Rift Valley fever virus

Rift Valley fever virus, abbreviated RVFV, is a mosquito-borne member of the family Phenuiviridae and the cause of a zoonotic disease that strikes livestock and humans together. It is above all a veterinary catastrophe that spills over into people: epizootics sweep through sheep, cattle and goats as waves of abortion and death in young animals, and human cases appear alongside them, mostly in the farmers, herders, abattoir workers and veterinarians who handle infected animals. Most human infections are a brief, self-limiting fever, but a small fraction progress to severe liver and haemorrhagic disease, to sight-threatening retinitis, or to a delayed encephalitis.

The virus is a creature of climate. It is maintained quietly in the eggs of floodwater Aedes mosquitoes, and its explosive outbreaks follow periods of unusually heavy rainfall that flood shallow depressions, hatch vast numbers of infected mosquitoes and ignite epizootics across whole regions. Because livestock amplify the virus and are the main source of human infection, the most effective way to protect people is to vaccinate animals, the logic of the One Health approach that dominates its control. There is no licensed human vaccine and no approved antiviral, though a single-dose vaccine candidate designed for both livestock and people has reached clinical trials.

First recognised in Kenya’s Rift Valley and long confined to Africa, the virus reached the Arabian Peninsula in 2000 and has a documented capacity to expand its range, which keeps it on lists of emerging pathogens of pandemic concern.

Discovery and historical significance

Rift Valley fever was defined in 1930 to 1931, when Daubney and Hudson investigated an outbreak of abortions and sudden lamb deaths on a farm near Lake Naivasha in the Rift Valley of Kenya and identified a filterable agent, naming the disease enzootic hepatitis. The pattern they described, mass abortion in ewes with high mortality in newborn lambs and a simultaneous febrile illness in the farm workers, has recurred in every large outbreak since.

For four decades the virus was regarded as an African veterinary problem. Its capacity for large human epidemics became clear in 1977, when it erupted in Egypt, causing an estimated 200,000 human infections and around 600 deaths after the virus reached the irrigated Nile Valley. A further landmark came in 2000, when Rift Valley fever appeared in Saudi Arabia and Yemen, its first confirmed emergence outside the African continent, carried across the Red Sea most likely in infected livestock. These events transformed the virus from a regional agricultural threat into a recognised emerging zoonosis, and it is now studied as a model of how climate, animal husbandry and arboviral ecology combine to produce explosive outbreaks.

Classification, structure, and genome

Classification

RVFV is the species Phlebovirus riftense in the genus Phlebovirus, family Phenuiviridae, order Bunyavirales. The family reorganisation of 2016 to 2017 moved the phleboviruses out of the old family Bunyaviridae into Phenuiviridae, so older texts place the virus in Bunyaviridae. Its genus contains the sandfly fever and Toscana viruses among many others, and the related severe fever with thrombocytopenia syndrome virus sits in the neighbouring genus Bandavirus. Despite its wide geographic range, RVFV is remarkably conserved genetically, with only about 4% to 5% nucleotide diversity among strains circulating since the 1970s, and reassortment between co-circulating lineages occurs but is hard to detect.

Virion structure

The virion is enveloped, roughly spherical and about 80 to 120 nm in diameter, its surface formed by the two glycoproteins Gn and Gc arranged as an ordered icosahedral lattice on the lipid envelope, a more regular architecture than the pleomorphic surface of the nairoviruses. There is no matrix protein. Within, the three genome segments are each coated by nucleocapsid protein and bound to the large L polymerase as ribonucleoprotein complexes.

Genome organisation

The genome is three segments of single-stranded RNA totalling about 12 kilobases. The large (L) segment is negative-sense and encodes the RNA-dependent RNA polymerase; the medium (M) segment encodes a glycoprotein precursor that is processed into the structural Gn and Gc together with a non-structural NSm and a larger 78 kilodalton protein; and the small (S) segment is ambisense, encoding the nucleocapsid protein in one orientation and, from the opposite-sense strand, the non-structural protein NSs. That NSs protein is the virus’s dominant virulence factor. The ambisense coding strategy, which lets a single small segment express two proteins from opposite strands through a shared intergenic region, is a defining feature of the phleboviruses and distinguishes RVFV from the strictly negative-sense nairoviruses.

Replication cycle

RVFV replicates entirely in the cytoplasm. Infection begins when the Gn and Gc glycoproteins attach to the cell and the virion is taken up by receptor-mediated endocytosis. Acidification of the endosome triggers a Gc-mediated fusion of the viral and endosomal membranes, delivering the three ribonucleoprotein segments into the cytoplasm.

There the L polymerase transcribes each segment, priming its messenger RNAs by cap-snatching, cleaving short capped leaders from host transcripts to initiate synthesis. Replication proceeds through full-length antigenomic intermediates. The ambisense S segment is expressed in two steps: the nucleoprotein is translated from a subgenomic messenger RNA made on the genomic strand, while NSs is translated from a messenger RNA made on the antigenomic strand only after replication has begun, so its production is delayed relative to the structural proteins.

Newly made nucleocapsid protein encapsidates the progeny genomes, and Gn and Gc mature through the secretory pathway and accumulate at the Golgi, the site of assembly and budding for this virus as for the other bunyavirals. Mature virions are carried to the cell surface and released. A hallmark of infection is the behaviour of NSs, which polymerises into a dense filament within the nucleus, an unusual location for a cytoplasmic virus’s protein, from where it executes the immune-suppressing functions that make it the principal determinant of virulence.

Pathogenesis

After a mosquito bite or contact with infected tissue, the virus is thought to be taken up first by macrophages and dendritic cells, carried to the draining lymph node, and then released into the blood as a primary viraemia that seeds the major organs. Replication is intense in the liver, spleen, adrenal glands and elsewhere, and titres in the blood run high. The liver is the principal target organ, and hepatic necrosis is the central lesion of severe disease, mirrored in the steep rise of transaminases and, in the worst cases, jaundice and liver failure. Because the virus is directly cytopathic, much of the tissue destruction reflects the virus killing cells outright.

The severity of disease turns on the interferon response, and the NSs protein is what tips the balance. NSs suppresses type I interferon on two fronts, shutting down general host-cell transcription by disabling the basal factor TFIIH and specifically blocking induction of the interferon-beta gene, and it also promotes the degradation of the double-stranded-RNA sensor protein kinase R. In both animal models and human cases, a failure to mount an early interferon response is associated with severe and fatal outcomes, and patients who die often fail to generate RVFV-specific antibody at all. A strong innate response followed by high-titre neutralising antibody is the correlate of protection.

The haemorrhagic form arises when this uncontrolled infection engages the coagulation system: extensive liver damage impairs the synthesis of clotting factors while procoagulant release and endothelial dysfunction drive disseminated intravascular coagulation. The delayed ocular and neurological complications, appearing one to four weeks after the acute illness when viraemia has usually cleared, are less well understood; how the virus reaches immune-privileged sites like the eye and brain remains uncertain, though direct viral injury with focal necrosis is seen in affected brain tissue. In livestock the same virus is a powerful abortifacient, crossing the placenta to cause fetal death, whereas maternal-to-fetal transmission in humans has only occasionally been documented.

Epidemiology

RVFV is found across sub-Saharan and North Africa, Madagascar and the Arabian Peninsula, with most epizootics reported from East and southern Africa. Its ecology is built around two kinds of mosquito. Floodwater Aedes mosquitoes are the maintenance vector and reservoir: they transmit the virus to their own eggs, and those eggs survive dry years in the soil, hatching infected when the rains return. The shallow depressions known in the region as dambos or vleis flood after unusually heavy rainfall, triggering an explosion of Aedes that pass the virus to nearby livestock. Once animals are viraemic, a second wave of vectors, chiefly Culex mosquitoes, amplifies and spreads the virus more widely, producing the near-synchronous regional eruptions that define an outbreak.

This dependence on rainfall makes the disease predictable in a way few arboviruses are. Outbreaks track periods of heavy precipitation, often linked to the El Niño cycle, and satellite measurements of rainfall and vegetation can forecast areas at risk months in advance, giving a window for pre-emptive livestock vaccination. Between epizootics the virus can vanish from view for years or decades, persisting in Aedes eggs until the next flood.

Although mosquitoes drive the animal epizootic, most human infection comes by a different route. People are usually infected by direct contact with the blood, tissues or fluids of infected animals, during slaughter, butchering, veterinary work and above all the handling of aborted material, rather than by mosquito bite. The virus is also highly infectious by aerosol, a well-documented hazard to laboratory workers, and can be acquired from unpasteurised milk. Occupational groups, farmers, herders, abattoir workers and veterinarians, therefore bear the greatest risk. Human-to-human transmission has not been documented. The scale of some epizootics means that even a small proportion of severe cases translates into a substantial burden: the 1977 Egyptian outbreak caused an estimated 200,000 infections, and the 2000 Arabian Peninsula outbreak produced nearly 900 hospitalised cases in Saudi Arabia with over 120 deaths.

Natural history

The incubation period is short, usually 2 to 6 days. The great majority of infections then take the form of a self-limiting febrile illness that resolves within about a week as antibody appears and viraemia clears. Only a small minority, of the order of 1% to 2%, progress to severe disease.

Severe disease takes three broad forms that differ in their timing. The haemorrhagic and hepatic syndrome develops during or just after the acute illness, within the first days, and is the most rapidly lethal. The ocular complication, retinitis, appears later, typically one to three weeks after the first symptoms, sometimes after the fever has settled. The neurological complication, meningoencephalitis, is the most delayed, usually beginning one to four weeks after onset and occasionally more than two months later. A single patient usually develops one of these forms rather than all three, and the late complications can follow an acute illness that was mild or even unnoticed.

Clinical presentations and complications

Uncomplicated Rift Valley fever is an abrupt, often biphasic influenza-like illness with fever, myalgia, arthralgia and headache, sometimes with neck stiffness, photophobia and retro-orbital pain that can suggest meningitis. It settles over four to seven days. The severe forms, though uncommon, define the disease’s reputation.

The haemorrhagic-hepatic form carries a mortality of up to around 65%. Haemorrhagic signs appear two to four days after onset as haematemesis, melaena, a petechial or purpuric rash, and bleeding from the gums, nose or venepuncture sites; thrombocytopenia is invariable, often with disseminated intravascular coagulation, and there is usually accompanying hepatitis with markedly raised transaminases or jaundice. Acute renal failure may complicate the picture through hypovolaemia, multi-organ dysfunction or direct viral injury.

Ocular disease, or retinitis, occurs in up to about 10% of symptomatic patients and usually presents one to three weeks after the first symptoms as painless blurring, reduced acuity or scotomata. Many lesions resolve over a few months, but where they involve the macula, up to 70% of affected patients are left with permanent loss of vision. Meningoencephalitis presents with intense headache, confusion, disorientation, hallucinations, vertigo and, in severe cases, convulsions and coma; its direct mortality is comparatively low, but residual neurological deficit is common and recovery slow.

Diagnosis

Because viraemia is high throughout the acute illness, RVFV is comparatively easy to detect. Reverse-transcription PCR on acute-phase blood is the mainstay, detecting viral RNA during the viraemic period, with real-time quantitative assays also giving the viral load that correlates with outcome. Virus isolation in cell culture or by intracranial inoculation of suckling mice is straightforward but requires containment. As the immune response develops, IgM-capture and IgG ELISA confirm recent infection, and paired acute and convalescent sera are particularly useful in outbreak investigation; haemagglutination inhibition and immunohistochemistry of fixed liver tissue are further options. Antibody-based methods have been built on both whole inactivated virus and recombinant nucleocapsid protein.

Handling of the virus requires enhanced biosafety at containment level 3, a level below the maximum containment demanded by Crimean-Congo haemorrhagic fever and the filoviruses, reflecting the absence of person-to-person spread, though the aerosol hazard means laboratory work is still tightly controlled. The clinical differential is wide, spanning the other viral haemorrhagic fevers, malaria, leptospirosis, and bacterial sepsis and meningitis; the combination of a compatible illness, an epizootic in local livestock and a history of animal contact after heavy rains is what raises suspicion.

Management

There is no approved antiviral therapy, and care is supportive: fluid and electrolyte management, correction of coagulopathy, and organ support. Early dialysis can improve outcome in those who develop renal failure. Ribavirin, although active in vitro, is not recommended for Rift Valley fever, having shown a paradoxical association with late-onset encephalitis in animal studies, and corticosteroids are likewise not recommended. Favipiravir protects animals when given very early but loses effect and may worsen neurological disease if delayed, and neutralising monoclonal antibodies are under investigation as future therapeutics.

Two practical points shape management. First, because the ocular and neurological complications appear after the acute illness, survivors should be followed for at least a month to detect retinitis or encephalitis early. Second, at first presentation Rift Valley fever cannot be distinguished from Crimean-Congo haemorrhagic fever, so where both are possible a patient is managed as the more dangerous, contact-transmissible CCHF, with isolation, barrier nursing and early ribavirin, until the laboratory result is known.

Prevention and public health

Vector control

Reducing contact between people, animals and mosquitoes is one arm of control. Larviciding of identified breeding sites is the most effective vector measure when the sites are limited and can be found, but during the heavy floods that trigger outbreaks the breeding sites become too numerous and widespread for larviciding to be feasible, so personal protection with repellents, treated bed nets and suitable clothing, and avoidance of the peak biting periods, take on greater importance. Because most human infection is from animal tissue rather than mosquito bite, the largest gains come from safe animal-handling practice.

Vaccination

Prevention rests on the One Health principle that vaccinating livestock prevents the epizootic and so protects people. Several veterinary vaccines exist. The live-attenuated Smithburn strain induces durable immunity after a single dose but is only partially attenuated and can cause abortion and fetal malformation in pregnant animals. Formalin-inactivated vaccines are safe in pregnancy but expensive, need repeated doses and give only short-lived immunity. Newer live-attenuated candidates aim to keep the single-dose protection while removing the risk: the naturally occurring Clone 13 strain carries a large deletion in the NSs virulence gene, the mutagenised MP-12 strain is widely studied, and engineered viruses lacking NSs or NSm are in development.

The table below sets out the main veterinary vaccine types and their trade-offs.

Vaccine	Type	Key advantage	Key limitation
Smithburn	Live-attenuated	Single dose, durable immunity	Abortogenic and teratogenic in pregnancy
Formalin-inactivated	Inactivated	Safe in pregnant animals	Multiple doses, short-lived immunity, costly
Clone 13	Live-attenuated (NSs-deleted)	Single dose, improved safety	Newer, less field experience
MP-12	Live-attenuated (mutagenised)	Broadly protective, well studied	Residual attenuation concerns

For humans there is no licensed vaccine. An older formalin-inactivated preparation has been used to protect laboratory and veterinary workers in small numbers. The most advanced current candidate is ChAdOx1 RVF, a chimpanzee-adenovirus-vectored vaccine built on the same platform as several other vaccines, which in a first-in-human phase 1 trial was safe, well tolerated and generated neutralising antibody after a single dose, and which is designed as a single vaccine usable in both livestock and people. It has moved into further clinical evaluation in endemic settings.

Infection prevention and control

Rift Valley fever is not transmitted from person to person, so patients do not require the isolation and barrier nursing that Crimean-Congo haemorrhagic fever demands, and standard precautions are sufficient for their clinical care. The real occupational hazards are elsewhere: the handling of infected animals and their tissues, and the aerosol risk in the laboratory. Protective clothing and gloves for those slaughtering, birthing or performing necropsies on animals during an outbreak, and appropriate containment for laboratory work, are the priorities.

Surveillance and notification

Rift Valley fever is a notifiable and internationally reportable disease, and its surveillance is inherently a One Health enterprise linking veterinary and human health. Reports of abortion storms and deaths in livestock are an early warning of impending human cases, and climate-based forecasting from rainfall and satellite data allows animal vaccination and vector control to be targeted before an outbreak breaks out. Integrated animal and human surveillance underpins the timely detection that resource-limited settings often struggle to achieve, since outbreaks are frequently recognised only once human cases appear.

Outbreak response

Once an outbreak is under way, the response combines restriction of livestock movement to limit geographic spread, emergency vaccination of animals where a safe vaccine can be deployed in time, vector control around settlements, and public messaging on safe slaughter, avoidance of sick animals and thorough cooking of meat and milk. Because human infection follows the animal epizootic by one to two weeks, prompt action on the animal side can still reduce human cases.

South African context

South Africa is endemic for Rift Valley fever, with the disease historically concentrated on the central interior plateau, and outbreaks that recur at long, irregular intervals dictated by rainfall. The largest recent epidemic ran from 2010 to 2011, when exceptionally heavy rains across the Free State and neighbouring provinces produced widespread disease: more than 14,000 animal cases were reported across eight provinces, and the National Institute for Communicable Diseases recorded 278 laboratory-confirmed human infections with 25 deaths. The occupational pattern was stark, with 83% of human cases in animal-contact occupations and 89% reporting direct contact with infected animals before falling ill. This followed a 35-year gap since the previous large epidemic of 1974 to 1976, with smaller focal outbreaks in the intervening decades and a further small farm outbreak in the Free State in 2018 that infected eight workers handling carcasses.

The vector ecology in South Africa shows why contact with animals, rather than mosquito bite, dominates human transmission. The floodwater Aedes that maintain and launch the virus feed on livestock near the flooded pans and do not fly far, so they rarely reach people, whereas Culex theileri, which amplifies the virus, will fly to homesteads and feed on both livestock and humans. Even so, the great majority of South African cases arise from handling infected tissue during slaughter, birthing and carcass disposal, which is why the disease clusters in farmers, farm workers, abattoir staff and veterinarians.

Rift Valley fever is a notifiable medical condition in South Africa, reported through the Notifiable Medical Conditions system, and confirmatory testing is performed by the Centre for Emerging Zoonotic and Parasitic Diseases and its Arbovirus Reference Laboratory at the National Institute for Communicable Diseases. Prevention follows the One Health model, with veterinary vaccines available locally and animal vaccination the mainstay of protecting people, supported by national guidance for healthcare workers on recognising and managing the disease. Patients need only standard precautions, since the virus does not spread between people, but where a haemorrhagic fever could equally be Crimean-Congo haemorrhagic fever it is managed as the latter until excluded. Because ocular and neurological complications can appear weeks after recovery, follow-up for at least a month is advised.

The comparison below sets Rift Valley fever against Crimean-Congo haemorrhagic fever, the other viral haemorrhagic fever endemic to South Africa, to highlight where the two diverge in vector, transmission and risk.

Feature	Crimean-Congo haemorrhagic fever	Rift Valley fever
Family, genus	Nairoviridae, Orthonairovirus	Phenuiviridae, Phlebovirus
Vector and reservoir	Hyalomma ticks (vector and reservoir)	Floodwater Aedes (maintenance), Culex (amplification) mosquitoes
Main route to humans	Tick bite, crushing ticks, livestock blood, nosocomial	Contact with infected animal tissue and blood; mosquito bite
Incubation	1 to 3 days after tick bite; 5 to 7 after blood contact	2 to 6 days
Hallmark severe disease	Haemorrhagic fever with hepatic necrosis and DIC	Hepatic and haemorrhagic disease, retinitis, encephalitis
Person-to-person spread	Yes (blood and body fluids)	Not documented
Biosafety level	BSL-4	BSL-3
Specific therapy	Ribavirin (contested)	None; supportive
Vaccine	None widely licensed (inactivated, Bulgaria only)	Veterinary vaccines; human candidates in trials

References and recommended reading

• Spiropoulou CF, Bente DA. Orthohantavirus, Orthonairovirus, Orthobunyavirus, and Phlebovirus. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2023. The principal source for the ecology, pathogenesis, clinical spectrum, diagnosis and prevention set out here.
• Barr JN, Weber F, Schmaljohn CS. Bunyavirales: The Viruses and Their Replication. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2023. The reference for the tripartite genome, the ambisense S segment, cap-snatching transcription and NSs biology.
• Mertz GJ, Ahlm C, Jonsson CB. Bunyaviridae. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. Background on the clinical virology of the bunyaviral zoonoses.
• Burrell CJ, Howard CR, Murphy FA. Bunyaviruses. In: Fenner and White’s Medical Virology, 5th edition. London: Academic Press; 2017. A concise account of phlebovirus classification, structure and replication.
• Jenkin D, Wright D, Folegatti PM, et al. Safety and immunogenicity of a ChAdOx1 vaccine against Rift Valley Fever in adults: an open-label, non-randomised, first-in-human phase 1 clinical trial. Lancet Infectious Diseases 2023;23(8):956-964. The source for the current human vaccine candidate and the One Health single-vaccine approach.
• National Institute for Communicable Diseases. Healthcare Workers Guidelines on Rift Valley Fever. Johannesburg: NICD; 2021. The source for the South African epidemiology, the 2010 to 2011 outbreak figures, transmission, diagnosis, notification and management set out in the South African context.