that affects the same species. E.g. RVF/Lumpy skin disease for cattle and RVF/pulpy kidney for sheep.

  Plans for stockpiling multivalent temperature resistant vaccines (no cold chain need to be maintained).

• Costs of above measures

  Not publicly known but probably high.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes. No epizootic outbreaks reported in 2015-2016 period. Sporadic human cases reported in Uganda, Tunisia and China (imported from Angola).

• WOAH disease card available

  http://www.oie.int/fileadmin/Home/eng/Animal_Health_in_the_World/docs/pdf/Disease_cards/RIFT_VALLEY_FEVER.pdf

• WOAH Terrestrial Animal Health Code

  http://www.oie.int/index.php?id=169&L=0&htmfile=chapitre_rvf.htm

• WOAH Terrestrial Manual

  http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.01.18_RVF.pdf

• Socio-economic impact

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

  No details but the overall case fatality rate for all patients with RVF fever is less than 1%. In humans, the incubation period is 2 to 6 days.

  However in more recent outbreaks the case/fatality rates increased.

  Limited to sub Saharan Africa in most years but has also occurred in Egypt, Yemen, Saudi Arabia, and several islands off the coast of Southern Africa, including Madagascar.

  RVFV is currently circulating in Tunisia.

  GAPS:

  Understand the nature of the increased CF ratio observed in some recent RVF outbreaks.

  Limited to sub Saharan Africa in most years but has also occurred in Egypt, Yemen, Saudi Arabia, Madagascar, Comoros and Mayotte.

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

  There is no treatment (apart from supportive therapy) for humans. Control of human disease depends of quality of public health systems. GAP: It would be extremely valuable to assess the economic damage of a future RVF epidemic as accurately as possible.

• Direct impact (a) on production

  The disease results in significant economic losses due to death and abortion among RVF-infected livestock. Restrictions on movements also have an economic impact especially with the export of small ruminants from Africa to the Arabian Gulf states.

  Major impact in Africa with mortality and morbidity.

  GAP:

  It would be valuable to assess the impact of RVF outbreaks on political instability in (the horn of) Africa.

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

  Unknown (= GAP).

• Indirect impact

  Major economic impact in nomadic areas with loss of food animals and restrictions on movements especially exports from Africa to the Middle East in particular the Arabian Peninsula.

• Trade implications

• Impact on international trade/exports from the EU

  No impact as the disease is not reported in the EU but can have a serious trade impact on those countries where the disease is endemic. Detailed standards for trade are described in the OIE Terrestrial Animal Health code.

• Impact on EU intra-community trade

  No impact as disease not currently reported in the EU.

• Impact on national trade

  No impact as disease not reported in the EU.

• Main perceived obstacles for effective prevention and control

  Fully safe available vaccines for use in Europe are lacking.

  Although some very promising experimental vaccines were developed in the past decade, vaccine manufacturers will not register these vaccines for application in Europe.

  GAPS:

  Licensing/registering current vaccine candidates in Europe. Set up a country-based contingency plan.

  Vaccines that are to be registered in African countries should be evaluated for safety and efficacy according to the guidelines and regulations of the OIE and European Pharmacopeia so that these vaccines may be applied as emergency vaccines in Europe following a future incursion.

• Main perceived facilitators for effective prevention and control

  Improved vaccines ensuring safety standards.

• Links to climate

  Seasonal cycle linked to climate

  Related to mosquito populations and breeding cycles.

• Distribution of disease or vector linked to climate

  Closely related.

• Outbreaks linked to extreme weather

  Sustained heavy rain. Studies on climate variability and RVF activity have focused on precipitation and epizootics. Periods of excessive rainfall are believed to increase the egg hatching and larval survival of certain African Aedes floodwater mosquito species. GAP: Impact on the climate change of the RVF spread. The role of soil composition and ground water levels is understudied. This may explain why predictions of outbreaks are still poor.

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

  Vectors may have the potential to extend their geographical distribution to Europe. Also, native mosquito species may be capable of spreading the virus, such as demonstrated for several European mosquito species already.

  GAPS:

  Competence of mosquitoes from Southern Europe (Greece, Spain, Italy) should be assessed

  Competence of ticks, phlebotomus, and culicoides from Southern Europe should be evaluated.

  More knowledge on the RVF vector competence of European and Asian-breed mosquitoes for RVFV is needed as well as about the different mosquito species present in Europe.

  Environmental factors (including vector microbiota) that may influence vector competence.

Risk

• Currently, RVF is a disease exotic to Europe but there is a risk of introduction, perhaps analogous to West Nile Virus in the US and/or Bluetongue in Europe. GAP: Produce risk analysis maps for the disease to occur.

Main critical gaps

Conclusion

• Anticipation of the incursion of RVF in Europe by studying epidemiology and preparing vaccine and diagnostic solutions is recommended. Contingency planning required to ensure availability of appropriate vaccines and diagnostics should there be incursions of RVF into Europe.MAJOR RESEARCH GAPS:

  1. Virology:

  - The role of virulence factors (accessory viral proteins, P78, NSm) in the mosquitoes and in mammals is largely unknown.

  2. Entomology:

  - Competence of mosquitoes, ticks, phlebotomus, and culicoides from Southern Europe (Greece, Spain, Italy).

  The biology of the virus in mosquitoes is poorly documented. Could this knowledge be used to block the transmission?

  3. Physiopathology:

  - Little is known about how the host immune response influences clinical outcome during the primary RVFV infection. We lack an integrated view of the host immune response to RVFV.

  - Why are most infected patients exhibiting low-grade fever while other patients suffer fatal hemorrhagic fever and/or encephalitis?

  - Identification of genes associated with high risk to develop severe forms of RVF disease in livestock and humans.

  - Mechanisms of clearance of the virus and prevention of RVFV-induced disease unknown.

  - Physio-pathological mechanisms poorly understood: entry in the central nervous system, encephalitis, retinal complications.

  4. Epidemiology

  - Identify wild reservoir(s) other than small mammals.

  - Horizontal transmission in livestock should be assessed.

  - Assess the possibility of sporadic sexual transmission through semen of infected patients.

  - The risk of consumption of raw milk should be assessed.

  5. New developments

  -Licensing candidate vaccines in Europe should be encouraged as well as plans for vaccine stockpiling

  -Additional commercial diagnostic kits should be developed for humans, and livestock. DIVA diagnostic tests.

  -Combined (multivalent) vaccines

  -Antiviral products for human patients treatment are needed

  -Could Wolbachia and other bacteria be used to fight RVFV transmission in Culex pipiens and Aedes vexans?

Sources of information

• Expert group composition

  Names of expert group members are included where permission has been given.

  Alejandro Brun Torres, INIA, Spain [Leader]

  Catherine Cetre-Sossah, CIRAD, France

  Jean Jacques Panthier, Institut Pasteur, France

• Reviewed by

  Project Management Board

• Date of submission by expert group

  30 September 2016

• References

  Online references:

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  • Food and Agriculture Organisation, 2003 Animal health manual number 17, Recognizing Rift Valley. Accessed 17 January 2010. http://www.fao.org/DOCREP/006/Y4611E/Y4611E00.HTM
  • World Health Organisation, Programmes and Projects, Fact sheet 207, 2007, Rift Valley fever., Accessed 17 January 2010. http://www.who.int/mediacentre/factsheets/fs207/en/
  • World Organization for Animal Health (OIE). OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals. Chapter 2.1.14 Rift Valley Fever. Version adopted by the World Assembly of Delegates of the OIE in May 2014. Accessed 22 May 2016. http://www.oie.int/eng/normes/mmanual/2008/pdf/2.01.14_RVF.pdf; http://www.oie.int/fileadmin/Home/fr/Health_standards/tahm/2.01.14_RVF.pdf
  • World Organisation for Animal Health (OIE) -WAHID interface- disease information – Rift Valley Fever -list of countries by disease situation: Accessed 17 January 2010; http://www.oie.int/wahis/public.php?page=disease_status_lists

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