GENERAL INTRODUCTION: BUNYAVIRIDAE

Introduction and history

Rift Valley fever (RVF) is a peracute or acute disease that mainly affects domestic ruminants and humans caused by a mosquito-borne RNA phlebovirus.³⁴⁶ In domestic animals, the disease is most severe in sheep and goats, resulting in high mortality in new-born lambs and kids and high percentage of abortion in pregnant sheep, goats and sometimes cattle. The infection in humans is usually associated with mild to moderate febrile illness (i.e. fever, myalgia, arthralgia, lethargy), but can progress to severe sequelae including ocular lesions and loss of vision, encephalitis, a haemorrhagic disease with necrotic hepatitis and a high case fatality rate in a minority of patients. Humans usually become infected from contact with virus-contaminated tissues and body fluids from infected animals, but mosquito bites can also transmit the virus. Outbreaks of the disease tend to occur when particularly heavy rains favour the breeding of competent mosquito vectors.

Since original isolation in Kenya,¹³⁵ RVF virus (RVFV) has been contained for decades within the African continent, but in the last 30 years emerged outside its historic boundaries⁵⁹³ including crossing significant geographic barriers: the Sahara desert into Egypt in 1977,³¹⁹ the Indian Ocean to Madagascar in 1991,^{439, 440} and the Comoros Islands in 2007,³⁴⁹ and  the Red Sea to the Arabian Peninsula in 2000/01.⁵⁵⁷ The unpredictable and sudden emergence of RVFV outside traditional endemic areas, unavailability of safe and efficacious antiviral treatment and prophylactic immunization, led the World Health Organization (WHO) to identify RVF as a priority disease for development of effective therapeutics and vaccines.⁴¹⁴

There have been multiple reviews including Henning,²⁵⁸ Weiss,⁶⁴⁹ Easterday,¹⁶⁷ Peters and Meegan,⁴⁹⁹ Shimshony and Barzilai,⁵⁵⁶ and Meegan and Bailey.⁴¹⁰ The renewed interest in RVF as a significant zoonotic threat has been a subject of numerous reviews covering various aspects of the disease, including epidemiology, pathogenesis, control/prevention, development of new diagnostic assays, therapeutics and vaccines,^{7, 35, 63, 66, 74, 165, 191, 271, 274, 287, 320, 331, 337, 361, 368, 383, 405, 416, 477, 485, 486, 490, 494, 503, 522, 593} molecular biology and genomics, ^{76, 209, 231, 270} viral and host determinants of virulence,²⁷⁴ surveillance, predictive models and control strategies emphasizing the One Health concept^{67, 203, 246, 331, 429} and ecological, climatic and anthropogenic factors that play a role in RVF emergence, re-emergence and spread.^{107, 384}

An acute and highly fatal disease of lambs associated with heavy rains and accompanied by reports of illness in humans was first recognized in the Rift Valley in Kenya at the turn of the century, but the causative agent was not isolated until 1930.^{134, 431, 579} Major outbreaks were subsequently recorded in Kenya in 1930/31, 1968, 1978/79, 1997/98, 2006/07, 2014/15 and 2019 and lesser outbreaks at irregular intervals during the intervening years.^{145, 146, 410, 666}

The disease was first recorded in southern Africa in the early 1950s when a large epidemic occurred in the western Free State, southern Gauteng and adjacent North West and Limpopo provinces of South Africa, although it was only recognized as RVF early in 1951 when humans became ill after assisting at a necropsy of a bull near Johannesburg.^{15, 453} Sheep farming dominates in some of the affected areas and it was estimated that 100 000 sheep died and 500 000 aborted in the epidemic, with smaller losses occurring in cattle.⁵⁴² Lesser outbreaks of the disease or sporadic isolations of virus were recorded in South Africa in 1952/53, 1955/59, 1969/71, 1981, 1996, and 2018.^{25, 45, 283, 392, 395, 402, 629, 649} After more than a decade with minor reported RVF activity, large outbreaks affecting most of South Africa occurred in 2009/10.^{30, 82, 418, 657}

The diversity of clinical disease presentation in humans was recognized first in Kenya, and during the 1950/51 epidemic in South Africa, when it was recognized that RVF could be accompanied by transient loss of visual acuity and serious ocular sequelae.^{217, 234, 539, 540} Human deaths following natural infection were first recorded in South Africa during the epidemic in 1975 when seven patients died of encephalitis and haemorrhagic fever associated with necrotic hepatitis.^{232, 233, 394, 403, 633} Human deaths were also recorded during the 1978 outbreak in Zimbabwe.⁵⁹² Subsequently, human deaths were recognized during outbreaks in several countries, including a large epidemic which affected the normally arid north-eastern region of Kenya and adjacent part of Somalia after heavy rains in 1997/98.⁶⁶⁶

Since 1955 extensive outbreaks of the disease occurred at irregular intervals in southern Africa including Zimbabwe,^{109, 560, 585, 586} Mozambique,^{392, 393, 502, 626} and Zambia.^{12, 268}

Major epidemics (1977/78, 1993 and 2003) were recorded in Egypt and are summarized by Kenawy, Abdel-Hamid and Beier.³¹⁹ The first time that RVF was recognized outside eastern and southern Africa was during 1977/78, when  a major epidemic occurred along the Nile Delta and Valley in Egypt, causing an unprecedented number of human infections and deaths, as well as numerous deaths and abortions in sheep and cattle and some losses in goats, water buffalo (Bubalus bubalis) and camels. Estimates of the number of human cases range from 18 000 to more than 200 000 with at least 598 deaths occurring from encephalitis and/or haemorrhagic fever.^{408, 409, 410, 499, 556} There was a marked decline in the occurrence of RVF in Egypt after 1978, but isolated foci of infection were detected up to 1981, with the virus being associated with meningitis in humans.^{17, 123, 124, 131, 132, 323, 379} It seems likely that the virus is endemic in these areas with isolated periodic reports of virus activity in livestock.^{1, 6, 33, 319, 418, 657}

The first known excursion of RVFV  beyond the continent of Africa occurred in Madagascar in 1979 when the virus  was isolated from mosquitoes and a laboratory worker, but no naturally occurring livestock infections were recognized until 1990/91 and 2008/09 when widespread disease in livestock and humans was reported.^{211, 438, 439, 440, 442, 443}

Rift Valley fever made dramatic impacts for the first time in West Africa in 1987, when a severe epidemic occurred in the Senegal River basin of southern Mauritania and northern Senegal. In Mauritania during this epidemic alone 232 human patients died of the disease, and there was a high rate of abortion in sheep and goats.^{291, 292, 293, 294, 335} After 1987, the prevalence of antibody to RVFV in livestock declined steadily in Mauritania, until an outbreak affecting sheep and goats was recorded in the south of the country in 1993, and a larger outbreak affecting livestock and humans occurred in the Hodh El Gharbi region of the south in 1998, with one human death.^{339, 457, 677} In northern Senegal, antibody prevalence in livestock also declined after the 1987 outbreak, although isolations of virus from mosquitoes and a low level of seroconversions were recorded in continuous monitoring, indicating that RVF is endemic in the region. Smaller outbreaks occurred in sheep and goats in Mauritania in 1994/95, 2010 and 2012 with the largest and most widespread and recent outbreak reported in 2015.^{108, 213, 243, 319, 577, 578, 600, 601, 602, 605, 658, 678}

Severe outbreaks of RVF have also been reported in other African countries³¹⁹ including Rwanda in 2012 /14 and 2016-2018, Senegal  2013/14, Niger 2016, Somalia  2006/07, Sudan 2007/08, 2010 and 2017-2019, Tanzania 2007, Uganda 2016 , Chad 2018, the Republic of Guinea 2006, Democratic Republic of Congo 2012, and The Central African Republic 2019.³⁸

In September 2000, RVF was reported in the Jizan Province of southwest Saudi Arabia and in adjoining Yemen.⁵⁵⁷ These outbreaks lasted until early 2001, and resulted in 95 laboratory confirmed human deaths and the loss of thousands of sheep and goats.^{5, 42, 373, 557} There had been heavy rains in the inland mountain range which runs parallel to the coast, with drainage from the mountains resulting in the creation of ideal mosquito breeding habitats.³⁰³ The main vectors in the outbreaks were Aedes vexans arabiensis, which is a floodwater breeding aedine ideally suited to the flood irrigation farming practised in the affected area, and Culex tritaeniorrhynchus, which breeds in pools of water in the wadis and dams at the base of the mountains.³⁰³ There was speculation at the time that the virus may have been imported from Africa with animals, or carried from Africa by wind-borne mosquitoes in 2000, but there were no known epidemics in the Horn of Africa at the time. It is more likely that infected animals were imported during the large 1997/98 epidemic in East Africa, and that infection had gone unreported on the Arabian Peninsula until ideal circumstances for an epidemic occurred following heavy rains in 2000.⁵⁵⁷ Subsequent phylogenetic studies showed that RVFV that caused the outbreaks in Saudi Arabia was closely related to the virus of the 1997/98 epidemic in East Africa.⁵⁵⁷ Commercial trade of livestock from the Horn of Africa to the Arabian Peninsula consists of about 5-7 million live small ruminants, especially during religious festival periods.^{5, 38, 557} It remains to be determined whether the virus has become endemic on the Arabian Peninsula, but serological surveys indicate the potential for low-level ongoing transmission in the area.⁴¹⁵

Between 2006 and 2011, a resurgence of severe outbreaks of RVF was reported from East Africa,^{428, 462, 555, 568}  Madagascar,⁹ and South Africa,^{30, 657} and for the first time RVF was reported in livestock and humans in the Islands of Comoros from 2008/11 and  Mayotte in 2008 and 2018/19.³⁴⁹ These islands form an archipelago of volcanic islands situated off the south-east coast of Africa, to the east of Mozambique and north-west of Madagascar.

In late 2017, the detection of RVFV antibodies in livestock were reported in Turkey, Iran and Iraq although with no confirmed cases of livestock deaths or human illnesses.^{196, 249, 451, 524, 673}

Both legal and illegal trade of live livestock including camels from Sudan, Mauritania and other countries in that region may contribute to the spread of RVFV to North African countries.^{38, 75, 154, 179, 458} It raised concerns for further spread of RVFV to closest Asian (particularly Saud Arabia) and other parts of the world.^{10, 36, 38, 80, 107, 150, 163, 225, 253, 315, 351, 384, 494, 645, 675}

Since the virus can be transmitted by a wide range of mosquitoes, and livestock circulate sufficiently high levels of virus to infect mosquitoes, many parts of the world would probably be receptive to the virus.^{411, 611, 617} A recent (2020) European Food Safety Agency (EFSA) Opinion publication³⁸ stated that the risk of introduction of RVFV into the EU Member States through the movement of infected animals is very low, because of strict EU policies for the introduction of live animals from non-EU countries. Similarly, the risk of RVFV entry into the EU through infected vectors was considered very low or low, ,but  the probability of the establishment of RVFV transmission, once introduced, was considered to vary from moderate to very high for all EU countries.

Aetiology

Taxonomy and molecular biology

Rift Valley fever virus is a member of Phlebovirus genus, family Phenuiviridae of the order Bunyavirales.³⁷⁴ The viral particles are spherical, 80 to 120 nm in diameter (Figure 1), and consists of an envelope and a ribonucleocapsid (RNP). The envelope is composed of a host cell-derived lipid bilayer containing heterodimers of virus encoded glycoproteins, which are the building blocks of 122 capsomers¹¹⁸ (110 hexamers and 12 pentamers) arranged in T – 12 lattice.⁵⁵⁴ It has a three-segmented, single-stranded, negative-sense RNA genome of about 12 kb comprised of large (L, 6.4kb), medium (M, 3.8kb) and small (S, 1.6kb) segments. The L and M segments are of negative polarity. The L segment encodes the RNA-dependent RNA polymerase (L protein). The M segment encodes four proteins in a single open reading frame: the precursor to the structural glycoproteins Gn and Gc and two non-structural proteins designated NSm1 and NSm2. The S segment utilizes an ambisense orientation to encode two proteins, the nucleocapsid protein (N) and a non-structural protein (NSs).^{76, 238, 506} The NSs forms a ribbon-like filament in the nucleus ⁵⁷⁸, which is particular to RVFV and not shared with the NSs proteins of other bunyaviruses. Rift Valley fever virus replication cycle is similar to that of other negative-stranded RNA viruses⁷⁶ and involves three major processes: 1. attachment, uptake and fusion, 2.primary transcription, transcription and replication, and 3.virus assembly and release.

Figure 95.1 Electron micrograph of Rift Valley fever virus particles

All RVFV replication steps occur in the cytoplasm of infected cells and each segment is a template for replication and transcription.¹⁸⁴ The virus enters host cells by receptor-mediated endocytosis employing a class II fusion mechanism.^{204, 367} After uptake, RVFV is trafficked along the endocytic pathway towards the perinuclear localized lysosomes.⁵³⁶ The low pH in endosomal compartments triggers fusion of the viral envelope and endosomal membrane²⁰⁴ followed by genome release into the cytosol, where primary transcription of the genomic-sense RNA (vRNA) is initiated by the ribonucleoprotein-associated RNA polymerase. Messenger RNA (mRNA) transcribed from all segments is translated and viral proteins accumulate. During the replication cycle each vRNA from L-, M-, and S-segments is transcribed into mRNA and is replicated through a process that involves the synthesis of the exact copy of the genome, called complementary RNA (cRNA). The latter serves as templates for vRNA and vice versa. Newly formed vRNAs are encapsidated by N protein and associate with the L protein to form RNPs in so-called viral factories composed of Golgi complex.²¹⁰ Upon synthesis the Gn and Gc proteins exit the endoplasmic reticulum and accumulate in the membranes of the Golgi complex where virions are assembled through budding.²⁷⁴ Newly formed virions travel from Golgi complex to the plasma membrane where they are released. Systems to manipulate the genome of RVFV, including assembly of minigenomes, have been established and are advancing research on RVFV replication strategy and the development of new generation vaccines.^{76, 81}

Functions and role of RVFV-encoded proteins

The glycoproteins mediate cell receptor recognition, virus entry by binding to specific cell surface receptors(s) and virions escape from infected cells.²⁰⁴ Both Gn and Gc likely contribute to  virion assembly and interact with N protein.²⁵⁰ These glycoproteins induce the production of neutralizing antibodies, which play an important role in protection of animals against reinfection with the virus.^{266, 381}

The N protein seems not be involved directly in pathogenesis, but it is essential for virion capsid formation, interacts with glycoproteins, and is involved in transcription and replication.³⁶² The N protein is the most abundant protein in phlebovirus-infected cells and strongly immunogenic,^{376, 595} but it does not elicit neutralizing antibodies. However, immunization with recombinant N protein induces a partial immune protection in animals. The expression of type I IFN is upregulated in the liver and spleen of mice immunized with recombinant N shortly after RVFV challenge, compared to a delayed upregulation of the same gene in non-immunized mice. Furthermore, various genes with pro-apoptotic and pro-inflammatory effects are strongly upregulated, and anti-apoptotic genes downregulated in the liver of non-immunized mice.²⁸⁶

The M-segment encoded Nsm1 and Nsm2 proteins that were postulated to play a role in triggering apoptosis through the caspase 3, 8 and 9 pathways.⁶⁶³

The S-segment encoded NSs protein is the main virulence factor^{223, 236, 636, 662} inhibiting host innate viral defenses, primarily by counteracting the antiviral IFN system. This is achieved by a number of mechanisms at the transcriptional and translational levels, including suppression of general transcription, inhibition of IFN-β promoter and downregulation of double-stranded RNA-dependent protein kinase PKR early in infection.^{250, 275, 276, 311, 341, 597} Removal of the NSs gene results in attenuation of RVFV, which has been demonstrated in naturally attenuated⁴⁵² and in recombinant viruses⁵⁹ lacking this gene. NSs gene contains five cysteine residues,^{39, 40, 151, 181} which are highly conserved in all known isolates of RVFV.^{11, 527} Cysteine is a highly reactive, hydrophobic amino acid, capable of forming covalent disulphide bridges that stabilize the tertiary and quaternary structures of proteins. A genetic mutant of a highly virulent strain of RVFV was shown to be completely attenuated in a BALB/c mice model after a double cysteine-to-serine substitution at residues 39 and 40 of the NSs protein.⁴³⁰ Since the NSs protein is the major virulence factor by antagonizing IFN responses, the direct attenuation of NSs function potentially limits virus replication due to a lack of inhibition of the primary host immune response.

The NSs and NSm genes were shown to play a role in RVFV replication in mosquito vectors. RVFV lacking NSs and NSm failed to infect Aedes aegypti, and in Culex quinquefasciatus infection rates were lower than for wild-type virus. The double deleted viruses might represent an ideal safe vaccine due to their inability to efficiently infect and be transmitted by mosquitoes.¹²⁶

The evolutionary history, dispersal, and genomics of RVFV are discussed below (see Epidemiology)

Epidemiology

Vector ecology and virus transmission

Multiple risk factors influence the extent (both in time and space) of re-emergence and expansion of RVF outbreaks in endemic regions and their emergence in previously RVF-free areas. These include, environmental conditions, susceptibility and immune status of host animals (herd immunity), vegetation density, climate change, trade of live livestock, animal movement and distribution of vectors .⁴¹⁸. Current data suggest that more than 50 mosquito species, many of which with global distribution, can potentially act as vectors of RVFV.⁴¹⁸

The outbreaks of RVF that occurred in North and West Africa (e.g. Egypt, Mauritania and Senegal) in recent years differed in many respects from the pattern of disease which occurred in sub-Saharan Africa: in the former, outbreaks occurred independently of rainfall in arid countries, apparently in association with vectors that breed in large rivers and dams²¹⁴ It is possible that a proliferation in the construction of farm and river dams (e.g. along the Nile and Senegal rivers) facilitated the spread of RVFV. In contrast to the outbreaks of RVF in the drier parts of North Africa, epidemics in eastern, central and southern Africa have usually been associated with above average rainfall at irregular intervals of 5 to 15 years or longer.^{145, 397, 587} Meteorological conditions⁶⁶⁶ favouring the breeding of mosquito vectors of the virus usually prevail over large tracts of southern, eastern and central Africa so that there has been a tendency for outbreaks in adjacent territories such as Zimbabwe, Mozambique, Namibia and South Africa or Kenya, Uganda and Tanzania, to coincide.^{145, 335, 586} It is clear that the ecology of RVF is a prime example of how climate change and human-induced landscape alterations can impact the emergence and re-emergence of arbovirus diseases such as RVF.⁶⁵⁷

The flooding of dambos (also refer to as broad vleis) or pans in sub-Saharan Africa and the humid weather conditions prevailing in epidemics favour the breeding not only of the floodwater aedine mosquitoes but also of non-aedine mosquitoes that serve as epidemic vectors (see Vectors: Mosquitoes- a southern Africa perspective), as well as other biting insects that are potential mechanical transmitters of RVFV.⁹³ Eggs of species that breed in water, other than aedine mosquitoes, cannot survive dry conditions and these insects re-colonize flooded dambos or pans from suitably close rivers or dams, so that a succession of vector species occurs once flooding takes place.^{356, 357, 358, 365} Infected livestock circulate high levels of virus and mechanical transmission of infection by mosquitoes, midges, phlebotomids, stomoxids, simulids and other biting flies is thought to play a significant role in epidemics.^{140, 161, 212, 307, 345, 618, 633} Infected animals appear to be more attractive to mosquitoes, and by implication other biting flies and midges, than non-infected animals and it has been shown that probing for blood and feeding proceed more rapidly and efficiently on viraemic hosts.^{40, 521, 612}

Apart from mosquitoes, sandflies were shown experimentally to be capable of acting as biological vectors of RVFV, but this is not known to occur in nature.⁶¹⁹ Experimentally inoculated Hyalomma truncatum ticks were  able to transmit RVFV by bite, but transmission attempts with several species of ticks fed on viraemic hosts were unsuccessful, thus  ticks are not thought to play a role in the epidemiology of the disease.^{134, 321, 360, 401}

During times of heavy rain dambos in eastern, central and southern Africa and the panveld of the inland plateau in South Africa, may become flooded and the water may remain standing for several months. Dambos or broad vleis and pans constitute ideal breeding habitats for floodwater aedines. Under these conditions large populations of floodwater Aedes mosquitoes are produced initially, which are subsequently replaced by large populations of Culex mosquitoes. Infection rates in vector populations may be quite low even during epidemics, usually below 0,1 per cent, but enormous numbers of aedines emerge from flooded dambos or pans and vertebrates are subjected to high mosquito biting frequency.^{307, 353} Infected livestock and wild herbivores serve as a source of virus for mosquitoes and once infection is amplified in them, secondary or epidemic vectors such as Culex spp. and anopheline mosquitoes and other biting arthropods may become involved in transmission. It is notable that in southern Africa the onset of epidemics tends to be recognized late in summer following an initial increase in vector populations.

In southern Africa there is considerable arbovirus activity in the tropical region of Mozambique and the Zambezi Valley and in the subtropical, moist northern belt that extends westwards from Zimbabwe and embraces the Okavango swamps in northern Botswana, and the Zambezi Region (formerly Caprivi strip) and Etosha pan in north-eastern Namibia.^{70, 248, 329, 330} Unfortunately, a good understanding of the natural cycles of many arbovirus infections, and to some extent also RVFV, especially concerning the role of mosquito vectors and reservoir host vertebrates is lacking and often speculative. The mosquito catalogue⁴⁴⁴ website serves as a useful resource for determining the distributions of mosquito species and a review by Braack et al 2018⁷⁹ provides a comprehensive list of all mosquito species from which mosquito-borne arboviruses have been isolated from in Africa.

In contrast to the tropical and subtropical regions in southern Africa, the inland plateau in South Africa has virtually no rain from May to October, while dry winters from June to August are harsh and night temperatures are often near freezing. Dambos, pans and small dams may remain dry sometimes for many years at a time. Usually no major RVFV activity is recorded on the interior plateau of South Africa in the inter-epidemic period following major epidemics, such as the outbreaks of1974 to 1976, despite the occurrence of floods in many districts in the following 15 to 20 years. However, following heavy rains in 1996, in the northern and eastern parts of South Africa, a small outbreak of abortion caused by RVFV was reported among captive African buffalo (Syncerus caffer) in a boma in the Kruger National Park, but no spread of infection to the interior plateau was detected.²⁵

The isolation of virus from a wild-caught mosquito is in itself not conclusive evidence for its role as a vector, especially if virus isolates have been made from whole mosquito bodies, as viruses may not be efficiently transmitted by the saliva despite being in other body parts. However, clues to potential vector species can be gained if multiple isolates of the same virus are made from a single species. Follow-up vector competence studies and virus isolations from salivary glands of wild-caught mosquitoes for those species should then be performed to confirm vector status. Inability to maintain colonies of many specific mosquito species and lack of expertise and facilities to conduct these follow-up studies, especially in Africa, add to the reasons for the paucity of confirmed African arboviral vector mosquito species.

Apart from virus isolation from wild-caught mosquitoes, the lines of evidence incriminating a mosquito species as a vector are its susceptibility to infection with, and its ability to transmit the virus concerned (vector competence) plus its relative density and ecological characteristics. Vector competence is assessed quantitatively in laboratory tests while data on density and ecology are obtained by field observations. Relevant aspects of bioecology are relative density, seasonal dynamics, feeding behaviour (including time of biting activity, host preferences, feeding frequencies), larval habitat associations and biology of the immature stages. Together, vector competence and aspects of adult bioecology that affect and condition transmission are usually expressed as vectorial capacity, a concept which was developed by Garrett-Jones²³⁰ after the mathematical modelling for malaria by MacDonald.³⁷¹

Different species of the Aedes and Culex genera (see Vectors: Mosquitoes- a southern Africa perspective) are the main biological vectors of RVFV.^{300, 359, 361, 402, 403, 613} The order of RVF vectorial importance in southern Africa is Cx. theileri, Ae. circumluteolus, Cx. zombaensis, Ae. mcintoshi and Ae. juppi. Of the Aedes species, Ae. mcintoshi, Ae. circumluteolus and Ae.caballus  have the widest distributions in southern African countries such as South Africa, Mozambique, Namibia, Botswana and Zimbabwe.

Aedes circumluteolus (a savannah group member of subgenus Neomelaniconion) is widespread in Africa.^{173, 263} It is often one of the most prevalent of all mosquitoes during the summer in southern Africa.^{152, 305, 391, 399, 400, 667} It feeds opportunistically on mammals such cattle, sheep, antelope and humans.^{305, 400, 482} Of all the “Savanna” group Neomelaniconion species, Ae. mcintoshi (formely named Ae. lineatopennis) is the most widespread in southern and eastern Africa. It would seem that Ae. juppi is adapted to temperate conditions and is endemic to the temperate regions of southern Africa. The development cycle of Ae. juppi and Ae. mcintoshi from egg to adult can be as short as five days after inundation.³⁰²

In 1982 and 1984 the virus was isolated from unfed male and female Ae.mcintoshi mosquitoes (reported as Ae. lineatopennis) hatched in dambos on a ranch in Kenya during inter-epidemic periods, indicating that it may be maintained by transovarial transmission in aedine mosquitoes. It is obligatory that the eggs of these floodwater aedine mosquitoes be subjected to a period of drying as water recedes before they will hatch when wetted again during the next flooding cycle. This biological requirement may provide a mechanism for seasonal survival (overwintering) of RVFV.^{353, 364, 365} It is thought that RVFV infected aedine eggs can survive for long periods in dried mud, possibly for several seasons if habitats remain dry.^{229, 299} Moreover, it appears that only a proportion of eggs hatch at each successive flooding, which clearly represents a survival mechanism to prevent the entire mosquito population from being lost when precipitation has been inadequate to sustain breeding.³⁶⁴ The finding furthermore suggests that sexual transmission could occur from transovarially infected males to female mosquitoes.³⁵⁹ It should be noted that Scott et al.⁵⁴⁸ had decades earlier found evidence of inter- epidemic transmission of RVF infection in cattle in Kenya. Moreover, Alexander in 1957 had made reference to the isolation of RVFV from unspecified mosquitoes reared from eggs collected from a pan in South Africa in a publication that was overlooked for almost three decades, and which pre-dated the demonstration of transovarial transmission of any other virus in mosquitoes by 16 years.^{68, 359, 364}

Floodwater Aedes mosquitoes do not mate in insectary conditions, preventing them from forming colonies, and the few vector competence studies performed on them have been done on individuals reared from field collected larvae, which is not ideal. In South Africa, transovarial transmission tests and testing of mosquitoes reared from field-collected eggs have been undertaken to try to incriminate various floodwater Aedes spp. as reservoir vectors of RVFV.^{228, 300, 401} Such studies have so far been directed mainly at Ae. juppi and indicated that this species has a low vector potential, that it is only a subsidiary epidemic vector, and that it is not involved in vertical transmission of the virus.

In contrast to aedine mosquitoes, Culex spp. deposit their egg rafts on the water surface, where, depending on the temperature, they hatch within two or three days. These eggs cannot survive drying, hence the preferred types of larval habitat are permanent or semi-permanent ground pools. Culex theileri is widespread, occurring throughout the east and southern African region and the Mediterranean region, extending into the Northern Oriental region. (see Vectors: Mosquitoes- a southern Africa perspective).It is moderately ornithophilic, but also feeds on a wide range of other hosts such as goats, cattle, sheep and humans and serves as an arboviral bridge vector.^{18, 297, 304, 306} It has been implicated as a potential vector for several bunyaviruses.⁶³⁵ Theoretically it might be possible for some infected Culex spp. to overwinter and initiate transmission the next spring, especially as small numbers of Cx. theileri adults have been collected in the winter in Johannesburg, South Africa.^{296, 298}

Field studies during RVF epidemics have shown only very low infection rates in the mosquito vectors.^{392, 401} In addition, high vector competence evidently requires high levels of viraemia in the vertebrate host.^{398, 401} Despite this, a striking feature of RVF epidemics among sheep on the inland plateau of South Africa and other parts of Africa is the rapidity with which infection spreads through flocks, causing heavy losses. To account for the high level of infection, biological infection by mosquitoes is almost certainly augmented by mechanical transmission by various haematophagous Diptera including Stomoxys spp., Culicoides spp. tabanid species, and several species of Aedes and Culex.^{261, 307} In view of the intense viraemia which occurs in RVF it is likely that virulent virus may be transferred when animals are vaccinated in succession with the same needle during an epidemic, and incidents where this appears to have happened were observed in South Africa during the 1974 epidemic.¹⁸⁷

Although contagion has been demonstrated on occasion under artificial conditions, non-vectorial transmission is not considered to be important in livestock, as opposed to humans.^{639, 640, 649, 671}

A high degree of herd immunity develops in locations where infection is most intense, as judged by high morbidity, mortality and antibody rates, and it can be surmised that this must be one of the factors that contributes to the abatement of epidemics. Nevertheless, the large numbers of animals that were on occasion vaccinated during outbreaks of RVF must ultimately have contributed significantly to the abatement of epidemics.

Apart from aedine and culicine mosquito vectors in southern eastern and central Africa Ae. caspius, Cx. pipiens, Cx antennatus and Cx. perexiguus have been reported as the main potential vectors during RVF outbreaks in Egypt³¹⁹ while Ae. vexans and Aedes ochraceus serve as maintenance vectors and Ae.  dalzieli and Cx poicilipes as possible secondary vectors in West Africa^{155, 212, 213, 605, 678} and Saudi Arabia.^{303, 420} Culex poicilipes and Cx. tritaeniorhynchus, were also important vectors of RVFV in the Saudi Arabia outbreaks.^{155, 303}

According to EFSA Opinion and other publications.^{37, 107} the following potentially competent RVFV vectors are present in EU countries: Ae. vexans, Ochlerotatus caspius, Ochlerotatus detritus, Cx. pipiens, Cx. theileri, Cx. perexiguus, Cx. antennatus, Cx. ritaeniorhynchus, and Ae. albopictus. Of these Ochlerotatus caspius and Cx. pipiens are considered to be the most competent vectors.^{227, 446, 620} Culex pipiens (the main vector during the RVF outbreaks in Egypt in 1977/78) and Ae. albopictus are widespread in European countries^{89, 610} and competent to transmit RVFV.⁸⁹ Few vector competence studies have been done on European mosquito species. Studies on field-collected mosquitoes in southern France and Tunisia found that Cx. pipiens was the most competent mosquito vector while among laboratory-established colonies of mosquitoes species, Ae. aegypti was most competent.⁴⁴⁶

Vector transmission is a complex process requiring the virus to enter and cross multiple intra-mosquito barriers and compartments. Briefly, following the ingestion of an infective blood meal by a susceptible mosquito there is an extrinsic incubation period of approximately one to two weeks before transmission can occur. During this time, RVFV replicates in the cells of the midgut, escapes to the haemocoel and is disseminated via the haemolymph to replicate in the salivary glands and other organs, but in a proportion of mosquitoes infection is confined to the midgut, implying that there is a mesenteronal barrier to the spread of infection.^{200, 201, 520, 615} In a small proportion of mosquitoes there is rapid dissemination of RVFV via a ring of cells at the junction of the foregut and midgut.^{347, 348, 519} Transmission rates increase to 100 per cent in some species of mosquito if the mesenteronal barrier is by-passed by intrathoracic inoculation of virus, but in other species some or all individuals remain unable to transmit the infection, indicating that there may also be a barrier to infection at the level of the salivary glands.^{609, 615} Infection of mosquito salivary glands by parasites, such as plasmodia, can facilitate penetration and transmission of RVFV.⁶³⁴

The proportions of mosquitoes in which infection, internal dissemination of infection and transmission of virus occur, and the duration of the extrinsic incubation period, tend to be characteristic for each vector species and do not appear to be influenced by strain of RVFV. However, increased doses of virus, and higher ambient temperatures during extrinsic incubation produce disseminated infection in a greater proportion of mosquitoes and result in higher transmission rates and shorter extrinsic incubation periods.^{88, 201, 608, 614, 615, 622} Thus, apart from favouring the breeding of vectors, warm weather may be an accessory factor in precipitating outbreaks of RVF through increasing vector efficiency. Different populations of the same mosquito species may vary in vector efficiency if there has been genetic selection, as could occur in the course of establishing a laboratory colony.²²⁷

Infection of mosquitoes with RVFV causes morbidity and mortality as evidenced by reduced fecundity, inefficient feeding and lowered survival rates, but the effects are not uniform in all species and vary with stress imposed on the mosquitoes.^{160, 202, 484, 607, 616} Inefficient feeding by infected mosquitoes manifests as repeated probing and partial engorgement, and may actually increase vector efficiency since attempts to feed may be made on a series of hosts in succession and transmission can occur each time a host is probed whether or not a blood meal is obtained. It appears that mosquitoes inoculate virus extravascularly.⁶²⁴ Feeding on immune animals does not appear to affect the subsequent ability of infected mosquitoes to transmit infection.⁴⁸³

Schreur et al.^{55, 483} showed that RVFV can be transmitted to lambs by laboratory-reared Ae.aegypti mosquitoes that were infected either by membrane feeding or by feeding on lambs that developed viraemia after intravenous inoculation of RVFV. These experimental models can be useful to investigate mosquito-mediated transmission of RVFV and to evaluate the efficacy of vaccines against mosquito mediated RVFV infection.^{55, 483} It should be noted that to date RVFV has not been detected in Ae. aegypti collected from the field. This may be due to differences in susceptibility between laboratory-reared mosquitoes and field-collected mosquitoes, as well as because of host preferences. Aedes aegypti is mostly found in urban areas, whereas RVFV is most prevalent in rural areas where domestic and wild ruminants reside.^{55, 483, 642} The efficient experimental transmission of RVFV to lambs by Ae. aegypti is of concern as this mosquito species is the primary vector of also of other arboviruses with major public health impacts, including chikungunya virus, dengue virus, yellow fever virus, and Zika virus.^{55, 241, 483} Growing populations of humans and livestock as well as peri-urban agriculture particularly in Africa may in future result in urban transmission cycles of RVFV.

Virus maintenance in the inter-epidemic period

While the ecological drivers of most RVF outbreaks are relatively well understood, the central enigma that remains in the epidemiology of the disease concerns the fate of the virus during the inter-epidemic periods (IEP).

For decades it was widely accepted that the virus was endemic in indigenous forests, where it circulated in mosquitoes and unknown vertebrates, and that it spread to livestock rearing areas when heavy rains favoured the breeding of epidemic mosquito vectors. Unfortunately, there is no scientific proof for this theory. A search was made for potential feral vertebrate hosts of RVFV in Zimbabwe with emphasis on rodents, which had been implicated since the early investigations in Kenya,^{133, 134} but neither in Zimbabwe nor elsewhere has definitive field or laboratory evidence been obtained to confirm rodents in cryptic cycling of the virus, despite the fact that several species develop transient high-titred viraemia following infection.^{136, 149, 234, 235, 257, 390, 423, 547, 590, 596, 646, 665} Rift Valley fever virus was isolated from a rat (Rattus rattus) during the Egyptian epidemic of 1977/78,²⁷⁷ but the finding was not considered to be epidemiologically significant.^{262, 499, 556} Viruses isolated from rodents subsequent to the Egyptian epidemic are thought to be uncharacterized phleboviruses.⁵⁵⁶ Antibody has been demonstrated in rodent sera in South Africa in areas where the disease has not been recorded for decades, and although the antibody tests are of dubious validity, the findings have led to renewed interest in rodents as reservoir hosts elsewhere. Similarly, surveys and laboratory studies have failed to prove that the virus is maintained in transmission cycles in birds, monkeys, baboons or other wild vertebrates, although it was felt at that time that wild ruminants could play a role similar to their domestic counterparts in areas where they predominate, as discussed below.^{66, 137, 138, 139, 141, 147, 195, 289, 382, 402, 522, 586, 590}

In South Africa in particular, but also in other African countries, many private farmers rear wildlife for ecotourism, conservation, trophy hunting and game meat production. The game ranching industry in South Africa is now worth more than $700 million annually and game animals become infected with a range of mosquito-borne arboviral infections including RVFV. Mixed livestock and game animal farms/conservation areas create ideal opportunities for interactions between different arboviral reservoir host animal populations and bridge mosquito vectors.^{259, 570} This in turn creates added risks of viral transmission for farm workers and veterinarians, especially via exposure to infected carcasses.⁶³²

Although RVFV was isolated from unfed male and female Ae. mcintoshi mosquitoes (reported as Ae. lineatopennis) hatched in dambos on a ranch in Kenya during IEPs in 1982 and 1984, the role of vertical transmission in Aedes spp. in the maintenance of RVFV in the IEP has been poorly studied.³⁶⁸ Recently vertical transmission of RVFV in colonized Cx. tarsalis mosquitoes has been reported in the laboratory ^{55, 483, 537} Specifically, it is not known if this transmission mechanism alone is sufficient to maintain RVFV endemicity, or if a continuous low-level virus amplification in domestic animals and wildlife is required to maintain the virus in the environment during IEPs⁶⁶ Numerous serological studies showed that there is continuous cryptic low-level virus transmission of RVFV during  IEPs ,without noticeable outbreaks of disease or clinical cases, particularly in less susceptible domestic livestock such as cattle, goats, camels as well as wildlife in different African countries (e.g., South Africa, Mozambique, Sudan, Kenya, ) and would seem to be important in the maintenance of RVFV.^{32, 38, 77, 95, 106, 182, 189, 264, 282, 322, 359, 361, 385, 387, 449, 477, 494, 516, 522, 582, 583, 627, 628} Rift Valley fever virus transmission during IEPs has also been  reported in humans in Tanzania,²⁵⁵ Kenya,³³⁶ Gabon⁵¹⁰ and Botswana.⁵³³

While field studies have shown infection with RVFV of both male and female Aedes mosquitoes reared from field-collected larvae in Kenya, these original findings could not be subsequently confirmed, and demonstration of transovarial transmission is hampered by the difficulty in establishing laboratory colonies of Aedes mosquitoes. It has been demonstrated that the larvae of Cx. pipiens, Ae. mcintoshi and Ae. circumluteolus can become infected after feeding on liver homogenates from an experimentally inoculated hamster but the epidemiological importance of this finding is not clear.⁶¹⁸

Rift Valley fever virus activity during the IEP in wildlife, certain domestic livestock and humans highlights the importance of a continuous cryptic endemic transmission cycle and virus evolution in suitable epidemiological/ecological settings. Clinical signs in these susceptible species are often mild or subclinical and are either underreported or misdiagnosed.⁴⁹⁰

The susceptibility of different livestock species and African wildlife species are discussed below (see Clinical signs).

Evolutionary history, dispersal, and genomics of RVFV

The evolutionary history of RVFV has been influenced by dramatic changes in the environment and land use throughout Africa in the past 150 years. Over this time span multiple levels of virus evolution have occurred, ranging from the macroscopic geographic translocations of virus genotypes across Africa to the molecular point-mutations and genome segment reassortment events.^{48, 61, 62, 71, 97, 218, 244, 525, 527, 529, 530, 557, 558, 576, 668} Genomic reassortment or homologous recombination are both potent mechanisms to generate genetic diversity and can eventually drive the emergence of novel RVFV variants. The reassortment of RNA genome segments within virus species such as RVFV and within other species of the order Bunyavirales and family Phenuiviridae has been reported frequently in both in vitro and in vivo studies; however, cross-species or cross-genera reassortants (e.g., Batai, Bunyamwera and Ngari viruses) occur less frequently.^{50, 51, 61, 73, 78, 84, 85, 103, 104, 237, 244, 529} In contrast, little evidence of homologous recombination among RVFV has been reported.^{61, 105, 244, 283, 338} Potential reassortant events have been identified involving each of the three RVFV genome segments (i.e., S segment: Lineage B viruses, M segment: Kenya 2006/07 strain #0608, L segment: CAR strain 73HB1230 and other examples).^{61, 62, 244, 283} The impact of these reassortment and potential recombination events on RVFV replication, fitness, and most importantly host pathogenicity is not fully known and requires further study.

As a consequence of the expanding genome sequence database, the number of identified lineages of  RVFV has increased from three in early analysis by Sall et al.⁵²⁶ to 15 lineages (designated A-O) in the recent publication by Grobbelaar et al.²⁴⁴ Lineage A contains isolates from North Africa, lineages B-M and O contain isolates from east, central and southern Africa, and lineage N groups isolates from West Africa. The sequence database makes it possible to estimate the number of years prior to the present that the progenitor of the known RVF viruses was in circulation.^{128, 364} Recent Bayesian analysis suggests that the time of RVFV divergence from the  most recent common ancestor (TMRCA) occurred relatively recently, with mean values of the TMRCA coalescing towards 90 to 140 years before the present, i.e., approximately 1880 to 1930.^{61, 62, 380} This time of origin and original dispersal from the ancestral homeland of the virus is broadly consistent with the early reports from Kenya at the beginning of the 1900s of a disease resembling RVF among animals. It also coincides with a time period of major ecological changes in eastern and southern Africa, with the establishment of colonial agriculture systems and the importation of large numbers of highly susceptible European breed livestock.^{251, 262}

However, despite extensive geographic dispersion, wide range of susceptible arthropod vectors and vertebrate hosts, and natural occurrence of reassortment,^{48, 529, 531, 623} RVFV displays low genetic diversity. Irrespective of the genome segment analysed, the genetic diversity is approximately 4 per cent at the nucleotide and 1 per cent at the protein coding levels^{61, 62, 244, 380} The low genetic diversity of RVFV may reflect the evolutionary constraint imposed on arboviruses by their altering replication in mammalian and arthropod hosts.⁶² It has been shown that serial passages of RVFV in baby hamster kidney cells 21 (BHK-21) or Aedes aegypti cells (Aag2) results in large deletion of the NSs gene, while serial alternating passages between BHK21 cells and Aag2 did not induce this deletion. These findings indicate that host alternation is important to maintain stability of the NSs gene, thereby promoting the virus capacity in evasion of the innate immune response.⁴⁴⁷ Nevertheless, the minor nucleic acid and deduced amino acid differences that have been reported could account for differences in pathogenicity.^{19, 48, 98, 496}

While no distinctive mutually exclusive correlation of virus genotype, virulence in livestock and humans, or geographic location can be observed with RVFV, virus isolates from one area tend to cluster together within each lineage, but virus genetic variants with distant origins are found within different lineages, providing evidence of widespread dispersal of RVFV throughout Africa. The magnitude of this long-distance and repeated translocation can be found by the monophyletic linkage of isolates from regions as distant as Egypt, Madagascar, and Zimbabwe or Kenya, Mauritania, Burkina Faso, Zimbabwe, and South Africa. The strong phylogenetic linkage of virus strains from distant geographic locations suggests that the movement of infected livestock and the dispersal of mosquitoes may account for the spread of RVFV throughout continental Africa, Madagascar, and the Arabian Peninsula.^{61, 244, 532} On the other hand, could it be that these virus strains have been present in these distant geographic locations and only now detected with the availability of improved molecular techniques?

During the 1977/78 epidemic in Egypt it was speculated that the transportation of infected sheep and cattle on the Nile river or overland from northern Sudan to markets in southern Egypt was the strongest possibility, and that movement of animals for slaughter by sea could account for the presence of antibody detected in the north and eastern coastal areas.^{222, 262, 409, 551} Although transportation on some routes could take a long time in relation to the course of the infection, RVFV antigen can persist particularly in the spleen, for up to 21 days after infection. Humans slaughtering or handling the tissues of such animals could have become infected and possibly served as the amplifying hosts for the infection of mosquitoes, since the putative vectors in Egypt include Ae. caspius, Cx. pipiens, Cx. attenuatus and Cx. perexiguus, which are known to feed on livestock and humans.^{221, 223, 224, 262, 288, 379, 620}

Likewise, the results of phylogenetic studies demonstrated that the RVFV detected on the Arabian Peninsula in 2000 was closely related to the virus that had caused the 1997/98 epidemic in East Africa.⁵⁵⁷ As stated above it is likely that infected animals were imported during the large 1997/98 epidemic in East Africa, and that infection smouldered until heavy rains precipitated the epidemic in 2000. Travelling time for animals exported from infected areas can be as little as 48 hours, well within the usual incubation period of the disease.

In previously RVFV-free countries/regions, RVF outbreaks result from the spread of a single lineage⁶² Early detection of the large 2006/07 RVF outbreaks in East Africa provided an opportunity to conduct more detailed molecular epidemiology studies. Genome segment sequences obtained from domestic livestock and wildlife and representing all affected regions of Kenya were all monophyletic with a virus isolate from the previous 1997/98 outbreak in East Africa. However, among the 2006/07 viruses analyzed, two separate sub-lineages (Kenya-1 and Kenya-2) were identified with increased genomic diversity relative to that observed among RVFV isolates from the Egyptian 1977/78 and Mauritanian 1987 outbreaks.⁶¹ Results from a similar study analysing RVFV isolates from humans and mosquitoes in Kenya and Tanzania indicate that the sequential RVF epidemics in the region were caused by 3 distinct lineages (Kenya-1, Kenya-2, and Tanzania-1), sometimes independently activated or introduced in distinct outbreak foci.⁴⁶⁰ While the shared evolutionary history of the 1997/98 and 2006/07 outbreak viruses was apparent based on phylogeny, further population genetics studies on Kenya-1 and Kenya-2 lineages revealed that the two lineages were more closely related to the 1997/98 RVFV prototype than to each other, indicating ongoing and separate evolutionary patterns since the previous outbreak. Moreover, it appears that the Kenya-1 lineage viruses had recently undergone geographic or spatial expansion, whereas the Kenya-2 lineage viruses had likely not. Interestingly, the timing of the Kenya-1 expansion event was calculated to have occurred approximately 2-4 years prior to the detection of the 2006/07 outbreaks. These results indicate ongoing RVFV activity and evolution during the inter-epidemic period and highlight the importance of a cryptic endemic transmission cycle that allows for the establishment of RVFV endemicity and to precipitate explosive outbreaks.

Results of a molecular epidemiology study by Soumaré et al⁵⁷⁶ suggest that Barkedji was a “hub” associated with three distinct introductions of the virus in Senegal from where it was then spread to other localities in West Africa. Barkedji, situated in the semi-arid region of central Senegal, was previously postulated to play a role as an important gateway for RVFV into Senegal and Mauritania based on serological and entomological surveys.^{605, 677, 678} It is an important crossroad of migration movements of wildlife between the southern and northern regions of Senegal, and to a larger extent, to southern Mauritania. Dispersal distances of most RVFV vectors from their breeding sites is short, and  is estimated to be about 1 km, varying from less than 150m for Aedes spp.to approximately 2 km for Cx. theileri.^{222, 553} Long-range dissemination of the virus in certain parts of Africa could be the result of infected members of roaming herds of livestock or wildlife.³³⁶

Mosquito bites constitute the principal infection mechanism of RVFV in animals, but the different dynamics of the virus spread during large epidemics suggest that other transmission mechanism may also exist. Results of space-time analyses of RVF outbreaks in South Africa in 2008 to2011 confirm the presence of an intense, short, initial transmission mechanism, which could be attributed to active vector dispersal, and highlight the presence of another transmission mechanism of lower intensity and over distances up to 40 to 90 km, within about 2 weeks. The appearance of long-distance spread could be explained by emergence of the virus at several foci as a result of hatching of infected Aedes eggs or multiple re-introductions of infected vectors, but as previously stated the importance of transovarial infection in aedine mosquitoes in the epidemiology of RVF remains speculative and must be further substantiated.⁴¹⁹

Host susceptibility

The susceptibility of livestock, wildlife and humans is discussed below (see Clinical signs)

Pathogenesis

Differences in virulence and lethality of RVFV isolates have been observed during the experimental infection of BHK cells,⁶⁵⁹ mice,⁴³³ sheep,⁴⁴⁷ and cattle.⁶⁵⁹ Mice inoculated intraperitoneally with different wild-type strains (ZH501, Kenya 9800523, Kenya 90058, Saudi Arabia 200010911, OS1, OS7, SA75, Entebbe, or SA51) showed that RVFV strains of different genetic lineages display distinct virulence in outbred mice, although those strains are antigenically similar.²⁷² Given the role of NSs as a major virulence factor for RVFV,^{57, 76, 250, 275} variability within its amino acid sequences could possibly account for the phenotypic differences between different virus strains.

The pathogenesis of RVF encompasses the spread of virus from the initial site of replication to critical organs such as spleen, liver and brain, which are either damaged by the lytic effects of the virus or immunopathological mechanisms, or else there is recovery mediated by non-specific and specific host responses.⁴⁹⁶ By analogy with the course of events believed to follow natural infection with other arthropod- borne viruses, it can be assumed that there may be an initial transient viraemia that of too low an intensity to be detectable or, more likely, that virus is conveyed from the inoculation site by lymphatic drainage to regional lymph nodes where there is replication and spill-over of virus into the circulation to produce primary viraemia. This in term leads to systemic infection with intense viraemia that results from release of virus following replication in target organs. Within this basic pattern there are individual and species-related variations in manifestation of disease, as exemplified by the different responses to experimental infection observed in mice, rats and rhesus monkeys.

In in vitro cultures, RVFV replicates in cells derived from virtually all tissues except primary macrophages and lymphoblastoid cell lines, yet in intact animals macrophages are infected. There is also selectivity for certain other tissues, as indicated by the demonstration of viral antigen in rats by immunofluorescence in littoral macrophages of lymph nodes, most areas of the spleen except T-dependent periarteriolar sheaths, foci of adrenocortical cells, virtually all cells of the liver, most renal glomeruli and some tubules, and scattered small vessel walls, as well as in necrotic foci in the brains of individuals with the encephalitic form of the disease.^{23, 496} In addition, the presence of diffuse virus antigen has been demonstrated in lung tissue in a rhesus monkey.⁴⁹⁷ The sites of virus replication inferred from the immunofluorescence studies correspond to the lymphoid necrosis in lymph nodes and spleen, hepatic necrosis and adrenal, lung and glomerular lesions seen in humans and livestock.  Immunohistochemistry staining of tissues of naturally infected adult sheep with RVFV showed positive antigen staining in a variety of cells including hepatocytes, adrenocortical epithelial cells, renal tubular epithelial cells, macrophages, neutrophils, epidermal keratinocytes, microvascular endothelial cells and vascular smooth muscle.⁴⁶⁸ In lambs (< 1-month-old) and foetuses viral antigen was detected in the aforementioned cells but also in renal juxtaglomerular and extraglomerular mesangial cells, cardiomyocytes, Purkinje fibres and skeletal muscle cells.^{470, 471} The results of titration of infectivity in organ homogenates indicate that liver and spleen are the major sites of virus replication.^{23, 496, 497}

Rift Valley fever virus, which attaches to receptors on susceptible cells, is internalized by endocytosis and replication occurs in the cytoplasm.²⁴ The non-structural NSs protein synthesized during replication enters the cell nucleus and forms the filamentous intranuclear inclusions seen histologically in RVF-infected tissues.^{328, 580, 581, 589} The carboxy terminal domain of the NSs protein is essential for formation of the filamentous structures, but not for intranuclear localization of the protein.⁶⁶⁹

Viraemia may become demonstrable in lambs less than one week old within 16 hours of peripheral infection with small doses of RVFV, and persists for the duration of the illness, which may terminate fatally within 36 to 42 hours.^{167, 168, 171} In older sheep, goats and cattle viraemia becomes demonstrable one to two days after infection and persists for up to seven days, usually being most intense on the second to fifth days after infection.^{167, 170, 171, 398, 594} Maximum titres of viraemia recorded were 10^10.1 MIPLD₅₀/ml (mouse intraperitoneal 50 per cent dose /ml) in lambs, 10^7.6 in sheep, 10^7.5 in calves, 10^8.2 in kids, and 10^5.6 in goats,^{168, 170, 171} although individual animals may fail to develop demonstrable viraemia.⁵⁹⁴ Virus has been shown to persist in visceral organs of sheep, particularly spleen, for up to 21 days after infection.⁶⁷¹ Viraemic titres of up to 10^8.6 MICLD₅₀/ml have been recorded in human patients.⁴⁹⁹

Viraemia of similar intensity and duration to that in domestic ruminants has been demonstrated in hamsters, mice, some laboratory strains of rat and various wild rodents.^{169, 206, 390, 396, 423, 424, 425, 496, 590, 646}  Viraemia of lower intensity and shorter duration has been detected in other animal species that have been studied, but quantitative tests were performed in a few instances only. Maximum intensities of viraemia recorded were 10^5,4 TCID50 (tissue culture 50 per cent infective doses/ml) in African buffalo, 10^4,9 MICLD50/ml in dogs, and 10^2,5 MIPLD₅₀/ml in ponies.^{141, 639, 672}

The peracute hepatic disease seen in mice given large doses of virus^{422, 423, 424, 425, 426, 496} most closely corresponds with that which occurs in other extremely susceptible hosts such as new-born lambs and kids.^{114, 117, 119, 168, 171} Other age groups and species of farm animals and humans commonly experience benign infection, but as with rhesus monkeys,^{125, 434, 497, 498} a variable proportion of adult sheep, cattle and goats and a small proportion of humans develop the fulminant hepatic form of the disease. In these hosts, however, hepatic necrosis may be a less dominant lesion than in mice, with evidence of lymphoid necrosis, vasculitis, nephrosis and haemorrhagic manifestations being relatively more prominent.^{118, 497, 633} The three genotypic responses of inbred rats to infection — highly susceptible in which there is rapidly fatal hepatic disease, moderately susceptible in which only a proportion of individuals die of encephalitis 7 to 28 days after infection, and resistant^{23, 90, 501} — mimic the disparate human phenotypic responses of fatal hepatic disease, encephalitis and benign infection.^{496, 501, 633} It is curious that the encephalitic form of the disease has not been reported in natural infection of ruminants, although it was described in a calf infected peripherally with wild virus.⁵¹⁵ Factors contributing to fatal outcome in the hepatic form of the disease include anaemia, shock and hepatorenal failure, with the kidney lesions possibly being as important as shock in producing anuria.⁴⁹⁶

Lesions in target organs such as the liver in the acute disease are produced by the direct lytic effect of the virus on infected cells. In the liver of new-born lambs, for instance, there is initial cloudy swelling and hydropic degeneration of randomly scattered hepatocytes, which soon become necrotic as manifested by acidophilic cytoplasm and pyknotic nuclei. The lesions rapidly progress to form scattered primary necrotic foci of five to eight affected hepatocytes, with the presence of acidophilic cytoplasmic or apoptotic bodies resulting from cytolysis, and infiltration of neutrophils. As the primary lesions enlarge, numerous degenerated and necrotic hepatocytes and acidophilic bodies appear throughout the parenchyma. Ultimately there is massive necrotic hepatitis in which the residual primary foci can still be recognized as dense aggregates of cellular debris infiltrated by leukocytes.^{117, 168}

The haemostatic derangement that occurs in RVF has been investigated in detail only in rhesus monkeys, and the mechanisms involved remain speculative.^{125, 497} Impairment of coagulation occurs even in benign infection in monkeys,^{125, 497} and it is notable that moderate thrombocytopenia has been observed in benign infection in sheep.⁵⁹⁵ However, haemostatic derangement is most severe in the fatal hepatic syndrome, which manifests as a viral haemorrhagic fever with bleeding tendency and evidence of disseminated intravascular coagulopathy.¹²⁵ Viraemia is intense and prolonged in individuals that develop the haemorrhagic syndrome, indicating that there is impaired clearance of viraemia and extensive dissemination of virus with attendant widespread tissue damage, and it is postulated that the critical lesions in the development of the haemorrhagic state are vasculitis and hepatic necrosis.^{125, 497, 498} Destruction of the antithrombotic properties of endothelial cells is thought to trigger intravascular coagulation, and the widespread necrosis of hepatocytes and other affected cells to result in the release of procoagulants into the circulation. Severe liver damage presumably limits or abolishes production of coagulation proteins and reduces clearance of activated coagulation factors, thereby further promoting the occurrence of disseminated intravascular coagulopathy, which in turn augments tissue injury by impairing blood flow. Vasculitis and haemostatic failure result in purpura and widespread haemorrhages.

Ocular lesions may occur as a complication to RVF infection in humans, occasionally appearing at the time of the acute febrile illness but usually up to four weeks later.^{122, 153, 217, 234, 377, 413, 539, 540, 564, 565} Reports of long term sequelae including permanent vision deficits and even blindness have increased the need for follow-up investigation of this potential outcome among human patients.^{13, 461} The essential lesion appears to be focal retinal ischaemia, generally in the macular or paramacular area, associated with thrombotic occlusion of arterioles and capillaries, and is characterized by retinal oedema and loss of transparency caused by dense white exudate and haemorrhages. Sometimes there is severe haemorrhage and detachment of the retina. Ocular lesions have not been recorded in limited experimental observations in infected rhesus monkeys or ruminants.^{114, 168, 435}

Encephalitis occurs from one to four weeks after the acute febrile illness in a small proportion of human RVF patients.^{340, 370, 413} Virus only appears in the brain at a late stage in rats that succumb to encephalitis, by which time viraemia and infection and lesions of viscera are no longer demonstrable, and circulating antibody is already present; hence it is suggested that there is an immunopathological basis to the encephalitic syndrome in addition to the direct cytopathic effects of the virus.⁴⁹⁶ In the brain there are focal necrotic lesions with associated polymorphonuclear cell infiltration as well as mononuclear cell infiltration and perivascular cuffing, which suggest participation of T-cells specialized for delayed hypersensitivity or cytotoxicity.^{496, 633} Complete or partial protection of highly susceptible laboratory animals against the fatal disease can be achieved by the administration of antibody, interferon inducers, recombinant interferon, interferon-induced proteins, or chemotherapeutic agents, (e.g., ribavirin or T705), but sometimes suppression of the usual rapidly fatal hepatitis can lead to the development of the late encephalitic form of the disease.^{54, 219, 496, 534, 535, 566, 567, 680, 681}

Work conducted using aerosol challenge in Sprague-Dawley rats and African green monkeys has established robust animal models of RVF encephalitic disease and revealed marked associations of survival with early increased proliferation of CD4+ and CD8+ lymphocytes and early induction of pro-inflammatory cytokines including gamma interferon (FN-γ), interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1) and antiviral (IFN-α) responses following infection, with late stage alterations after virus invasion of the central nervous system in vascular permeability mediated by matrix metalloprotease-9 (MMP-9) prior to death.^{254, 644, 664}

Abortion is the typical, but not universal, outcome to infection of pregnant sheep, cattle and goats but it has also been reported in other animal species including camels and African and Asian buffalo.^{26, 350, 409, 670} Abortions which occur soon after infection may be related to the febrile illness of the dam since there may be no evidence of foetal infection, but in most instances abortion follows foetal death with lesions in the foetus resembling those in new-born lambs, including extensive hepatic necrosis.^{114, 118, 649, 670} However, the brain is also frequently infected and virus or antigen can usually be recovered from foetal viscera and brain.^{560, 585, 586} Virus can be isolated from the placenta and viral antigen was demonstrated in sheep in epithelial (syncytial) cells of the maternal villi and foetal trophoblasts.^{595, 678} Widespread necrosis of these cells may cause abortion.^{471, 480, 586, 670} Septic metritis can occur as a sequel to retention of the placenta, which commonly follows abortion. In a recently described pregnant rat model direct infection and crossing of the placental barrier appears to be a primary mechanism of foetal infection.⁴⁰⁴ This promising development could allow for the in-depth investigation of RVF-induced foetal infections,but structural differences between ruminant, human, and rodent placentation should be considered before direct extrapolation and interpretation of results. In humans, an attempt to relate the occurrence of abortion to evidence of RVF infection in Egypt produced inconclusive results,^{3, 413} but recently human miscarriage and vertical transmission events reported RVFV as the causative agent.^{8, 31, 49} (see Clinical signs).

Another potential foetal adverse event associated with RVFV has been demonstrated among foetuses of ewes inoculated with the live-attenuated Smithburn vaccine strain at 42 to 74 days of gestation may develop various brain and other anomalies such as porencephaly, hydranencephaly and micrencephaly as well as arthrogryposis, which in some cases is associated with hydrops amnii, prolonged gestation and dystocia.¹¹⁵ This vaccine strain was prepared by serial passage intracerbrally and peripherally in rodents and likely has retained high-level neurotropism in foetuses and should be used with caution in pregnant animals.^{16, 571}

The congenic progeny produced by cross-breeding of susceptible and resistant strains of rat exhibit the fulminant hepatic and benign phenotypic responses to infection in approximately equal proportions, suggesting that resistance is inherited as a simple Mendelian gene of large effect, which does not appear to be linked to genes of the major histocompatibility complex.^{21, 496} Work with whole genome scanning of cross-bred rats used historically in studies of the RVFV stain ZH-501 (highly susceptible Wistar-Furth lineage with highly-resistant Lewis lineage rats) has revealed a genetic locus on chromosome three of as yet undetermined function that underlies this differential susceptibility.⁹¹ The same appears to be true for other vertebrate species. It has been found, for instance, that when gerbils (Meriones unguiculatus) are infected with minimal doses of virus about half will die, while the mortality is not increased significantly by administering high doses, i.e. half the gerbil population is susceptible to the lowest dose inoculated and half resist the highest dose.⁴⁹⁶ It has been estimated from figures generally reported for mortality during epidemics that up to one third of sheep may be susceptible to fulminant hepatic disease, and it is suggested that it may be possible to breed resistant flocks.⁴⁹⁶ This is a promising area of research, but complicated by the background of genetic diversity with respect to resistance to RVF even within well-defined inbred strains of laboratory animals.⁵¹⁷

The understanding of the exact molecular mechanisms underlying virulence and genetic resistance in animal models and humans to RVFV remains an area of intense research.^{74, 91, 151, 366, 495, 643, 679}  Immunosuppression of resistant of moderately susceptible rats with cyclophosphamide, which inhibits humoral response but not interferon production, reduces but does not entirely abolish resistance to RVF. This effect can be reversed by passive administration of antibody.^{23, 496}  Moreover, viraemia and organ titres of infectivity are already very different in susceptible and resistant strains of rat by 24 hours post-infection, which suggests that factors which determine the outcome of infection are operative before humoral and cell-mediated immunity can be activated.⁴⁹⁶ Fibroblast or macrophage cultures derived from susceptible and resistant rats do not differ in their abilities to support or resist RVFV replication, but somewhat higher titres of virus are achieved in cultures of hepatocytes derived from susceptible as opposed to resistant rats.^{24, 496}

Clinical signs

Despite large amounts of data regarding individual species susceptibility, it should be noted that the pattern of RVF can differ across individual herds and flocks, between separate epidemics, and during the course of a single epidemic. For instance, disease may predominate in either sheep or cattle at a particular location or stage of an epidemic, and outbreaks, which occur after long intervals or in new locations, may be characterized initially by abortions and disease of adults, and at a later stage of the outbreak, by disease of neonatal or immature animals.^{109, 135, 177, 240, 335, 542} It is understandable that abortion and disease of adult animals should be the major manifestations when an epidemic occurs in an immunologically susceptible herd or flock at a critical stage of the breeding cycle, or that disease of neonatal animals predominates after lambing or calving has taken place. Immune ewes confer colostral immunity on their lambs that is protective for up to five months,⁵⁷¹but it was observed in the 1974 to 1976 epidemic in South Africa that lambs subjected to attack by large numbers of mosquitoes as soon as they were born could undergo irreversible infection before colostral immunity became effective.¹⁸⁷

The clinical signs of RVF in livestock have been reviewed by several authors.^{135, 156, 167, 188, 206, 258, 477, 556, 649} Signs of the disease in domestic ruminants tend to be nonspecific, rendering it difficult to recognize individual cases of RVF. During epidemics, however, the simultaneous occurrence of numerous cases of abortion and disease in ruminants, together with disease of humans, tends to be characteristic of RVF. Figures for morbidity and mortality rates can be derived accurately for specific animals in the laboratory, but the perceived figures in the field vary with challenge rate, herd immunity and predisposing conditions. Factors that determine the morbidity and mortality associated with outbreaks of RVF include the virulence of the strain of virus and the susceptibility of the vertebrates involved.^{19, 21, 496, 501, 603, 606} Vertebrates are usually classified with respect to susceptibility to peripheral infection with RVFV on the basis of laboratory and field observations (see Table 1).^{19, 133, 134, 135, 139, 144, 147, 167, 168, 169, 170, 171, 205, 206, 208, 390, 410, 427, 496, 546, 556, 590, 639, 640, 646, 649, 660} In some instances extrapolations of mortality rates have been based on very few laboratory observations, while in other instances there are marked discrepancies in the patterns of disease observed in the field, which can partly be explained on the basis of differences in challenge rate and age, acquired immunity and reproductive status of the animals involved, as discussed below.

Most laboratory observations on the pathogenicity of RVFV for farm animals were made in breeds exotic to Africa and many of the experiments were conducted outside the continent. It has been suggested that exotic sheep and cattle are less resistant to RVF than indigenous African livestock,¹³⁸ but it was shown that West African and Egyptian sheep are highly susceptible to experimental infection.^{475, 603, 618}     Moreover, indigenous livestock were severely affected by the disease in the 1973, 1977/78 and 1987 RVF epidemics in the Sudan, Egypt and West Africa, respectively.^{176, 335, 386}

Although new-born lambs are extremely susceptible and can be infected lethally with as little as 0,1 MIPLD₅₀ of RVFV, it is frequently difficult to produce disease in non-pregnant sheep and cattle with high doses of ostensibly virulent virus.^{111, 171, 194, 252, 545, 595}

Sheep and goats

In new-born lambs and goat kids the incubation period may be as short as 12 hours but is usually 24 to 36 hours. Onset of the disease is marked by the development of fever which may exceed 41 °C and which is often biphasic with a remission of 12 to 18 hours following the initial rise in rectal temperature. The fever subsides sharply a few hours prior to death. Affected animals are listless, disinclined to move or feed, and evidence of abdominal pain can be elicited. Respiration is rapid and often abdominal in terminal illness. The course of the disease is usually peracute and lambs rarely survive longer than 24 to 36 hours after the onset of the first signs of illness; many are simply found dead. In animals less than a week-old mortality is 90 per cent or greater.

Lambs and kids older than two weeks and mature sheep and goats are significantly less susceptible than new-born lambs to RVFV and may develop inapparent, acute or peracute disease. In the peracute disease animals die suddenly without exhibiting noteworthy signs of illness. Under field conditions most animals develop the acute disease. Following an incubation period of 24 to 72 hours there is fever of up to 42 °C that lasts for 24 to 96 hours, anorexia, weakness, listlessness and an increased respiratory rate. Some animals may regurgitate ingesta and develop melaena or foetid diarrhoea and blood-tinged, mucopurulent nasal discharge. Occasionally, animals may be icteric.

Reports on the progression of natural disease in goats are inconsistent. Although abortion in goats and mortality in kids were recorded in Kenya in 1930, the Sudan in 1973, South Africa and Namibia in 1974/75, and in West Africa in 1987, goats were considered to be more resistant to the disease in the Egyptian outbreak of 1977/78; goats infected experimentally developed  high-levels of viraemia post-infection.^{135, 177, 277, 278, 334, 335, 379, 556, 648}

Pregnant animals may abort at any stage of gestation as a result of the febrile reaction and/or placental necrosis.^{26, 471} Aborted foetuses are usually autolysed. Although there is no evidence that fertility is impaired after abortion, this is possible in instances where retained placenta and purulent metritis occur as complications to abortion. Mortality and abortion rates vary between and within epidemics, but in southern Africa mortality rates varying from 5 to 30 per cent and abortion rates of 40 to 100 per cent were estimated for sheep.^{46, 114, 542} In contrast, it was estimated that up to 60 per cent of sheep died and 80 to 100 per cent of ewes aborted on some farms during the Egyptian epidemic of 1977/78.⁴⁰⁹ Goats were said to be resistant to the disease in Egypt, whereas mortality in goats was reported to be 50 per cent in Sudan in 1973 and the abortion rate was estimated to be nearly 100 per cent in Mauritania in 1987.^{174, 294, 379}

A range of anomalies of the central nervous system including porencephaly, hydranencephaly and micrencephaly, as well as arthrogryposis, and other defects in foetuses associated with hydrops amnii, prolonged gestation and dystocia¹¹⁵ may occur if ewes are inoculated with live Smithburn strain vaccine between about five and ten weeks of gestation.¹¹⁵ If ewes are inoculated before this stage there may be unnoticed early loss of the conceptus, while inoculation at a later stage may result in abortion, stillbirth or birth of immune or viraemic progeny,^{115, 116, 649, 650} Teratology following such vaccination has been recorded in the progeny of up to 15 per cent of pregnant ewes in flocks, but on average it appears to affect less than 2 per cent of ewes and abortion probably occurs in less than 10 per cent of pregnant ewes.^{115, 187, 316, 649, 650, 651}

Cattle

The disease in calves resembles that in lambs and sheep, with occurrence of fever, inappetence, weakness and bloody or foetid diarrhoea, but a higher proportion of calves may develop icterus. In fatal disease, death generally occurs two to eight days after infection. Estimates of mortality during epidemics range from less than 10 per cent for all ages of cattle to 20 per cent for calves,^{114, 177, 542, 586} but a mortality rate of 70 per cent was reported in experimentally infected one-week-old calves.¹⁶⁸

Infection is frequently inapparent in adult cattle,^{111, 118} but some animals develop acute disease characterized by a high fever of 24 to 96 hours’ duration, anorexia, staring coat, lachrymation, salivation, nasal discharge, dysgalactia and bloody or foetid diarrhoea.^{118, 135, 502} The death rate in cattle does not generally appear to exceed 10 per cent, but was reported to be 30 per cent among cattle that aborted in Egypt.^{114, 135, 156, 312, 542, 548, 586, 649} Illness tended to run a prolonged course of 10 to 20 days in cattle in Sudan in 1973, with severe icterus being a marked feature of the disease, although most animals recovered spontaneously.¹⁷⁷ Sometimes abortion is the only manifestation of the disease in a herd. Average abortion rates of 15 to 40 per cent may occur in epidemics.^{114, 156, 316, 327, 560, 586, 591}  As in sheep and goats, cows may abort at any stage of gestation, the aborted foetus usually being moderately autolysed.^{116, 541}

Unusual manifestations, such as dermatitis crustosa of pigmented and unpigmented skin of the muzzle, face, perineum, udder and scrotum, catarrhal and erosive stomatitis, coronitis, laminitis, and exungulation of the hooves have been reported in association with outbreaks of RVF in cattle, but it is believed that these lesions may have been caused by concurrent infection with other agents, such as bluetongue virus.

Other domestic and wildlife animal species

Pigs, horses and donkeys

Data suggests that adult and young piglets are resistant to experimental infection but develop transient viraemia if a high dose of virus is administered.^{135, 170, 544} No isolations of RVFV have been made from pigs, and no antibodies were detected subsequent to the large scale Egyptian epidemic.²⁷⁸ However, more recently antibody positive pigs were reported among animals sampled at abattoirs in Egypt in 2009.⁶⁷⁴

Horses develop only low-grade viraemia following experimental infection,^{135, 672} but during the Egyptian epidemic, there was one isolation of virus from a horse, and four abortions in donkeys were ascribed to RVF, while a low prevalence of antibody to the virus was detected in the two species.²⁷⁸

Camels and camelids

Antibodies were detected in old-world camels (Camelus dromedarius) in a part of Kenya where abortions occurred during a RVF epidemic in 1962, and again during a survey following the 1978/79 epidemic.^{143, 546} However, while there was only one isolation of RVFV from a camel during the 1977/78 Egyptian epidemic, 56 deaths and one abortion were ascribed to the disease, albeit on circumstantial evidence.²⁷⁸ The full potential impact of RVFV on camelids became apparent when large scale die-offs and abortions in dromedary camels occurred in 2009/10 in Mauritania. New- world camelids (alpacas) that were imported for fibre production into South Africa developed lethal infection during the 2008/2010 RVF outbreaks.^{183, 282}

Although infection in camels is generally subclinical in mature animals, pregnant camels may abort at any stage of pregnancy and neonatal deaths have been reported in Egypt and Sudan.^{2, 199, 203, 458, 473} During an unprecedented outbreak that occurred in 2010 in the northern Sahelian region of Mauritania, high mortality rates, haemorrhagic septicaemia and severe respiratory distress were reported.¹⁸²

Antibodies to RVFV in camels have been detected in many African countries including Sudan, Tanzania, South Africa, Mauritania, Kenya, Niger and Nigeria, as well as Saudi Arabia; seroprevalence rates varied from 3 to 57 per cent.^{2, 86, 143, 175, 179, 183, 476, 584}

Water or Asian buffalo

High seroprevalence of anti-RVFV antibodies, abortion rate of 12 per cent and mortality rate of 7 per cent were found in domesticated Asian water buffalo (Bubalus bubalis) during the 1977/78 epidemic in Egypt.

Wildlife species

Antibodies against RVFV have been detected in many African wildlife species including topi (Damaliscus korrigum), red fronted gazelle (Eudorcas rufifrons), dama gazelle (Nanger dama), scimitar-horned oryx (Oryx dammah), common reedbuck (Redunca redunca), African buffalo (Syncerus caffer), Dorcas gazelle (Gazella dorcas), Thomson’s gazelle (Gazella thomsonii), gerenuk (Litocranius walleri), lesser kudu (Tragelaphus strepsiceros), impala (Aepyceros melampus) sable antelope (Hippotragus niger), waterbuck (Kobus ellipsiprymnus), warthog (Phacochoerus aethiopicus), African lion (Panthera leo), giraffe (Giraffa camelopardalis), Burchell’s zebra (Equus burchellii), black rhinoceros (Diceros bicornis), springbok, (Antidorcas marsupialis), wildebeest (Connochaetes taurinus), African elephant (Loxodonta africana), kongoni (Alcelaphus buselaphus), bats (Micropteropus pusillus, Hipposideros caffer, Hipposideros abae), and waterbuck (Kobus ellipsiprymnus).^{66, 72, 86, 95, 143, 189, 290, 486}

Several serological investigations of African buffalo in the Kruger National Park (KNP), South Africa found that older animals were more likely to be seropositive for anti-RVFV antibodies than younger animals and herds in the south of KNP were more likely to be seropositive than herds in the north.^{52, 336} Abortion as a result of RVF was reported in the late 1990s in African buffalo that were kept in a boma at Skukuza in the KNP.²⁴⁵

Experimental RVF infection of a seven-month-old African buffalo in Kenya produced fever and malaise,¹³³ and in another experiment four out of five individuals exhibited transient viraemia and one of two pregnant cows aborted.¹⁴¹ It was noted on some properties involved in the 1950/51 epidemic in South Africa that abortion occurred in springbok (Antidorcas marsupialis) and blesbok (Damaliscus dorcas phillipsi) antelope, but this was not confirmed to be due to RVF.^{290, 295}

To date, no experimental infections of any  European wildlife have been reported.⁶⁶ North American white-tailed deer (Odocoileus virginianus) were recently found to be highly susceptible to lethal disease characterized by severe clinical illness and high-titre viraemias. These animals are the most abundant large wild ungulate species in the US and this experimental study and computer modelling simulations suggest that this species could serve as an amplification host should RVFV be introduced.^{310, 660}

Humans

Humans become infected from contact with infected tissues or from mosquito bites.^{102, 370, 403, 592}. The majority of RVF infections in humans are inapparent or a transient influenza- like illness. It was recognized from the outset in Kenya in 1930 that the influenza- like illness in humans could be accompanied by transient loss of visual acuity, but the occurrence of serious ocular sequelae was first reported in the 1950/51 epidemic in South Africa.^{217, 234, 539, 540} A minority of patients develop ocular lesions, encephalitis or severe hepatic disease with haemorrhagic manifestations.^{242, 294, 340, 403, 410, 413, 499, 556, 565, 592, 633} Acute renal failure, with or without hepatic involvement, was described in patients in Sudan and Saudi Arabia.^{14, 181}

After an incubation period of two to six days, the onset of the benign illness is usually very sudden and the disease is characterized by rigor, a fever that persists for several days and is often biphasic, headache, retro-orbital pain, photophobia, weakness, and muscle and joint pains. Sometimes there is nausea and vomiting, abdominal pain, vertigo, epistaxis and a petechial rash. Symptomatic improvement occurs in four to seven days in benign RVF and recovery is often complete in two weeks.

One of the most detailed descriptions of the clinical features associated with moderate to severe RVF was reported from patients admitted to the Gizan regional referral hospital during the first outbreak of the disease in Saudi Arabia in 2000. Among 165 patients who were treated and prospectively studied, the major clinical characteristics included hepatic failure (75.2 per cent of patients), acute renal failure (41.2 per cent), haemorrhagic manifestations (19.4 per cent), retinitis (9.7 per cent), and meningoencephalitis (4.2 per cent). Of those patients, 56 died (33.9 per cent), and there was no difference in case fatality rate with regard to the sex of the patients. Hepatorenal failure, shock, and severe anaemia were the major factors associated with death.¹⁴

Rare cases of miscarriage and stillbirth have been reported recently.^{8, 31, 49} Infected pregnant women had more severe bleeding, joint pain and malaise than their uninfected counterparts.⁴⁹ Rift Valley fever virus appears to be capable of infecting both the syncytiotrophoblast and cytotrophoblast layers of the placenta, which may potentially result in the in utero infection of foetuses.^{404, 480} While recent experimental data highlight the threat of infection with RVFV to pregnant women and their unborn babies in endemic areas of Africa,⁴⁰⁶ more work is required to understand the underlying pathological mechanisms leading to miscarriages and/or abortions, epidemiological aspects and socio-economic burden of the disease in this group of at risk people.

There are numerous reports of humans becoming infected while investigating the disease in the field or laboratory.^{206, 215, 262, 295, 326, 386, 421, 453, 523, 543, 559, 572, 592, 647} Generally, persons who become affected are involved in the livestock industry, such as farmers who assist in dystocia of livestock, farm workers who salvage carcasses for human consumption, veterinarians and their assistants, and abattoir workers.^{82, 83, 102, 370, 403, 450, 466, 586, 592} The putative vectors in the outbreaks in Egypt in 1977/78 included Ae. caspius, Cx. pipiens, Cx. attenuatus and Cx. perexiguus, which are known to feed on livestock and humans,^{221, 223, 224, 262, 288, 379, 620} while the principal mosquito vectors of RVF in southern Africa tend to be zoophilic and sylvatic but it is thought that humans can become infected on occasion through transmission by Cx. theileri and Cx. zombaensis.

The results of an antibody survey following the 1974 to 1976 epidemic in South Africa revealed that 14.5 per cent of farm residents became infected, a remarkably similar proportion to the estimate of 10 to 15 per cent made for the 1950/51 epidemic.^{403, 542} Antibody was found in 9 per cent of farm residents in Zimbabwe following the 1978 epidemic.⁵⁸⁸ No outbreaks of the disease have been recognized in urban consumer populations and it is surmised that the fall in pH associated with the maturation of meat in abattoirs is deleterious to the virus.^{102, 586}

Human infection presumably results from contact of virus with abraded skin, wounds or mucous membranes, but aerosol and intranasal infection have been demonstrated experimentally and circumstantial evidence suggests that aerosols have been involved in human infections in the laboratory, and in the field during epidemic.^{6, 30, 87, 167, 209, 215, 262, 317, 326, 403, 472, 479, 494, 543, 572, 658, 666} Low concentrations of virus have been found in milk and body fluids, such as saliva and nasal discharges of sheep and cattle, and although contact transmission is not considered important in livestock, it appears that there may have been a connection between human infection and consumption of raw milk.^{15, 44, 247, 252, 293, 336, 463, 466, 556, 649}

Despite the intense viraemia that occurs in humans and the fact that virus has been isolated from throat washings, there are no records of person-to-person transmission of infection.^{215, 293, 556}

In the minority of patients who develop ocular lesions these may occur at the time of the initial illness or anytime up to approximately four weeks later.^{122, 153, 217, 234, 274, 377, 413, 539, 540, 564, 565} It was estimated following the 1974 to 1976 epidemic in South Africa that ocular complications occur in up to 20 per cent of human infections,⁴⁰³ but estimates ranged from less than 5 per cent to less than 1 per cent for the Egyptian epidemic of 1977/78.^{340, 499} The ocular disease usually presents as a loss of acuity of central vision, sometimes with development of scotomas. The essential lesion appears to be focal retinal ischaemia, generally in the macular or paramacular area, associated with thrombotic occlusion of arterioles and capillaries, and is characterized by retinal oedema and loss of transparency caused by dense white exudate and haemorrhages. Sometimes there is severe haemorrhage and detachment of the retina. The loss of visual acuity generally resolves over a period of months with variable residual scarring of the retina, but in instances of severe haemorrhage and detachment of the retina there may be permanent uni or bilateral blindness.^{13, 461}

Probably less than 1 per cent of human patients develop the haemorrhagic and/or encephalitic forms of the disease. The haemorrhagic syndrome starts with sudden onset of influenza-like illness similar to the benign disease, but within two to four days there may be development of petechial rash, purpura, ecchymoses and extensive subcutaneous haemorrhages, bleeding from needle puncture sites, epistaxis, haematemesis, diarrhoea and melaena, sore and inflamed throat, gingival bleeding, epigastric pain, hepatomegaly or hepatosplenomegaly and tenderness of the right upper quadrant of the abdomen and deep jaundice. This is followed by pneumonitis, anaemia, shock with racing pulse and low blood pressure, hepatorenal failure, coma and cardiorespiratory arrest.^{340, 413, 592, 633} A proportion of the less severely affected patients may make a protracted recovery without sequelae.

Signs of encephalitis in humans may supervene during the acute illness, or up to four weeks later and include severe headache, vertigo, confusion, disorientation, amnesia, meningismus, hallucinations, hypersalivation, grinding of teeth, choreiform movements, convulsions, hemiparesis, lethargy, decerebrate posturing, locked-in syndrome, coma and death. A proportion of patients may recover completely, but others may be left with sequelae, such as hemiparesis.^{340, 370, 413, 592, 633}

The first known human fatality was recorded in 1934 in a laboratory worker in the USA soon after the initial isolation of the virus,⁵⁴³ but since the infection was complicated by thrombophlebitis and the patient died from pulmonary embolism the potential lethality of RVFV for humans was overlooked until seven fatal infections were recognized during the 1974 to 1976 epidemic in South Africa.^{403, 633} This was followed in short succession by reports of at least 598 human deaths in the Egyptian epidemic of 1977/78 and five deaths in the 1978 epidemic in Zimbabwe, and latterly by an estimate of at least 224 deaths in the 1987 epidemic in Mauritania.^{294, 408, 592} Since then fatalities in humans have been reported in many countries during outbreaks of RVF in livestock.^{340, 408, 412, 499}

An antibody prevalence rate of 29.6 per cent was detected and the human population estimated at one to three million in the areas affected by the 1977/78 Egyptian epidemic.^{409, 556} Following the Mauritanian outbreak of 1987, 34.8 per cent of people in the town of Rosso were immune. It was estimated that there had been 9,320 infections in the town, of which only 1,013 had been symptomatic, with 47 deaths.²⁹² Hence, the case fatality rate was 4.6 per cent, but the death rate in relation to total infections was only 0.5 per cent. An association between deaths in humans and increasing virus load and titre was found among patients hospitalized during the Saudi Arabia outbreak in 2000, suggesting that lack of immune control and rapid induction of innate immunity are potential determinants of poor patient outcome.³⁷³

Since the early 2000s, there have been reports of potentially increased case fatality among humans during outbreaks, sometimes exceeding 20 per cent.³⁹ However, it is unclear if these reported increases are actually related to changes in virus virulence, underlying host-comorbidities, or surveillance bias due to more robust identification of severe cases during outbreaks.^{39, 66} Regardless, it is clear from large-scale serological surveys after epidemics and during inter-epidemic periods that the vast majority of RVFV infections in humans are self-limiting, and do not lead to lethal outcomes.

Table 1. Susceptibility of vertebrates to Rift Valley fever virus infection. (Information derived from sources cited in the text)

* See Pathogenesis

Pathology

Even in benign disease in livestock there may be marked leukopenia during the first three to four days of infection, usually corresponding with peak fever and viraemia, and this may be followed by leukocytosis during early recovery.^{135, 167, 206, 595} At the same time there may be marked increases in serum levels of enzymes such as sorbitol dehydrogenase and glutamate dehydrogenase, which are indicative of hepatocyte necrosis, or aspartate aminotransferase, which is suggestive of hepatocyte degeneration, but gamma-glutamyltransferase levels remain normal, which is in keeping with the relative sparing of bile ducts in RVF, while alanine aminotransferase which is used as an indicator of liver damage in humans, is of no value in monitoring the disease in herbivores.

Prolonged clotting times have been recorded in mice,⁴²² and thrombocytopenia in sheep with benign infection,⁵⁹⁵ but most information on haemostatic derangement in RVF comes from studies in rhesus monkeys.^{125, 497, 498} It was found that monkeys may have prolonged activated partial thromboplastin times and prothrombin times even in benign infection, and in severe liver disease there may be depletion of coagulation factors II, V, VII, IX, X and XII, thrombocytopenia and platelet dysfunction, increased schistocyte counts and depletion of fibrinogen (factor I) together with raised fibrin degradation product levels. Many of these findings suggest the occurrence of disseminated intravascular coagulopathy, a conclusion which is supported by the finding of fibrin deposits in glomeruli, intertubular vessels of the renal medulla and the spleen.^{125, 497} The findings in monkeys are compatible with the scant observations available on humans, except that leukocytosis and anaemia are marked in some patients.^{592, 633} The presence of fibrin thrombi in the liver, spleen, kidneys and lungs of sheep and cattle that succumb to RVF indicate that disseminated intravascular coagulopathy is also a feature of the disease in domestic ruminants.^{114, 116, 118, 119, 280}

The hepatic lesions of RVF are essentially similar in all domestic animals and humans, varying mainly with the age of the affected individual.^{4, 114, 117, 118, 119, 135, 168, 170, 171, 206, 207, 280, 541, 633} The most severe lesions occur in aborted sheep foetuses and new-born lambs in which the liver is usually moderately to greatly enlarged, soft, friable and yellowish-brown to dark reddish-brown in colour with irregular congested patches and sometimes haemorrhages of varying size scattered throughout the parenchyma (Figures 2 and 3). Numerous greyish-white necrotic foci, 0,5 to 1,0mm in diameter, are invariably present in the parenchyma but may not be clearly discernible due to the discoloration of the organ. Fibrinous perihepatitis and subcapsular haematomas are seen occasionally. There may be oedema and haemorrhages in the wall of the gall bladder and hepatic lymph node. Icterus is evident in only about 10 per cent of affected new-born lambs because of the peracute course of the disease.

The hepatic lesions in adult sheep are generally not as severe or as widespread as in new-born lambs, but icterus may be more evident because of the less peracute nature of the disease. Pin-point reddish to greyish-white necrotic foci may be distributed throughout the parenchyma (Figure 4), and in a small proportion of sheep there are centrilobular haemorrhages and necrotic lesions which impart a mottled appearance (Figure 5) to the organ and render lobulation more distinct than normal.

Figure 2 New-born lamb: note yellowish-brown discoloration of liver and congested patches and haemorrhages in the parenchyma

Figure 3 New-born lamb: congested areas and small, greyish foci of necrosis in the liver

Figure 4 Adult sheep: greyish-white foci of necrosis are scattered throughout the parenchyma of the liver

Figure 5 Adult sheep: mottled appearance of the liver as a result of severe centrilobular necrosis and haemorrhage

Figure 6 Adult sheep: haemorrhages in the gall bladder wall

Haemorrhages and oedema of the wall of the gall bladder are common, and the lumen may contain a blood coagulum or blood-tinged bile (Figure 6).

The livers of aborted cattle foetuses resemble those of lambs, while the livers of calves and adult cattle are swollen, friable, discoloured orange-brown, and sometimes show congested areas and haemorrhages in the parenchyma with accentuation of the lobulation.¹¹⁸ While only scattered, greyish-white foci of necrosis, 0,5 to 1,0 mm in size, are seen in the livers of adult cattle, numerous foci are usually discernible in calves.

The hepatic lesions in new-born lambs are almost invariably accompanied by numerous petechiae and ecchymoses in the mucosa of the abomasum, and its contents are dark chocolate-brown as a result of the presence of partially digested blood (Figures 7 and 8). The contents of the small intestine may be similar in appearance. Most mature sheep and cattle have haemorrhages and oedema in the abomasal folds (Figure 9), and sometimes copious amounts of free blood in the lumen of the intestines. In most animals the spleen is slightly to moderately enlarged, with haemorrhages in the capsule. Infarcts are occasionally evident on the edges of the spleen in adult sheep as dark blueish-red, circumscribed areas, 10 to 20mm in diameter.¹¹⁶

In all animals the peripheral and visceral lymph nodes are enlarged, oedematous, and may have petechiae.

Figure 7 New-born lamb: presence of copious amounts of chocolate-brown, partially digested blood in the abomasum

Figure 8 New-born lamb: note numerous petechiae and ecchymoses in mucosa of the abomasum

Other changes include widespread subcutaneous, serosal (Figure 10) and visceral haemorrhages, mild to moderate effusion of fluid, often blood-tinged, into body cavities, congestion and oedema of the lungs, enlargement of the adrenals with small haemorrhages in the cortex, and nephrosis which may be particularly severe in mature sheep. Haemoperitoneum is occasionally present in new-born lambs.

Figure 9 Adult sheep: note numerous petechial haemorrhages in the abomasal mucosa

Figure 10 Adult bovine: note numerous haemorrhages in the serosa of the intestine

Hepatic necrosis is the most striking microscopic lesion of RVF in all domestic animals and humans.^{114, 117, 118, 119, 135, 167, 168, 206, 207, 265, 280, 468, 541, 633} In aborted sheep foetuses and neonatal lambs, primary foci of necrosis comprising dense aggregates of cytoplasmic and nuclear debris, some fibrin and a few neutrophils and macrophages can be discerned against a background of parenchyma reduced by nuclear pyknosis, karyorrhexis and cytolysis to scattered fragments of cytoplasm and chromatin, with only narrow rims of degenerated hepatocytes remaining reasonably intact close to portal triads (Figures 11 and 12). Destruction of hepatocytes may be so marked that most of the normal architecture of the organ is lost, giving the liver almost the appearance of lung tissue (Figure 11). Intensely acidophilic cytoplasmic bodies which resemble the Councilman bodies of yellow fever are common, and rod-shaped or oval eosinophilic intranuclear inclusions (Figure 13) are found in about 50 per cent of affected livers. Mineralization of necrotic hepatocytes may be evident as small purplish-blue cytoplasmic granules (Figure 14) in haematoxylin and eosin-stained sections in approximately 60 per cent of lambs, and bile casts are present in about 30 per cent of livers.¹¹⁴ Other noteworthy lesions in new-born lambs are pyknosis and karyorrhexis of lymphocytes in lymphoid tissues, cloudy swelling and hydropic degeneration of the epithelial cells of the convoluted tubules of the kidney and necrosis of some of the cellular elements in the glomeruli in ten per cent of lambs, and multifocal necrosis and haemorrhages in the adrenal cortex.^{114, 468}

Figure 11 New-born lamb: severe lytic necrosis of most hepatocytes in the lobules. Note primary foci of necrosis

Figure 12 New-born lamb: primary focus consisting of cellular and nuclear debris and a few inflammatory cells

Figure 13 New-born lamb: note rod-shaped intranuclear inclusion bodies in necrotic hepatocytes. Haematoxylin and phloxin-stained section

Figure 14 New-born lamb: mineralization of necrotic hepatocytes evident as purplish-blue cytoplasmic granules

Figure 15 Adult sheep: paracentral focus of necrosis in the liver

In older sheep, liver necrosis is not usually as diffuse as in neonates and tends to be multifocally distributed (Figure 15) throughout the parenchyma and icterus is more common than in lambs. The hepatocytic changes in these foci are similar to those described for primary foci of necrosis in lambs. However, occasionally centrilobular necrosis and haemorrhage are also evident. Severe nephrosis which occasionally occurs in mature sheep is characterized by marked tubular degeneration and necrosis, intracytoplasmic accumulation of proteinaceous droplets in tubular epithelial cells and presence of hyaline casts in tubular lumens, while haemorrhages, necrosis and deposition of fibrin and haemorrhage may be present in glomeruli (Figure 16). A few acute subcapsular infarcts are occasionally present at the edges of the spleen and the sinuses may contain accumulations of excess fibrin.

Primary foci of necrosis are particularly numerous and conspicuous in the livers of affected calves (Figure 17) and aborted cattle foetuses, and are sometimes accompanied by massive hepatic necrosis, presenting a pattern similar to that described for new-born lambs.^{118, 168}

Vasculitis, thrombosis and sinusoidal fibrin deposition are sometimes present in the livers of both adult cattle and calves. Apart from hepatic lesions, there is necrosis of lymphoid tissue, and numerous foci containing fibrin (fibrinoids) are sometimes evident in the red pulp of the spleen.

The extent of hepatocellular involvement in adult cattle varies greatly.^{118, 135, 168, 541}

Figure 16 Adult sheep: haemorrhage, necrosis and deposition of fibrin in a glomerulus in the kidney

Figure 17 Calf: numerous primary foci of necrosis in the liver

Marked centrilobular eosinophilic necrosis and haemorrhage, frequently extending to the middle of the lobule, occur in about 60 per cent of field cases of RVF, with individual or small groups of necrotic hepatocytes and acidophilic bodies being dispersed among the intact but degenerated hepatocytes in the rest of the lobule. Massive necrosis involving almost all hepatocytes (Figure 18) occurs in approximately 30 per cent of livers of field cases, while focal necrosis occurs in the remainder. The pathognomonic residual primary foci of necrosis, present in most new-born lamb livers,¹¹⁴  are sparse in the livers of mature cattle.¹¹⁸ Intranuclear inclusions, frequent in new-born lambs and aborted sheep and cattle foetuses, are less common in other animals and are only seen in about 20 per cent of livers of adult cattle. Other lesions in cattle are similar to those described for calves.

Many animals have lung congestion, alveolar and interstitial oedema, haemorrhages, a few fibrin thrombi in alveolar walls, scattered neutrophil infiltration, and necrosis of a few cells in alveolar walls, interlobular septa and peribronchial lymphoid tissue.

Varying degrees of lymphocyte necrosis have been described in the spleen and lymph nodes in sheep, cattle and humans.^{113, 118, 178, 190, 192, 469, 470, 471, 633} Necrosis of lymphocytes in the spleen of adult sheep is most apparent in the germinal centers of the white pulp. In young lambs and foetuses, the lymphocytes in the red pulp and the peripheral regions of the periarteriolar lymph sheaths are mainly involved. Karyorrhexis and karyolysis of the nuclei of lymphocytes in the spleen and lymph nodes as well as atrophy of the white pulp have been reported in fatal cases in humans.^{178, 633}

In humans, encephalitis is characterized by focal necrosis with leukocyte infiltration and perivascular cuffing.⁶³³

Figure 18 Adult bovine: massive hepatic necrosis

Information on ultrastructural changes in RVF is scant and most reports deal with viral morphology and morphogenesis.^{119, 185, 186, 265, 344, 389, 455} The most conspicuous changes in hepatocytes include clumping and margination of chromatin, pyknosis, karyorrhexis, karyolysis, bizarre nuclear profiles, focal cytoplasmic degradation and sequestration with the formation of acidophilic or dark bodies (Figure 19), and cytoplasmic fragmentation or disintegration.^{119, 185, 186}  Single or small groups of virions may be seen free among cytoplasmic organelles, inside smooth membrane-bound structures in a small proportion of hepatocytes, in cellular fragments and debris, or within sinusoids. Occasionally the viral particles may be associated with phagocytosed necrotic material within Kupffer cells, neutrophils or macrophages.¹¹⁹ Rod-shaped intranuclear inclusions (Figure 20), occupying up to half the length of the nucleus and composed of bundles of microfilaments or fibrils less than 10nm in diameter, occur in some infected cells.^{119, 185, 186, 265, 589} Sinusoidal endothelium is generally preserved but isolated endothelial cells may be necrotic late in the course of the infection.¹¹⁹

Figure 19 Electron micrograph of an acidophilic or dark body in the liver. Note condensation of cytoplasm and clumping of chromatin of the nucleus

Figure 20 Electron micrograph of an intranuclear inclusion body. Note parallel arrangement of microfilaments

Diagnosis

Suspicion of RVF should be aroused when heavy rains are followed by the occurrence of abortions in sheep, cattle and goats together with fatal disease, particularly in young and pregnant animals, which is marked by necrotic hepatitis and widespread haemorrhages. Frequently, there is also an influenza-like illness in farm workers and others with contact to infected animal tissues.

The usually regional nature across national borders of RVF outbreaks and involvement of multiple species requires an integrated One Health approach to outbreak investigation, diagnostics, and counter-measure responses.^{313, 331, 429} Due to the severe potential economic impacts of RVF outbreaks in animals, animal health professionals should familiarize themselves with the specific guidelines and requirements listed in the World Organization for Animal Health (OIE) Manual for diagnostics and regulatory reporting requirements.⁴⁷⁴

Field biosafety and biosecurity concerns for veterinarians and other health personnel

Rift Valley fever virus has proven on multiple occasions to be easily transmitted to people from infected animal tissues and body fluids in farm settings. If RVFV is suspected among livestock, standard biosafety and biosecurity protocols and procedures should be followed to avoid infection of animal health workers and other personnel involved in the collection of diagnostic specimens. At a minimum for on-site field investigations, gloves, eye/face protection, and dedicated field clothing and boots should be worn and thoroughly disinfected with appropriate disinfectants labelled for virucidal activity against lipid-enveloped viruses. Ideally, when handling suspected RVFV infected animal carcasses or materials, personal-protective equipment (PPE) and practices should be supplemented by disposable coveralls and respiratory protection such as properly fitted N95 respiratory masks. Health workers should consult their national agricultural and public health authorities for proper guidance related to PPE and safe sampling procedures relevant for local conditions and practices.

Work with live infectious virus, non-inactivated clinical specimen materials, and experimentally infected animals should be conducted in laboratories (i.e., BSL-3 or higher) with appropriate biosafety facilities and PPE practices.¹⁹⁷

Specimen collection

Specimens to be submitted for laboratory confirmation of the diagnosis include either EDTA, heparinized or clotted whole blood, plasma or serum of live affected animals or tissue samples, including liver, spleen, kidney, lymph nodes and heart blood of dead animals. Samples from aborted foetuses should include brain since this is usually less autolysed or putrified than viscera when obtainable.^{560, 586} Placenta specimens, if available, can also be collected.

Specimens should be securely packaged and submitted at 4 °C to a suitable laboratory for isolation or detection of virus or demonstration of antibody. Where delay in getting specimens to the laboratory is unavoidable or the material has to be transported at ambient temperature, tissue samples can be preserved in glycerol-saline solution. Tissue specimens from the liver, spleen, lymph nodes and kidney should also be collected in 10 per cent buffered formalin for histopathological and immunohistochemical examination. In animals that survive the disease, paired serum samples, one taken during the acute illness and the other two to three weeks later, should be submitted for antibody tests.

Diagnostic assays

Molecular detection assays: The frontline diagnostic assays routinely employed in centralized diagnostic laboratories are nucleic-acid amplification tests such as real-time reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time PCR, or whole genome sequencing.^{60, 162, 456, 652, 661} These detection assays require moderate laboratory sophistication and technology, but are routinely available in most regional diagnostic centres. Multiple broadly reactive assays have been described and are routinely used to rapidly and accurately identify RVFV genome in a wide variety of submitted specimens (e.g. blood, plasma, serum, homogenized tissues, and other fluids). Viral nucleic acid can readily be detected in serum and other tissues of infected humans and livestock, as well as mosquitoes, by RT-qPCR.^{162, 226, 269, 301, 303, 528} and  real-time reverse transcription-loop-mediated isothermal amplification assay.³⁴²

Antigen detection assays: RVFV antigens can be detected by immunofluorescence and immunocapture ELISA assays. Zaki et al.^{284, 676} reported an immunofluorescence assay, that utilizes a pool of mouse IgG monoclonal conjugates for the detection of RVFV-specific antigens. Although it was shown to be highly sensitive in detection of RVFV in patient sera, it’s use requires tissue culture amplification and handling of live virus. Jansen et al.²⁸⁴ developed a safe sandwich ELISA (sAg-ELISA) for the detection of RVFV NP antigen in specimens inactivated at 56 °C for 1 h in the presence of 0.5% Tween-20 (v/v) before testing. The test can be used for the detection of RVFV NP antigen in human and animal sera, homogenates of liver and spleen tissues of domestic and wild ruminants, and mosquito homogenates. The lateral flow immunochromatographic test for the detection of RVFV NP in animal sera and fluids from aborted foetuses is a valuable diagnostic tool for onsite rapid detection of RVFV.^{101, 284}

Virus isolation and culture: Long considered the gold-standard of virus diagnosis, this technique requires relatively high levels of biosafety and biosecurity and has become less favoured than molecular diagnostic assays. However, obtaining high quality virus isolates from field specimens is essential for further research work and development and should be considered where adequate laboratory facilities and trained staff are present. Rift Valley fever virus can be isolated readily in a variety of cell cultures) including Vero, CER, BHK21, mosquito line cells, and primary calf, lamb and goat kidney or testis cells, or in suckling and weaned mice or hamsters inoculated intracerebrally or intraperitoneally.^{22, 136, 157, 167, 410, 499, 556, 586, 594, 649} Cytopathic effect (CPE) may be evident one to five days after inoculation of cell cultures, but virus can be identified and the diagnosis accelerated by performing immunofluorescent (IF) tests on cultures at 24 hours or even earlier and it is always necessary to perform IF tests on inoculated mosquito cells since CPE is not readily apparent in them. More commonly, virus isolated in cell cultures is identified with reference antiserum by performing neutralization tests.^{166, 594} Inoculation of suckling mice by the intracerebral route is used extensively for isolation of RVFV,⁵⁸⁶ and mice generally die two to five days after inoculation with field material.

The virus can be grown in and readily produces cytopathic effect and plaques in virtually all common continuous line and primary cell cultures, including Vero and BHK21 line cells, primary calf and lamb kidney or testis cells, the only major exceptions being primary macrophages and lymphoblastoid cell lines.⁴⁹⁶ Virulent virus readily gives rise to chronically infected cell cultures derived from a proportion of cells which escape cytopathic effect, the phenomenon being associated with production of defective RNA in all three segments of the genome.⁵⁸ The virus can be grown in embryonated chicken eggs and a variety of laboratory animals including suckling or weaned mice and hamsters inoculated by intracerebral or intraperitoneal routes. Lambs are extremely susceptible, but some strains of rat are resistant, as are rabbits, guinea pigs, horses, and chickens.^{167, 410, 499, 556}

Infectivity of virus stocks is highly sensitive to temperature and storage conditions. Controlled studies of the Clone 13 vaccine strain revealed that virus particles retain infectivity in serum and can be recovered after prolonged (weeks to months) storage at 4 °C; however increased temperature rapidly degrades virus particles and infectivity is lost within hours at 56°C.¹²⁸ The virus is very stable at temperatures lower than –60°C or after freeze drying. It is inactivated by lipid solvents, low concentrations of formalin, and is very sensitive to acidic conditions with infectivity rapidly lost below pH 6.8.⁵⁵⁶

Microscopic pathology and immunohistochemistry: Histopathological lesions are very characteristic and, in particular, the liver lesions of new-born lambs and kids leave little room for doubt about the diagnosis of RVF.^{114, 117, 118, 119, 135, 167, 168, 206, 207, 265, 280, 541} Virus antigen can be detected in tissues of infected animals by immunohistochemistry.^{468, 630}

Antibody detection assays: Antibody to RVFV can be demonstrated by different assays including ELISAs, multiplex-bead based arrays, indirect immunofluorescence, and virus plaque reduction neutralization test (PRNT).^{69, 110, 166, 175, 335, 465, 487, 504, 511, 549, 563, 574, 594, 631} All techniques except neutralization tests can be performed with inactivated antigens to enhance biosafety in the laboratory. Although regarded as a gold standard, virus neutralization assays are laborious, expensive, and require 5-7 days for completion. They can be performed only when a standardized stock of live virus and tissue cultures are available. Consequently, they are rarely used, and only in specialized laboratories equipped with high biocontainment facilities. Recently, a neutralization test based on an avirulent RVFV expressing an enhanced green fluorescent protein was developed and reported to be more sensitive than the classical neutralization test and safe to be used outside level 3 biocontainment facilities.⁵³⁸

Various ELISA formats have been developed and validated in recent years for specific detection of anti-RVFV antibodies in humans and animals, based on inactivated sucrose-acetone-extracted antigens derived from tissue culture or mouse brain.^{488, 489, 493} While they were shown to have high diagnostic specificity and diagnostic sensitivity compared to virus neutralization assays, the production of antigen for these assays also requires bio-containment facilities to limit the risk of exposure of laboratory personnel to infection. To address these problems, indirect ELISAs based on the recombinant NP and GP proteins have been developed for the detection of anti-RVFV antibodies in domestic ruminants, wildlife and humans.^{193, 281, 285, 491, 492} An ELISA platform based on recombinant NP and NSs proteins is able to distinguish infected from vaccinated animals. This diagnostic capacity is important for allowing moving of vaccinated animals, given the strict regulations for movement and export of animals.³⁸⁸

Since a wide range of domestic and wild animal species are susceptible to RVFV, the development of inhibition and competitive ELISAs provide an additional advantage of allowing multi-species RVFV antibody detection using the same diagnostic procedure without requirements for species-specific conjugates.^{493, 625}

Recent or current infection must be distinguished from pre-existing immunity and, conventionally, serological diagnosis of recent disease is confirmed by demonstrating seroconversion or a four-fold or greater rise in titre of antibody in paired serum samples.⁵⁶³ The introduction of the IgM-capture ELISA for detection of antibody to RVFV in humans and domestic ruminants, however, allows diagnosis of recent infection to be made on a single serum sample.^{335, 465, 488, 489}

Results obtained in experiments with sheep indicate that neutralizing antibody may become demonstrable as early as three days following infection and by the fourth to sixth day antibody is detectable by ELISA. Antibody titres detected by ELISA are maximal from two weeks to approximately six months after infection.⁵⁹⁴ Thereafter ELISA titres decline over a period of several years, while neutralizing antibody tends to maintain a plateau level after an initial post-convalescent decline and probably remains demonstrable for the life of the individual. Kinetics of IgM and IgG responses were studied in sheep experimentally infected with wild-type RVFV and in sheep vaccinated with live-attenuated Smithburn strain of RVFV.  IgM and IgG seroconversion was detectable 4-6 days post-infection with IgG antibody reaching the highest level on Day 21 and IgM antibody on Day 11 after infection. Compared to sheep infected with wild-type virus, the IgG and IgM responses in vaccinated animals were less rapid and antibody levels and especially those of IgM were lower. IgM antibody could be detected only in 12.5 per cent of infected sheep 72 days post-infection.⁴⁸⁸ The time dependent detectability of anti-RVFV antibody, and especially IgM, may be of significance for epidemic situations, where the disease stage may affect the outcome of an assay result and interpretation of the data. The only information available on the duration of the IgM antibody response following natural infection relates to 195 cattle monitored after the 1991 epidemic in Madagascar; less than 30 per cent had IgM antibody two months after infection was diagnosed, and all were negative by six months.⁴⁴¹

Theoretically, the antigenic cross-reactivity of the phleboviruses could present problems in making a serological diagnosis of RVF infection and for this reason neutralization tests, which are least affected by serological cross-reactivity, would seem to be most suitable for confirmatory diagnostic use.^{410, 561, 562, 598, 599}

Establishing a definitive diagnosis in cases of teratology caused by the live modified RVF vaccine virus can be very difficult. Several viruses, other agents, and plant toxins can cause similar teratology. Foetuses may not be immunocompetent at the time that they undergo teratogenic infection and thus may not have virus or antibody at the time that the malformations become apparent, thus limiting diagnostic options for specific testing. Regarding serological diagnoses of new-born animals, those that are able to suckle acquire maternal IgG but not IgM antibody from milk ingestion. Compounding this, dams of affected foetuses will generally no longer have IgM antibody by the time that malformations become apparent. Identification of the teratogenic agent may need to rely heavily on risk-factor analysis and epidemiology to support a tentative aetiological diagnosis.

Differential diagnosis

Rift Valley fever, Wesselsbron (WSL) disease and other arthropod- borne virus diseases such as Schmallenberg virus tend to occur under the same climatic conditions (see Wesselsbron disease). Both RVF and WSL viruses can cause mortality in lambs, kids and calves and occasionally abortion in ewes, but RVF is associated with much higher mortality and abortion rates.^{114, 120, 121, 649} In experimental infection, RVF can produce a mortality rate of 90 per cent or greater in neonatal lambs, while WSL disease is lethal in about 30 per cent of lambs. Moreover, RVF infection produces severe disease and deaths in adult sheep and goats while WSL disease is usually inapparent in these animals. In the field, outbreaks of disease in sheep were ascribed to WSL disease virus shortly after its original isolation in South Africa in the 1950s, but some of the outbreaks were complicated by plant or copper poisoning,^{53, 343} and since then isolations of the virus from livestock have been few and sporadic.  It is pertinent that WSL virus has never been isolated from an aborted foetus from the field. On the other hand, misuse of live modified WSL disease vaccine in pregnant animals during the 1974–76 RVF epidemic in South Africa and Namibia is believed to have caused foetal and neonatal teratology on a large scale.¹¹⁵

Definitive diagnosis of RVF and WSL disease ultimately depends on virological and serological examination of appropriate specimens but the diseases can also be distinguished on the basis of the hepatic changes found in each.^{114, 121}  Lesions in the livers of young animals that succumb to WSL disease are usually less extensive than those in RVF, and tend to be less acute as evidenced by the occurrence of bile stasis, bile ductular and Kupffer cell proliferation, and hepatocellular regeneration. Hence moderate to severe icterus is a regular finding in WSL disease, whereas it is absent in most neonates which succumb to peracute massive hepatic necrosis in RVF infection. Although there may be extensive hepatic necrosis in WSL disease, neither the parenchymal hemorrhages nor the primary necrotic foci characteristic of RVF are evident macroscopically or microscopically in WSL disease. In both diseases, mucosal haemorrhages and free partially digested, chocolate-brown blood are found in the abomasum.

Agents causing mortality associated with hepatic lesions, haemorrhages and/or icterus which may superficially resemble RVF in domestic ruminants include poisonous plants affecting the liver in southern Africa such as Senecio spp., Crotalaria spp., Lasiospermum bipinnatum, Cestrum spp., Pteronia pallens and Hertia pallens, and an alga, Microcystis aeruginosa,³¹⁸ as well as bacterial septicaemias such as pasteurellosis, salmonellosis (calf paratyphoid) and anthrax. Generally, domestic ruminants only eat toxic plants if forced to do so by scarcity of feed. Beyond southern Africa, peste des petits ruminants, Nairobi sheep disease, Schmallenberg virus, and possibly Thogoto virus infection¹⁴⁸ could be confused with RVF. Diagnoses can be established in poisonings by instituting appropriate epidemiological and toxicological investigations, and in infectious diseases by means of appropriate microbiological and serological investigations.

Sometimes abortion is the only sign of RVF in cattle and diseases, which must be eliminated by appropriate laboratory investigations, include brucellosis, leptospirosis, chlamydiosis, Q fever, and salmonellosis. In instances where teratology is involved, investigations should include Schmallenberg virus, bluetongue virus, Simbu-serogroup bunyaviruses, Palyam serogroup orbiviruses, WSL and other flaviviruses such as West Nile and Banzi.^{46, 591} (see Bluetongue, Palyam serogroup orbivirus infections, and  Diseases caused by Akabane and related Simbu-group viruses).

Rift Valley fever  belongs to a group of viral haemorrhagic fever(VHF) diseases with worldwide distribution, but their specific aetiological agent is usually restricted to a known endemic region depending on the presence of natural reservoirs or/and competent arthropod vectors. As for most VHFs, the non-specific clinical manifestations of RVF makes it difficult to diagnose clinically. Therefore, the differential diagnoses of RVF in humans include a broad spectrum of conditions especially when first cases are encountered during a yet unrecognized outbreak. These include malaria, rickettsial infections, Q fever, typhoid fever, dysentery, plaque, brucellosis, leptospirosis, meningitis, sepsis from bacterial infections, viral hepatitis, other VHFs such as Lassa fever, Crimean Congo haemorrhagic fever, Marburg disease, Ebola fever, and the haemorrhagic fever associated with the renal syndrome caused by hantavirus infections. Non-infectious causes of disseminated intravascular coagulopathy and acute leukaemia should also be considered. Availability of laboratory results and epidemiological information usually help to narrow the spectrum of differential diagnoses. A provisional diagnosis can sometimes be made based on recent travel and exposure history (e.g., mosquito bites, or contact with animals or their tissues or products in endemic regions. An aetiological diagnosis is usually possible by considering all available laboratory results, and clinical, pathological, and epidemiological data. Rift Valley fever in humans should be suspected when there is a sudden outbreak of febrile illness with headache and myalgia in humans, in association with the occurrence of abortions in domestic ruminants and high mortality of young animals such as lambs and kids. Cases of RVF are sometimes only recognized weeks after infection by the occurrence of ocular complications. Haemorrhagic or encephalitic clinical manifestations may be present occasionally in residents of RVF-free countries following a visit to endemic areas.^{485, 593}

Control

Vector control

The large number of mosquito species that can transmit RVFV and the vast number of breeding sites, particularly after heavy rains, makes it difficult to control mosquitoes on a large scale.^{38, 41} Mosquito control during outbreaks is in most instances thus not practical and is almost never applied. Strategically-timed application of larvicides can be used to suppress mosquito breeding.  Other measures, such as chemical or biological control of adult vectors (see Vectors: Mosquitoes- a southern Africa perspective), movement of stock from low-lying areas to well-drained and wind-swept pastures at higher altitudes, or confining of animals to mosquito-proof stables, can be challenging to implement in the face of a RVF epidemic.^{7, 159, 375, 448, 518} In the case of dairy farms, the milking sheds should be made mosquito proof, and perhaps Culicoides-proof, and monthly spraying of their interior walls should be carried out with a residual insecticide other than an organochlorine. Organophosphate insecticides, such as malathion, fenthion (Baytex), fenitrothion (Sumithion), or carbamates such as carbaryl (Sevin) and propoxur (Arprocarb), can be used.⁵⁵²

Recent advances in genetic manipulation of mosquito populations through so called “gene drives” are potential mechanisms that could in the future be utilized to reduce the population level of mosquito vectors for a variety of arboviruses and other pathogens (e.g. malaria) if technical and bioethical hurdles can be overcome to allow for widespread use.^{372, 481}

One Health approaches, vaccination and therapeutics

The central role of particularly viraemic livestock as a risk factor for human infection highlights the need for comprehensive One Health control strategies.^{65, 66, 67, 203, 331} For the successful long-term control and management of RVF in endemic areas, a multifaceted approach is needed that can reduce the level of virus circulation and amplification among mosquito vectors, livestock, and ultimately humans. Targeting one of the key amplification components, namely livestock, of the RVFV epidemic cycle could eliminate some of the greatest risk factors for human infection while at the same time greatly improving the economic and nutritional well-being of livestock producers and animal product consumers. Critical for this control approach to be successful will be the ready availability of inexpensive and effective vaccines that can be used safely in livestock or humans regardless of pregnancy and age status. Fortunately, the past 10 years have witnessed a resurgence in the development of a wide variety of novel vaccine candidates and therapeutics.^{35, 67, 165, 191, 279, 331, 383, 505, 535}

Importantly, many of these candidate vaccines allow for the differentiation of naturally infected from vaccinated animals (DIVA) on the basis of serological testing. The capacity for pen-side DIVA testing of animals would allow compliance with international trade restrictions that are routinely imposed during RVF outbreaks and that further exacerbate the negative economic consequences of the disease. The key challenge ahead is moving these prototype vaccines from the laboratory into field trials, then past regulatory approval and eventual commercial viability.

Vaccines – historical and recent approaches

Vaccines have been an important component of routine management and emergency outbreak responses to RVF since the 1950s.^{63, 67, 191, 260, 273, 279, 494} The impact and cost-effectiveness of livestock vaccination have been recently assessed in RVF high-risk areas or epidemics using simulation modelling that demonstrated that animal vaccination is the most effective control measure, preventing both human and livestock cases.^{220, 325, 417} The renewed interest in RVF since its emergence in the Arabian Peninsula in 2000 and re-emergence of large RVF outbreaks in Africa in the last two decades have resulted in significant advances in our basic knowledge of RVFV replication strategy and virulence factors. This progress benefits and aids the development of novel vaccines both for humans and animals, including genetically modified-live vaccines, recombinant protein vaccines, DNA vaccines, virus-like particles (VLPs), virus replicons and virus-vectored vaccines^{165, 191, 198, 271} and the development antiviral drugs.^{459, 550} Considerable efforts have also been made in the establishment of reliable RVF challenge models for testing of potential vaccines and therapeutics.³³³

Wild-type RVFV, also referred to as hepato-, viscero-, or pantropic virus, has been attenuated to produce vaccine or candidate vaccine strains by serial passage in highly permissive systems such as suckling mice or cell cultures, by selection of small plaque variants and by chemical mutagenesis with 5-fluorouracil. The 5-fluorouracil^{94, 445, 571} mutagenized MP12 candidate vaccine virus has mutations in all three segments of the genome.^{527, 637} The Smithburn vaccine strain was developed by serial intracerebral passage of a Ugandan wild-type virus in suckling mice until it lost its tropism for the liver and became neuroadapted, i.e. until it no longer killed mice following peripheral inoculation yet retained its intracerebral lethality and its immunogenicity.⁵⁷¹ Clone 13, a naturally occurring and highly attenuated mutant obtained by plaque selection of clones from a human isolate of RVFV from the Central African Republic, proved to have a 549 nucleotide deletion comprising 69 per cent of the NSs protein gene in the S RNA segment of the genome.³⁷⁹ The thermostable RVFV Clone 13 vaccine (CL13T) has been developed via a selection of viable virus populations at 56⁰C from the culture supernatant of Vero cells infected with the original Clone 13 strain of the virus, and then lyophilized in the presence of a stabilizer.¹²⁸

Attenuated Smithburn strain and formalin- inactivated vaccines: The mouse neuroadapted Smithburn strain of RVFV is used at slightly different passage levels in laboratory host systems for production of livestock vaccines in South Africa and Kenya, while wild strains of RVFV are used for preparation of formalin-inactivated cell culture vaccines in South Africa and Egypt.^{15, 43, 45, 96, 112, 180, 316, 571, 649, 650} The Smithburn strain, received from Uganda after 82 intracerebral passes in suckling mice, was subjected to further passaging in mice and embryonated eggs in South Africa before being issued as an experimental vaccine in 1951. After minor adjustments in passage level were made during the following few years the strain was used until 1958 in a form which had undergone 102 intracerebral passages in suckling mice, followed by 50 egg passages and a further 16 mouse passages,and then provided as freeze-dried 10 per cent mouse brain vaccine. In 1958 reversion was made to seed virus of lower mouse passage level and since 1971 the same virus has been propagated in BHK21 cells for preparation of freeze-dried vaccine.^{43, 45, 316, 649, 650} The Smithburn strain has been used at the 106 intracerebral mouse passage level to produce vaccine for sheep and cattle in Kenya since 1960.^{96, 112}

In contrast to the Smithburn vaccine, formalin-inactivated vaccines are safe for use even in pregnant animals, but they are expensive to produce and induce short-lived immunity, so that the administration of annual booster doses is necessary to ensure adequate protection.

The modified live Smithburn vaccine can readily be produced in large quantities, is inexpensive, and induces durable immunity in sheep six to seven days after a single inoculation, but in a proportion of pregnant animals it may cause abortions or teratology of the central nervous system of the foetus and hydrops amnii and prolonged gestation in the dam.¹¹⁵ The virus is, therefore, only partially attenuated and its use in pregnant animals should only be contemplated in the face of an epidemic when its adverse effects may be outweighed by the dangers of allowing the disease to take its natural course.¹³⁷ It is considered theoretically possible, although not proven, that the virus could revert to full virulence if passaged through hosts such as mosquitoes which become infected as a result of feeding on animals in the viraemic stage following administration of the vaccine, and hence it is advised that inactivated vaccines should be used in situations where it is considered necessary to immunize animals in countries where the presence of RVF has not been proven.^{34, 621}

The Smithburn RVF vaccine induces a poor antibody response in cattle,^{43, 45, 112} and they should preferably be immunized with formalin-inactivated vaccine to ensure that cows are able to confer colostral immunity to their offspring. Cattle should receive a booster dose three to six months after initial vaccination, followed by annual boosters before the rains are due, since immunity only lasts about one year.⁴⁵ Formalin-inactivated vaccine can also be used in pregnant sheep to avoid abortion and foetal teratology.

Inactivated vaccines are normally used in non-endemic RVF countries.^{38, 467}

MP12: The mutagen-derived MP12 candidate vaccine virus generated after 12 passages of the parental ZH548 strain (Egypt 1978) in the presence of the mutagen 5’-flurouracil was shown to be safe and effective for use in pregnant sheep and cattle, and has even been inoculated directly into bovine foetuses without apparent deleterious effects.^{47, 265, 432, 436, 437} However, the experiments were conducted with animals beyond the first trimester of pregnancy, after organogenesis has occurred when foetuses are less susceptible to the teratogenic effects of attenuated viruses. Teratology occurred in 14 per cent of lambs of sheep inoculated at an earlier stage of pregnancy.²⁶⁷ However, the MP12 vaccine has proven to be a safe and effective animal and human vaccine among non-pregnant individuals and recently was successfully tested in small scale Phase I/II human clinical trials.^{508, 509} Further iterations of the MP12 vaccine include recombinant- based deletions of the NSm nonstructural protein and codon usage deoptimization strategies.^{271, 369}

Clone 13 vaccine: It is a live-attenuated vaccine based on a naturally attenuated strain (RVFV 74HB59) that was isolated in the Central African Republic from a RVF patient. It  lacks 69 per cent of the NSs gene, a major virulence factor of the virus.^{452, 597} Experimental and field trials have shown that  a single dose of the vaccine was highly immunogenic in domestic ruminants  and did not cause abortion or foetal teratology in pregnant animals^{164, 363, 452, 466, 597} and conferred protection in calves against abortion on challenge with wild virus.⁶³⁸ Available data indicate that the Clone 13 vaccine did not cause detectable viraemia in vaccinated ruminants, thus minimizing the risk of virus transmission to the foetus or to mosquitoes and genome segment reassortment events with wild- type viruses. Since 2010, Clone 13 vaccine has been registered in South Africa, Namibia, Botswana, Zambia and Mozambique. More than 28 million doses of the vaccine have been used in South Africa by 2018, with more than 10 million doses used during the 2009-2010 RVF outbreaks.⁶³⁸ However, a recent report indicated that Clone 13 virus could cross the ovine placental barrier and be associated with foetal infections, malformations, and stillbirths when administered in an overdose to pregnant ewes at 50 days of gestation.³⁷⁸ Nevertheless, the Clone 13 vaccine at the recommended dose  is considered to be safe and efficacious in domestic ruminants.^{129, 130}

DDvax: The recombinant DDvax candidate was generated by the targeted deletion of the NSs and NSm virulence factors on the S and M genome segments of the parental ZH501 strain (Egypt 1978), respectively. This construct has proven safe and effective in a wide variety of animal species including sheep, cattle, non-human primates, and pregnant ewes vaccinated in the first trimester of gestation.^{59, 64, 569} While highly attenuated in mammals, this vaccine also was found not to be transmitted by mosquito vectors due to an inability to cross the midgut barrier caused by the deletion of the NSm gene and the associated gene products.^{126, 309}

Four-segmented RVFV (RVFV-4s) – Bunyavax: An alternative approach to attenuation was pursued by splitting the RVFV M segment that contains the Gn and Gc glycoprotein coding regions into two separate genomic fragments using a recombinant plasmid-based system.^{653, 655, 656} Initial results were promising with marked attenuation and safety in a variety of animal species including rodents and livestock.^{653, 656} Later generation versions of this construct also contain a deletion of the major virulence factors the NSs gene on the S segment coding region likely further enhancing the safety of this vaccine candidate.

Virus-like particles and non-spreading replicon particles (multiple approaches): While virus-like particles (VLPs) are essentially virus-like shells comprised of virus glycoproteins and nucleoprotein, the more advanced concept of non-spread replicon particles seeks to capitalize on the safety advantages of killed vaccines with the inherent immunological boost derived from de novo virus genome replication and protein synthesis. Multiple groups of scientists have established VLP and replicon systems, some with the ability to undergo multiple rounds of genomic synthesis and replication, but without the ability to produce progeny virus-like particles.^{56, 158, 204, 256, 279, 332, 337, 454, 478, 654} These non-spreading virus-like or replication competent particles have proven to be safe and immunogenic in limited animal model studies, but could provide a mechanism for robust and rapid protection especially in non-endemic or at-risk countries.

Challenges to vaccination acceptance

It is advisable in African countries with large sheep and goat populations to immunize the offspring of vaccinated ewes and nannies on a regular basis at six months of age, when colostral immunity has waned, with a single dose of the modified live Smithburn vaccine. This should afford life-long protection.³⁴ Lambs and kids of susceptible unvaccinated dams can be immunized at any age.⁶⁵⁰

Epidemics of RVF tend to occur at irregular intervals of many years, and it is usually difficult to persuade farmers to vaccinate livestock during long inter-epidemic periods when no apparent losses are occurring to justify vaccination costs. Compounding the sometimes long inter-epidemic periods is that the occurrence of epidemics is difficult to predict and outbreaks typically have a very sudden onset. Ideally, in African countries where RVF is endemic, large sheep and goat populations should be immunized routinely. The offspring of previously vaccinated livestock could be vaccinated on a regular basis at six months of age, when colostral immunity has waned, with a single dose of a modified live vaccine. Typically, this class of vaccines should provide life-long protection.³⁴

Theoretically, the timing of livestock breeding programmes could be altered to avoid the worst effects of the disease on pregnant or young stock,¹³⁵ but RVF epidemics occur too irregularly to make this feasible and other considerations such as the state of pastures in various seasons possibly have a more important bearing on breeding policy.

Due to the sporadic nature of RVF outbreaks, it is difficult to obtain the necessary political or donor support for routine or strategic RVF vaccinations for livestock. The burden of RVF in endemic countries has also not been well determined. To gain political support, research that demonstrates the long-term benefits of routine RVF vaccinations of livestock for public health, economic benefits, and threat reduction is critical. Economics likely remain a key determinant for RVF vaccine development and use. The infrequent nature of RVF disease outbreaks jeopardizes the incentive for manufacturing companies to produce and stockpile vaccines. The vaccine price could be the single most important constraint to livestock producers in developing countries to adopt routine or strategic livestock vaccination.^{165, 191, 271} The use of multivalent vaccines that could provide immunity against a prevalent disease (preferably for which vaccination is mandatory) while immunizing against other diseases of more sporadic nature, such as RVF would be a potentially acceptable strategy to overcome problems related to vaccine production costs. Bivalent recombinant virus-vectored vaccines designed to protect against RVF and  lumpy skin disease^{573, 641} and RVF and bluetongue⁹² have been developed and were shown to be effective in mice and sheep.

No RVF vaccine has been authorised for use in the EU Member States: only emergency vaccination is permitted after authorization and following proper EU procedures.³⁸

Vaccination of at-risk humans

It is essential that humans living in endemic areas and especially veterinarians and others engaged in the livestock industry should be made aware of the potential dangers of exposure to zoonotic agents in handling tissues of diseased animals, and that biosafety and biosecurity precautions should be increased during RVF epidemics. Currently only one human vaccine is approved for emergency use in humans. It is a formalin-inactivated cell culture vaccine (TSI-GSD 200) produced in the USA that is used only to immunize laboratory and field workers who are regularly exposed to RVF infection such as during outbreaks.^{172, 314, 407, 464, 500, 512, 513, 514} The vaccine induces low antibody tires, but human volunteers immunized with three doses administered on Days 0, 7 and 28, and given one booster, remained seropositive for up to eight years, while rats had partial immunity to aerosol infection six months after immunization.^{20, 216, 507}

Recently, efforts to promote the development of licensed RVFV vaccines for humans has gained momentum.^{100, 414} These efforts led by the World Health Organization and the Coalition for Epidemic Preparedness Innovations have united multiple international aid organizations to provide funding and organized efforts to enable several experimental RVFV vaccines to progress towards human safety and efficacy assessment. With this renewed prioritization it is highly likely that the further development of next-generation vaccines for humans will be achievable in the near future. Vaccines lacking infectious genetic material (e.g. recombinant protein-based, VLPs) and replication-deficient virus vectored or replicon vaccines with a high safety profile could be the most appealing in getting regulatory approval for use in humans. Due to the rigorous regulatory requirements and approval process required for human vaccines, the mass vaccination of human populations against RVF may not be a viable option. A more rational strategy would be  to vaccinate at risk personnel or groups: farmers, herders, veterinarians, slaughterhouse workers, and laboratory and research staff, and military and non-military personnel for deployment in RVF endemic risk zones.¹⁹¹

Surveillance and forecasting of outbreaks

Surveillance can be planned with different objectives and approaches and can include forecasting, early warning, raising awareness, outbreak investigations, environmental surveillance, vector surveillance and sentinel herd monitoring.^{199, 203}

Three surveillance methods for RVF, namely, syndromic surveillance, participatory surveillance and risk-based surveillance are recommended by the OIE. The focus of syndromic surveillance is on the detection of clinical disease such as abortions, mortality in livestock and wildlife particularly in newborn and young lambs, kids or calves especially during favourable weather conditions conducive for vector transmission of RVFV. Participatory surveillance focuses on how best animal owners can be helped to identify and solve their health problems and to better understand the risks of RVF. Risk-based surveillance is the surveillance of locations, populations, and periods with increased disease threats with the aim to improve disease detection rapidly and therefore better use of resources. Risk-based surveillance uses quantitative or qualitative information that helps in disease control.^{199, 203}

Sentinel herds are particularly useful to detect inter-epidemic transmission of RVFV.¹⁹⁹ The activities at sentinel sites should include clinical observations and serological monitoring of herds, measurement of rainfall and other climatological parameters and vector sampling and surveillance.¹⁹⁹

Recently, epidemiological models have become available to investigate the various aspects of the epidemiology of RVF.^{127, 416, 575, 604} with the aim to get a better understanding of the factors at play among vectors, hosts and the environment. Predictive models have been developed to act as early warning systems for RVF outbreak occurrence so that surveillance systems can be set up to detect RVFV circulation in mosquitoes and livestock.²⁸

Attempts have been made to utilize satellite imaging to predict RVF outbreaks through the development of green vegetation indices or through monitoring of southern Pacific and Indian Ocean surface temperatures.^{27, 142, 229, 352, 354, 355} A close association between epidemic outbreaks of RVF in East Africa and the occurrence of El Niño has been described.²⁹ NASA developed an outbreak risk mapping system that records monthly RVF risk for Africa and the Middle East based on interpretation of satellite vegetation indices.³⁰⁸

New approaches for the establishment of early warning systems for RVF should include monitoring of climatic data of different environments.^{99, 239} The objective of early warning systems is to provide National Veterinary Services with risk information in order to better plan in advance the resources and the activities to be put in place and to respond promptly and thereby minimizes the impact of the disease on animal and human health. Similarly, the provision of vaccines, trained staff, and suitable diagnostic tests is of paramount importance in infected countries.^{253, 260}

Climate change and extreme weather events during the last decades may support the expansion of the geographical range of RVF northwards and into the Mediterranean countries.²³⁹ Forecasting models and livestock trade/movement data^{239, 324} may be useful in future to predict outbreaks of RVF outbreaks.²³⁹

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