Additional commercial diagnostic kits ELISAs should be validated for testing human serum samples.Testing performance of current ELISAs with human sera.
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.
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
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.
Improved tests for screening and surveillance.
GAP: Development of a Quick RVF antigen/antibody detection diagnostic test that could be used by the farmer.
Live attenuated RVF virus vaccines Clone 13
and Smithburn vaccine. Available in Africa.
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 . 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.
GAP: Development of multivalent vaccines against RVF and other important ruminant diseases.
GAP: Exploring efficacy of antiviral drugs approved for human use.
Need improved tests.
GAP: Quick rapid test to detect specific RVF antibodies as well as the detection of the virus itself (within 2 hours).
Current commercial diagnostic kits cannot differentiate animals vaccinated with attenuated or inactivated RVFV 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.
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.
No for animals. Yes for humans.
GAP: Testing efficacy of current antivirals against RVFV.
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 ).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.
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.
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 .
Host range includes
GAP: Since camels are a susceptible host for the virus, vaccine efficacy studies in these animals may be needed.
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.
Identify wild reservoir other than small mammals.Transovarial transmission was only demonstrated once and should be confirmed, at least with Aedes mcintoshi mosquitoes.
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  or experimental animals (rats) .
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 . 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.
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 .
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%
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.
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%.
Mechanism that triggers haemorrhagic fever, entry to the brain, or retinal complication are unknown .
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.
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.
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 .
GAP: Genes associated with RVF clinical disease in high-risk populations remain to be identified in experimental animals, livestock, and humans.
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.
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 .
GAP: The risk of consumption of raw milk and transmission through semen (as Zika virus) should be assessed.
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 . Absence of RVFV in domestic and wild ruminants from southern Spain has been reported .
GAP: In the Northern part of Africa and particularly in Tunisia, RVF has been reported to be present . No data are available for Morocco and Algeria which are countries closely linked together and to Europe.
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.
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.
Related to mosquito populations and breeding cycles.
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.
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.
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 .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.
Development of sensitive specific rapid bench testsPerform RVF diagnostic ring trials among European and northern African countries.
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.
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 . Not tested in human patients;
- Screenings for compounds with antiviral activities are currently performed in cell cultures [40-43].
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).
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).
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.
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.
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.
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).
Yes. No epizootic outbreaks reported in 2015-2016 period. Sporadic human cases reported in Uganda, Tunisia and China (imported from Angola).
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.
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.
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.
It would be valuable to assess the impact of RVF outbreaks on political instability in (the horn of) Africa.
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.
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.
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.
- The role of virulence factors (accessory viral proteins, P78, NSm) in the mosquitoes and in mammals is largely unknown.
- 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?
- 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.
- 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?
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
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