Critical Reviews in Microbiology

ISSN: 1040-841X (Print) 1549-7828 (Online) Journal homepage: http://www.tandfonline.com/loi/imby20

Vector independent transmission of the vectorborne bluetongue virus Mirjam Tineke Willemijn van der Sluijs, Abraham J. de Smit & Rob J. M. Moormann To cite this article: Mirjam Tineke Willemijn van der Sluijs, Abraham J. de Smit & Rob J. M. Moormann (2014): Vector independent transmission of the vector-borne bluetongue virus, Critical Reviews in Microbiology To link to this article: http://dx.doi.org/10.3109/1040841X.2013.879850

Published online: 19 Mar 2014.

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http://informahealthcare.com/mby ISSN: 1040-841X (print), 1549-7828 (electronic) Crit Rev Microbiol, Early Online: 1–8 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/1040841X.2013.879850

REVIEW ARTICLE

Vector independent transmission of the vector-borne bluetongue virus Mirjam Tineke Willemijn van der Sluijs1, Abraham J. de Smit2, and Rob J. M. Moormann3,4 MSD Animal Health, Research and Development, Wim de Korverstraat, Boxmeer, The Netherlands, 2Merial, Research and Development, Lyon, France, 3Central Veterinary Institute, Lelystad, The Netherlands, and 4Department of Infectious Diseases and Immunology, Virology Division, Utrecht University, Yalelaan, The Netherlands

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Abstract

Keywords

Bluetongue is an economically important disease of ruminants. The causative agent, Bluetongue virus (BTV), is mainly transmitted by insect vectors. This review focuses on vector-free BTV transmission, and its epizootic and economic consequences. Vector-free transmission can either be vertical, from dam to fetus, or horizontal via direct contract. For several BTV-serotypes, vertical (transplacental) transmission has been described, resulting in severe congenital malformations. Transplacental transmission had been mainly associated with live vaccine strains. Yet, the European BTV-8 strain demonstrated a high incidence of transplacental transmission in natural circumstances. The relevance of transplacental transmission for the epizootiology is considered limited, especially in enzootic areas. However, transplacental transmission can have a substantial economic impact due to the loss of progeny. Inactivated vaccines have demonstrated to prevent transplacental transmission. Vector-free horizontal transmission has also been demonstrated. Since direct horizontal transmission requires close contact of animals, it is considered only relevant for within-farm spreading of BTV. The genetic determinants which enable vector-free transmission are present in virus strains circulating in the field. More research into the genetic changes which enable vector-free transmission is essential to better evaluate the risks associated with outbreaks of new BTV serotypes and to design more appropriate control measures.

Bluetongue, cattle, sheep, transmission, vaccination

Introduction Bluetongue is a disease in wild and domestic ruminants, caused by Bluetongue virus (BTV), an orbivirus in the Reoviridae family. BTV is a non-enveloped virus with a complex structure: two concentric protein shells encapsidate a double stranded RNA genome, comprised of 10 segments (Roy, 2005). These 10 segments encode 11 proteins: structural proteins VP1 to VP7 and non-structural proteins NS 1 to 4. The outer layer of the viral capsid is formed by VP2 and VP5; these proteins are involved in cell attachment and entry of the virus particle. Once a BTV particle has entered the cell, the outer layer of the viral capsid is removed, revealing an infectious core particle which consists of VP3 and VP7 (the inner layer of the capsid), the transcription complex formed by VP1, VP4 and VP6, and the ds RNA (Roy, 2005). The BTV serogroup is a relatively heterogeneous group within the Orbivirus genus. The group can be divided into serotypes, which are largely determined by variations in the outer layer protein VP2. Currently, 24 serotypes have been officially recognized, isolates from Kuwait, Switzerland have

Address for correspondence: Mirjam Tineke Willemijn van der Sluijs, DVM, MSD Animal Health, Research and Development, Wim de Korverstraat 35, PO Box 31, Boxmeer 5830 AA, The Netherlands. E-mail: [email protected]

History Received 26 October 2013 Accepted 18 December 2013 Published online 19 March 2014

been proposed as 25th and 26th serotype (Hofmann et al., 2008; Maan et al., 2011). But even within one serotype, considerable genetic and phenotypic variation can be found. Like other RNA viruses, BTV can generate genomic variation by both mutations during RNA replication and by recombination (Bonneau et al., 2001). Furthermore, the segmented genome of BTV allows for re-assortment of genome segments in host cells that are concurrently infected with two different BTV strains (Maan et al., 2010, 2012; Shaw et al., 2013). As a result, a BTV strain exist as a swarm of closely related variants with one or more dominant sequences (quasispecies) (Bonneau et al., 2001), which confers a high potential to adapt to changes in the environment and thus for rapid evolution of the virus. The natural route of BTV transmission is through hematophageous Culicoides midges (Du Toit 1994); only 50 of the approximately 1500 known Culicoides species are known to be effective BTV vectors. Until 1998, BTV was known to be present in tropical or temperate regions, stretching from approximately 35 S to 45 – 50 N (Gibbs & Greiner, 1994; Mertens et al., 2002). Outbreaks in Europe were limited to the southern areas, where the (sub)tropical BTV vector C. imicola was present. From 1998 onwards, different BTV serotypes invaded Europe from the south and the south-east, transported by Culicoides species that were previously not known to be effective BTV vectors in the field (De Liberato et al., 2005).

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After inoculation by the bite of a Culicoides midge, BTV replicates primarily in the endothelial cells of capillaries and small blood vessels. This results in endothelial damage, which induces vascular thrombosis and infarction, hemorrhages and ultimately necrosis. The course of a BTV infection can vary from acute to chronic, with clinical signs ranging from fever, edema, erosions of the mucosa, salivation, anorexia, nasal discharge, coronitis, to severe loss in condition and death. The typical cyanotic tongue, to which the virus owes its name, is seen only in a limited number of cases. Sheep is the domestic species which is clinically most severely affected; apart from BTV-8, clinical BTV cases in cattle and goats are rare. The clinical manifestation of the disease can vary substantially between different breeds of sheep and even between individuals. Mortality in sheep ranges from around 5 to 30%, sometimes even up to 70% (Gambles, 1949). Exactly these high mortality outbreaks of BTV have in the past caused concern among countries in which sheep rearing is an economically important sector. The potential severe impact of a BTV outbreak in those countries prompted the World Organization for Animal Health (OIE) to include BTV in the list of notifiable diseases (Gibbs & Greiner, 1994). The subsequent imposition of strict guidelines on movement of animals, embryos, semen and other animal products from BTV endemic regions has caused substantial economic damage to the BTV affected areas; even more damage than the direct economic losses caused by BTV-induced morbidity and mortality (MacLachlan & Osburn, 2006).

History of Bluetongue and BTV-vaccination Bluetongue was first described in South Africa, with the introduction of fine-wool sheep breeds in the late nineteenth century. Spreull was one of the first to document a detailed study on Bluetongue sheep in 1905 (Spreull, 1905), suggesting the name ‘‘Bluetongue’’ for the disease that was at the time known as malarial catarrhal fever, epizootic catarrh, beksiekte or bloutong. The disease had a major impact on sheep farming, not so much because of the disease mortality, but rather by the great loss in condition, wool break and abortions. Therefore, several attempts were made to find a means to protect sheep against the disease. In 1908, Theiler (1908) reported that a BTV strain, which was passed through several generations of sheep, could induce protection against BTV-associated mortality. Although this primitive vaccine had severe side effects and limited cross protection, it was used frequently until the 1940s (Verwoerd, 2009), since it allowed for rearing sheep in otherwise unfavorable areas (McKercher et al., 1957). However, the Theiler vaccine failed to protect during outbreaks of more antigenically distinct BTV strains. Attempts to repeat sheep passage attenuation with other isolates of BTV were unsuccessful, probably because the Theiler strain was already low pathogenic in nature, and the sheep passage did not induce a true attenuation of the virus (Neitz, 1948). In 1940, Mason et al. managed to culture and subsequently attenuate BTV by multiple passages on embryonated chicken eggs (ECE) (Mason et al., 1940), which then became the

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method of choice for the production of live attenuated BTV vaccines. The cultivation of BTV on cell culture by Haig et al. (1965) was another major achievement in the history of Bluetongue research. Soon after that discovery, the vaccine production was converted from ECE to cell culture; a production method that is still used today.

Transplacental transmission of BTV Bluetongue outbreaks in the USA in the early 1950s, instigated the development of live attenuated vaccines, using the South African ECE method (Hardy & Price, 1952; McGowan, 1953; McKercher et al., 1957). These vaccines were used extensively in the areas where BTV was present. In 1955, Shultz & DeLay (1955) reported an increase in stillbirths and weak, spastic or blind live lambs in flocks that were vaccinated with the live, egg-attenuated, BTV vaccine. Necropsy revealed severe degenerative central nervous system lesions. Several reports from the field confirmed the association between vaccination against BTV and congenital malformations in sheep, and later also in cattle (Brown & MacLachlan, 1983; McKercher et al., 1970). Many experiments have since been done to investigate the causative relationship between BTV and fetal central nervous system defects, by direct inoculation of BTV into the fetus (Enright & Osburn, 1980; MacLachlan & Osburn, 1983; Osburn et al., 1971a,b; Waldvogel et al., 1992), by inoculation of the dams at different gestational stages (Concha-Bermejillo et al., 1993; Parsonson et al., 1994) or by infected Culicoides vectors (Luedke et al., 1977a). Throughout the years, transplacental transmission has been demonstrated for several BTV serotypes, which are listed in Table 1. It should be noted, though, that most of these experiments used BTV strains that had been given multiple in vitro passages, or that had been isolated from the field in areas where live attenuated vaccines were used and therefore might have been circulating vaccine strains (Barnard & Pienaar, 1976). Other strains, which had been given only a limited number of in vitro passages failed to induce transplacental transmission (Flanagan et al., 1982; Roeder et al., 1991). This led to the hypothesis that transplacental transmission was a characteristic exclusive to live attenuated vaccine strains. Due to the detrimental effects on pregnant animals, the egg-produced vaccines were withdrawn from the market and replaced by cell culture attenuated vaccines. This reduced the incidence of transplacental transmission of BTV under natural conditions, and the incentive to research the mechanisms of transplacental transmission declined.

Field isolates versus attenuated vaccine strains In 1985, Richardson et al. (1985) demonstrated that a BTV-4 isolate, which had never been passaged in vitro, was also capable of crossing the placenta and causing infection in fetal lambs. The fact that this strain was not adapted to cell culture was substantiated by the fact that in vitro culture of this virus was not possible. Recently, transplacental transmission of BTV-2 in experimental conditions has been demonstrated with a strain

Vector independent transmission of the vector-borne bluetongue virus

DOI: 10.3109/1040841X.2013.879850

Table 1. Transplacental transmission of various serotypes of BTV reported in literature (in order of serotype and year of publication). Serotype BTV-2

BTV-4 BTV-8

Species Cattle, sheep, goat Sheep Sheep Sheep Cattle Cattle Cattle Cattle Cattle Sheep Cattle Sheep Cattle Sheep

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Cattle Cattle Cattle, sheep, goat BTV-10 Sheep Sheep

BTV-9

Cattle Cattle

Type of study

Reference

Field observation* Savini et al. (2014) Experimental Experimental Experimental Field observation Field observation Field observation Field observation Experimental Field observation Field observation Experimental Field observation Experimental

Rasmussen et al. (2013) Richardson et al. (1985) Gibbs et al. (1979) Menzies et al. (2008) De Clercq et al. (2008) Desmecht et al. (2008) Darpel et al. (2009) Backx et al. (2009) Saegerman (2011) Santman-Berends (2010) Worwa et al. (2009) Wouda et al. (2008) van der Sluijs et al. (2011) Experimental van der Sluijs et al. (2012) Field observation Zanella et al. (2012) Field observation* Savini et al. (2014)

Field observationy Schultz & Delay (1955) Experimental Anderson & Jensen (1969) Field observation McKercher et al. (1970) Field observation Brown & MacLachlan (1983) Experimental Parsonson et al. (1994) Experimental Stott et al. (1982)

Sheep BTV-11 Cervus canadensis (elk) BTV-13 Cattle Experimental BTV-16 Sheep Experimental BTV-23 Sheep Experimental

Luedke et al. (1977a) Gibbs et al. (1979) Flanagan & Johnson (1995)

*This paper describes the transplacental transmission of the BTV-2 and BTV-9 vaccine strain. yThe BTV serotype was not mentioned in the original paper. This paper describes the transplacental transmission of the live attenuated vaccine, which was BTV-10 based.

isolated during the Italian outbreak in 2001 (Rasmussen et al., 2013). Transplacental transmission had previously been shown for the live attenuated BTV-2 vaccine strain that was used in Italy (Savini et al., 2014). A Spanish isolate of BTV-1, which had had three in vitro passages, has been demonstrated to be able to cross the placenta and infect lamb fetuses with severe pathological consequences (van der Sluijs et al., 2013b). Although BTV-1 has never been present in modified live vaccines used in Europe (Savini et al., 2008), sequence analysis of BTV-1 isolates from Morocco – from which the BTV-1 outbreak in Spain originated – showed similarities with the South African BTV-1 vaccine strain (Maan et al., 2008). Moreover, the western BTV-2 and BTV-4 field strains show a high sequence similarity to the South African BTV-2 and BTV-4 vaccine strains for several of their genome segments (Maan et al., 2010). Despite these similarities, none of the other BTV strains have demonstrated transplacental transmission to the extent of BTV-8 in natural circumstances, even though transplacental transmission was reported under experimental conditions. Transplacental transmission of BTV has always been attributed to multi-passaged live attenuated vaccine strains.

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Reports of ‘‘natural’’ transplacental transmission in unvaccinated ruminants were reported in areas where live attenuated vaccines have been used previously, and as such these ‘‘natural’’ cases were disregarded, since they were considered to be caused by circulating vaccine strains or re-assortants thereof (MacLachlan & Osburn, 2008). This touches upon a difficult issue in the discussion on transplacental transmission of BTV. Live attenuated BTV vaccine strains are known to spread and recombine with other BTV strains (Batten et al., 2008). These vaccines have been used for several decades in various parts of the world (Coetzee et al., 2012; Savini et al., 2008; Wark et al., 1982), which makes it almost impossible to prove that a field strain is completely free of vaccine virus-derived genome sequences. Bluetongue viruses, like most RNA viruses, lack a proofreading subunit in their RNA-dependent RNA polymerase (Bonneau et al., 2001); therefore, errors in the RNA replication process will result in spontaneous mutations. Multiple in vitro (or in ovo) passages will lead to a positive selection for sequence variants which have a higher capability to grow in the artificial culture system. These sequence variants also may have other phenotypic characteristics such as decreased virulence (hence they were used as live attenuated vaccine strains), or changes in tissue tropism or host range (Akita et al., 1994; Kirkland & Hawkes, 2004). It is interesting to speculate, though, what happens if such a multi-passaged vaccine strain starts to circulate in the field. Would multiple passages through its hosts and vector, and absence of the positive selection pressure for growth in vitro, reverse or further alter the selection for minor sequence variants induced by the in vitro passages? This is of course very difficult to determine, but it can be postulated that, without the selective pressure of in vitro culture, BTV strains are not likely to retain those phenotypic changes over several generations unless they provide other advantages in the field. Even though BTV is considered a very well characterized virus, the molecular determinants that influence the process that enables it to cross the ruminant placenta are not yet known. More research is needed to identify the viral proteins and cells involved in the underlying mechanisms of BTV transplacental transmission. Once the changes to the viral proteins involved have been identified, the information may shed light on whether transplacental transmission is either truly caused by mutations induced via multiple in vitro passages or an intrinsic property of certain strains of BTV.

Introduction of BTV-8 in north-western Europe In August 2006, a BTV serotype 8 strain (BTV-8\net2006) caused an unprecedented outbreak of Bluetongue in northwestern Europe. It was not only the single most economically damaging BTV outbreak ever, but this particular BTV-8 strain also had some unique epizootical and pathological properties. The initial outbreak in 2006 was relatively limited, infecting merely 2000 holdings in the Netherlands, Belgium, Luxemburg, Germany and France. However, the virus resurfaced in 2007 and again in 2008, causing infections in an area ranging from Sweden to Italy and from the UK to the Czech Republic and Hungary (Saegerman et al., 2008). The spreading of BTV-8 involved Culicoides obsoletus and

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C. pulicaris, which were previously not known to be very effective BTV vectors in the field (Wilson & Mellor, 2008). Following the BTV-8 epizootic, an outbreak of hydranencephaly was noted in aborted calves (Wouda et al., 2008); spleen tissue of several fetuses was positive for BTV RNA. Reports from other countries confirmed the ability of BTV-8\net2006 to cross the placenta and infect the fetus both in cattle and sheep (Darpel et al., 2009; De Clercq et al., 2008; Desmecht et al., 2008; Saegerman et al., 2011; Zanella et al., 2012). The brain lesions in these animals closely resembled the lesions seen in fetuses experimentally or naturally infected with the live attenuated BTV vaccine strains, reported previously in the USA and in other countries. These new properties led to the speculation that BTV-8\net2006 was of vaccine origin. However, sequence analysis showed that BTV-8\net2006 differed from the BTV-8 vaccine strain incorporated in the South African Group B multivalent vaccine (93.4 and 94.8% nucleotide sequence homology in segment 2 (VP2) and segment 6 (VP5), respectively) (Maan et al., 2008). BTV-8\net2006 showed a higher similarity with a Nigerian isolate of BTV-8 (VP2: 97% and VP5: 97.7% nucleotide identity).

Epidemiological relevance of alternative transmission routes Transplacental transmission and viral persistence The relevance of non-vector associated transmission routes for the epizootiology of BTV has been a subject of debate for years. It has been recognized that transplacental transmission could play a role in the overwintering mechanisms of the virus (i.e. survival during periods of vector absence due to adverse weather conditions) (Gibbs et al., 1979). If transplacental transmission plays a role in the epizootiology of BTV, infectious virus should be present after the birth of the in utero infected lambs/calves, in sufficiently high titers and for a sufficiently long period to allow for infection of Culicoides. In 1977, Luedke et al. (1977a) demonstrated that BTV-13 infection of pregnant cattle could lead to transplacental infection of calves, associated with persistent viremia and lack of antibody induction. Culicoides, feeding on these calves, became infected with BTV, suggesting that these calves could start a new round of BTV transmission (Luedke et al., 1977b). More recently, the validity of this work has been challenged, since others failed to induce clinically normal persistently infected calves (MacLachlan & Osburn, 1983; MacLachlan et al., 1985; Roeder et al., 1991). Presence of infectious BTV after the birth of the in utero infected offspring has been demonstrated, but only for a limited time period in most experiments (De Clercq et al., 2008; Gibbs et al., 1979; Jochim et al., 1974; Richardson et al., 1985; Savini et al., 2012). In many cases, the new-born animals had a poor condition and died soon after birth. In the animals which survived, the presence of BTV RNA persisted for a longer time period, sometimes up to 160 days after birth (Darpel et al., 2009). The significance of the presence of BTV RNA in the blood of new-born lambs for the epizootiology is not known. Prolonged presence of viral RNA in blood has

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been described after BTV infection of both adult sheep and cattle (Bonneau et al., 2002; Katz et al., 1994), but this RNA positive, virus isolation negative blood was neither infectious for sheep nor for the vector C. sonorensis (Bonneau et al., 2002; MacLachlan et al., 1994). In an experiment conducted by van der Sluijs et al. (2013a), infectious BTV could be isolated from the blood of 5/23 lambs for maximum 1 week after birth, but BTV RNA persisted until 14 weeks after birth. The BTV RNA persistence in these lambs differed from the prolonged RNA persistence in adults in two aspects: (i) the RNA load at birth was as high as the RNA load at the peak of viremia after experimental infection (Moulin et al., 2012), and (ii) lambs with low Ct values (Ct ¼ threshold cycle: the number of PCR cycles at which the fluorescence exceeds the threshold. A low Ct value is indicative for a high RNA load) showed an increase in the humoral immune response during the 14 weeks after birth, which might imply that there is still some infectious virus present in the lambs. It remains to be determined whether or not the blood from these lambs was infectious to Culicoides. Field experience from the recent BTV-8 outbreak and experimental findings indicate that there is no evidence of induction of BTV persistence in the offspring after in utero infection. Many viruses replicate in fetal tissues. This is not surprising, since the developing fetus provides a unique niche that offers both multiplying pluripotent cells and protection from the adult immune system. In many cases, like bovine herpes virus and bunyaviruses, infections in utero cause damage in the developing fetus leading to resorption, abortion, or the birth of weak or malformed offspring. Therefore, it is unlikely that transplacental transmission is important for the epizootiology of these viruses. In contrast, transplacental transmission plays a significant role in the epizootiology of pestiviruses, especially in bovine viral diarrhoea virus (BVDV). Infection with non-cytopathogenic BVDV during a certain stage in the development of the fetus – i.e. after the first critical embryonic stage and before the development of immunocompetence – can lead to life-long persistence of the infection. Most of these persistently infected (PI) animals have an impaired general condition and many succumb to mucosal disease within the first two years of life (Potgieter, 2004). Yet, there are reports of PI heifers reaching the reproductive period, leading to the birth of a new generation of PI animals (McClurkin et al., 1979). PI bulls can also produce a new generation of PI animals: a healthy, normally developed, two-year old PI bull was used at an artificial breeding center; insemination with the semen of this bull (which was of normal quality and morphology) led to the birth of 2 PI calves on a total of 61 (Kirkland et al., 1994). One of the characteristics of PI animals is the lack of development of a (humoral) immune response against the virus with which they were infected in utero, whereas for BTV, in almost all cases antibodies are induced at some time point after in utero infection. This would suggest that the immunological mechanisms that play a role in the prolonged BTV viremia differ from the mechanisms that allow true persistence of pestiviruses. Possibly, true persistence of virus

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DOI: 10.3109/1040841X.2013.879850

Vector independent transmission of the vector-borne bluetongue virus

infection requires special features which deregulate the host’s immune system. For BVDV, both the Npro protein (autoprotease and inhibitor of the type I interferon pathway) and the Erns protein (ribonuclease and inhibitor of dsRNA-induced IFN synthesis) are associated with transplacental transmission and subsequent persistent infection (Peterhans & Schweizer, 2013). Recently, two BTV proteins have been associated with the mechanisms that counteract the hosts antiviral response: NS3 has been shown to interfere with interferon synthesis pathway (Chauveau et al., 2013) and NS4 of BTV-8 conferred a replication advantage in cells in an antiviral state (Ratinier et al., 2011). It remains to be investigated, if these immuneevasive functions are involved in transplacental transmission of BTV. In contrast to BVDV, transplacental transmission of BTV is considered of little to no importance to the epizootiology in endemic areas. Yet, experiences in Northern Ireland demonstrate that BTV can be introduced in a previously free zone via in utero infected calves (Menzies et al., 2008). A new BTV introduction leads to the implementation of a series of rules and measures to contain the BTV outbreak. These measures seriously impact livestock farming and severely disrupt international trade of animals and animal derived materials. Transplacental transmission of BTV might therefore be unimportant from an epizootiological viewpoint; the possible economic impact of BTV transplacental transmission should not be neglected. Horizontal transmission Apart from its features to cross the ruminant placenta, BTV-8 has also shown the ability to transmit horizontally in the absence of the insect vector. Menzies et al. (2008) describe a BTV infection of cattle through direct contact, possibly due to ingestion of BTV contaminated placentas. Also in an experimental setting, colostrum spiked with BTV-8 infected blood led to oral BTV-8 infection of a calf (Backx et al., 2009). This is, however, not unique to BTV-8 (see also Table 2). Batten et al. (2012) describe direct contact transmission of BTV-26 in goats under experimental conditions; they were able to detect BTV-26 RNA in the nasal swabs of two infected goats. In an experiment with BTV-1 infection in red deer, a contact deer became infected with BTV-1, possibly via blood transfer from fighting wounds (Lo´pez-Olvera et al., 2010). Both BTV-8 and BTV-1 can be transmitted horizontally between sheep in a vector-free environment (van der Sluijs et al., 2011, 2013b). Control ewes that were in close contact with BTV-8 or BTV-1 infected ewes became BTV RNA

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positive approximately 2–3 weeks after the inoculation of the infected ewes. The route of infection in these contact animals is not known. In both our experiments, the direct infected control animals were housed together with ewes experiencing severe clinical signs of BTV, sharing drinking water and trough. Therefore, we consider infection through saliva/blood contaminated feed or water is the most likely route of infection in our experiments. However, infection through nasal virus excretion cannot be excluded, since nasal swabs were not taken during these experiments. Current literature indicates that vector-free horizontal transmission of BTV probably is an infrequent event which requires close contact of animals. The relevance for the epizootiology is therefore limited, especially in endemic areas. It can, however, influence the morbidity rates within a farm; these findings might instigate adaption of hygiene measures and veterinary practices during a BTV infection on a farm (Zientara et al., 2010).

BTV vaccination Vaccination is a very effective and practical way to protect animals from BTV infection. The use of BTV vaccines in Europe has been reviewed extensively by others (Savini et al., 2008; Zientara & Sa´nchez-Vizcaı´no, 2013). Basically, there are three major categories of vaccines: live attenuated, inactivated and ‘‘next generation’’ vaccines, the latter category containing several (experimental) vaccine types such as recombinant viruses and virus-like particle vaccines. This review focuses on the inactivated vaccines, since they are the currently preferred vaccine type in Europe due to their proven efficacy and safety profile. Various inactivated BTV vaccines have been shown to effectively reduce disease incidence and severity in different ruminant species (Bre´ard et al., 2011; Hamers et al., 2009; Moulin et al., 2012; Savini et al., 2009). Furthermore, vaccination reduces within farm transmission of BTV, even if not every individual animal is protected (Gubbins et al., 2012). Vaccination with an inactivated vaccine has also a proven effect on transplacental transmission. Galleau et al. (2009) demonstrated the efficacy of an inactivated BTV-8 vaccine against transplacental transmission of BTV-8 in a field situation in cattle. In an experimental setting, vaccination with an inactivated BTV-8 vaccine has been shown to very efficiently block transplacental transmission in sheep (van der Sluijs et al., 2012). In cattle, the incidence of transplacental transmission was too low to demonstrate a significant

Table 2. Horizontal transmission of BTV reported in literature (in order of serotype and year of publication).

Serotype BTV-1 BTV-2 BTV-8 BTV-11 BTV-26

Species

Type of study

Suggested route of transmission

Reference

Sheep Cervus elaphus (red deer) Sheep Cattle Cattle Sheep Cattle Goats

Experimental Experimental Experimental Field observation Experimental Experimental Field observation Experimental

Direct contact/oral Oral/wound Oral Oral (placenta) Oral (colostrum) Direct contact/oral Oral (colostrum) Direct contact

van der Sluijs et al. (2013b) Lo´pez-Olvera et al. (2010) Rasmussen et al. (2013) Menzies et al. (2008) Backx et al. (2009) van der Sluijs et al. (2011) Mayo et al. (2010) Batten (2013)

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reduction of transmission; however, vaccination prevented BTV viremia in the heifers. This suggests that the vaccine might prevent transplacental transmission in cattle as well. Vaccination could therefore help to reduce the economic losses caused by transplacental transmission of BTV. The incursion of multiple serotypes into Europe has prompted the development of multivalent vaccines, since the individual serotypes of BTV provide limited to no crossprotection to other serotypes. However, there is a limit to the number of serotypes that can be included in a single vaccine, since interference of strains, leading to unsatisfactory vaccine efficacy, has been reported (Verwoerd, 2009). Therefore, more research is needed on next generation vaccines, which allow a quick response upon the incursion of new serotypes, larger combinations of serotypes and flexible and affordable vaccine production.

Concluding remarks Transplacental transmission of BTV has been regarded a feature exclusive to multi-passaged vaccine strains and as such a ‘‘man-introduced’’ artefact, relatively unimportant for the epizootiology of BTV. However, the discussion whether transplacental transmission is exclusively caused by multi-passaged vaccine strains is irrelevant in our view. The recent BTV-8 epizootic has shown that the genetic determinants which influence the ability to cross the placenta are circulating in the field, regardless of their origin. Given the capability of BTV to reassort genome segments, it is not unlikely that other BTV serotypes might acquire the same abilities. In fact, it has recently been demonstrated that field isolates of BTV-1 and BTV-2, which have been given 2 or 3 in vitro passages, are capable of crossing the ruminant placenta (Rasmussen et al., 2013; van der Sluijs et al., 2013b). Therefore, more research is essential to gain a better understanding of the mechanisms underlying the genotypic changes that drive the ability to cross the placenta. For one, if the genetic determinants of transplacental transmission are known, vaccine strains could be screened for the presence of these determinants. Moreover, when a new BTV strain emerges in the field, knowledge on the presence of these genetic determinants would allow for a better assessment of the risk this new strain poses for the livestock industry. This would allow for BTV control measures which are tailor-made for the new BTV strain and avoid unnecessarily stringent control measures, evoking unnecessary damage to the livestock industry.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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