Epidemiology of bovine virus diarrhoea virus

A better understanding of the epidemiology and pathogenesis of bovine virus diarrhoea virus (BVDV) has emerged in recent years. Fetal infections and in particular those resulting in birth of persistently infected calves are of central importance for the epidemiology of BVDV. A prevalence of persistently infected, viraemic animals of about 1% is found in Denmark and elsewhere by examination of randomly collected blood samples. A recent field study shows that 53% of randomly selected herds in an area in Denmark where BVDV is endemic had one or more persistently infected animals. Persistently infected cows may breed and will always transmit the infection to the calf. Such familial occurrence of persistent infection seems to be a fairly common phenomenon. Persistently infected cattle are important sources of infection to other cattle. Transiently infected cattle following experimental exposure will usually not transmit the infection by contact but this may not always apply to cattle after natural infection. Knowledge of the occurrence and potential for spread of virus from persistently infected bulls is reviewed. Virus is excreted with semen of both persistently and transiently infected bulls and BVDV may be transmitted by use of infected semen for insemination. The potential for spread of the infection through embryo transfer should be avoided by the use of adequate testing and controls.     

Electron microscopy of bovine virus diarrhoea virus

Bovine virus diarrhoea virus (BVDV) has been (tentatively) identified by electron microscopy in purified virus preparations, in infected cell cultures and in tissues and cells from infected animals. These studies have revealed a spherical membrane-bound particle with a diameter of 40-60 nm. The membrane is smooth, bilaminar and surrounds a dense or semi-dense core of 20-25 nm. The core particle may be isometric or hexagonal. In studies of the morphogenesis of BVDV in infected cell cultures, it was found that assembly and maturation of the viral particles occur via a condensation process within membrane-bound vesicular organelles, in which the virions subsequently accumulate. Release of the virus occurs when the cell finally lyses and/or via exocytosis. Thus, both with regard to morphogenesis and to morphology, BVDV bears close resemblance to the Flaviviridae.     

Molecular biology of bovine virus diarrhoea virus

Our understanding of the molecular biology of bovine virus diarrhoea virus (BVDV) has greatly increased over the past several years. The development of monoclonal antibodies (MAB's) has identified a key antigen of BVDV while at the same time providing evidence for considerable variation in this protein. MAB's, particularly those directed against the p80 protein, can be developed for use in diagnostic tests while others may be useful in molecular epidemiological studies of BVDV. The successful cloning of BVDV and hog cholera virus can provide nucleic acid probes for use in routine diagnostic testing, for use in pathogenesis studies and for the detection of BVDV contamination in biological materials. With the identification of the key antigens of BVDV and its molecular cloning, the future holds the promise of vectored vaccines which can provide the efficacy of modified-live vaccines with the safety of killed vaccines. However, much work still must be done to define the significance of the antigenic variation of BVDV as it relates to providing protection for the developing fetus.     

The pathogenesis of bovine virus diarrhoea virus infections

Bovine virus diarrhoea virus (BVDV) disease in cattle ranges from the transient acute infections, which may be inapparent or mild, to mucosal disease which is inevitably fatal. On occasions the acute infections can lead to clinical episodes of diarrhoea and agalactia but as these syndromes cannot be reproduced experimentally, the pathogenesis remains unclear. The immunosuppressive effect of acute BVDV infections can enhance the clinical disease of other pathogens and this may be an important part of the calf respiratory disease complex. Although BVDV antigen has been demonstrated within the lymphoid tissues, for prolonged periods, the evidence for viral latency remains to be proven. Venereal infection is shown to be important in the transfer of virus to the foetus and congenital infections can cause abortions, malformations and the development of persistently viraemic calves. The two biotypes of the virus, non-cytopathogenic and cytopathogenic, are described. Their sequential role in the pathogenesis of mucosal disease arises from the initial foetal infection with the non-cytopathogenic virus and the subsequent production of persistently viraemic calves. These calves may later develop mucosal disease as a result of superinfection with a "homologous" cytopathogenic virus. The possible origin of this biotype by mutation is discussed. Chronic disease is defined as a progressive wasting and usually diarrhoeic condition; it is suggested that this may develop following superinfection of persistently viraemic cattle with a "heterologous" cytopathogenic biotype.     

Clinical aspects of bovine virus diarrhoea virus infection

Bovine virus diarrhoea virus (BVDV) infection of cattle results in a wide range of clinical manifestations. This article reviews the clinical responses associated with BVDV and discusses these diseases in terms of acute infection in immunocompetent cattle, fetal infection, infection in cattle immunotolerant to and persistently infected with BVDV and finally mucosal disease.     

Immunological responses to bovine virus diarrhoea virus infections

Infection of normal calves with bovine virus diarrhoea virus (BVDV) is a transient self-limiting infection that can result in a period of immunosuppression. The virus appears to be able to replicate in all of the major lymphocyte sub-populations as well as in accessory cells. This may result in the leukopenia that is often a sequel of infection and affects B-cells as well as the T-cell sub-populations expressing either BoCD4 or BoCD8 antigens. B and T-cell responses are affected as a consequence of exposure to BVDV and there is a reduced ability to control other infections. Evidence is summarised and shows that immunoglobulin is an important mediator of immunity to infection with BVDV. Although the foetus can mount an immune response in the latter part of gestation, during the first trimester it does not. A specific state of tolerance is induced and this is associated with change in the proportion of certain lymphocyte sub-populations and ability to respond to immune stimulation.     

Prevalence of bovine viral diarrhoea virus antibodies in India

A study was undertaken regarding the prevalence of bovine viral diarrhoea virus (BVDV) antibodies in bovine sera which tested negative for rinderpest and peste des petits ruminants virus antibodies. The samples were collected between January 1996 and December 1997. A total of 439 samples (327 cattle and 112 buffalo from 17 states of India) were tested using a commercial enzyme-linked immunosorbent assay (ELISA) kit. The mean prevalence of BVDV antibodies in cattle was 15.29% (50/327) in 16 states compared to 23.21% (26/112) in buffalo in 9 states, with an overall prevalence of 17.31% (76/439) in 17 states. The serological evidence that BVDV infection is widespread in India is of utmost practical importance because of the clinical resemblance to rinderpest. A differential diagnosis between these two diseases is critical in view of the declaration by India of provisional freedom from rinderpest disease; active sero-surveillance is to begin in 2000 to achieve certification of freedom from rinderpest infection by the Office International des Epizooties.     

A novel subunit ISCOM vaccine against bovine virus diarrhoea virus.

The preparation and preliminary testing of a subunit ISCOM (immunostimulating complex) vaccine against bovine virus diarrhoea virus (BVDV) is described. Vaccination of calves with this vaccine yields high neutralising titres against a panel of Danish BVDV field isolates. The serological difference between virus isolates and vaccine strain selection is discussed.     

Incidence, epidemiology and control of bovine virus diarrhoea virus in South America

Outbreaks of diarrhoea associated with mucosal erosions of the mouth, tongue and digestive tract, clinically diagnosed as bovine virus diarrhoea-mucosal disease (BVD-MD), have been reported in Argentina and Brazil since the 1960's. However, primary isolation of the virus of BVD-MD is fairly recent, occurring in 1974 for Brazil, 1984 for Argentina, 1985 for Chile and 1981 for Colombia. In Argentina both cytopathogenic and non-cytopathogenic BVD virus strains have been identified. Elsewhere in South America this differentiation does not seem to have been carried out. Serological surveys have confirmed the existence of BVD virus infection in six countries (Argentina, Brazil, Chile, Colombia, Peru and Uruguay), with an incidence rate ranging between 37 and 77% of cattle in the areas surveyed. Diarrhoea in calves between 3 and 18 months of age, often associated with mucosal erosions, has been the most commonly observed syndrome. In some cases an upper respiratory tract involvement was described. In one epizootic, in the Sabana de Bogota plateau of Colombia, reproductive failure associated with abortions or birth of weak calves was the main clinical syndrome.     

The control of bovine viral diarrhoea virus in Europe: today and in the future

This paper summarises the views of a European group of scientists involved in the control of bovine viral diarrhoea virus (BVDV), as part of a European Union Thematic Network. The group concludes that the technical tools and the knowledge needed to eradicate BVDV are at hand, as proven by successful national control schemes in several European countries. A generic model for BVDV control is presented, which includes biosecurity, elimination of persistently infected animals and surveillance as central elements. These elements are termed 'systematic', in contrast to control efforts without clear goals and surveillance to evaluate progress. The network concludes that a systematic approach is needed to reach a sustainable reduction in the incidence and prevalence of BVDV in Europe. The role of vaccines in systematic control programmes is considered as an additional biosecurity measure, the effect of which should be evaluated against cost, safety and efficacy. It is also concluded that active participation by farmers' organisations is a strong facilitator in the process that leads up to the initiation of control, and that public funding to support the initiation of organised BVD control programmes can be justified on the basis of expected wider societal benefits, such as animal welfare and reduction in the use of antibiotics. If applied successfully, the focus on biosecurity in systematic BVD control programmes would also reduce the risk of the introduction and spread of other epizootic and zoonotic agents, thereby improving both cattle health and welfare in general, as well as increasing the competitiveness of the cattle industry.     

Bovine virus diarrhoea virus: an introduction

In view of the recently established genome organisation of pestiviruses, their classification as members of the togavirus family is no longer tenable. They should rather be provisionally considered as a new genus of the Flaviviridae, irrespective of differences in the nonstructural genes. Like other positive-stranded RNA viruses, pestiviruses are highly variable; apart from point mutations, recombinations are expected to contribute to their capricious behaviour. One trait of expected pathogenetic significance in infections with bovine virus diarrhoea virus is a change from the non-cytopathogenic to a cytopathogenic biotype. Cooperation of both variants in an animal to produce the severe disease picture known as mucosal disease is unique in virology; elucidation of this mechanism may shed light on the pathogenesis of other sporadic diseases with suspected viral origin.     

An inactivated bovine virus diarrhoea virus (BVDV) type 1 vaccine affords clinical protection against BVDV type 2

This study was designed to answer to two distinct questions. Firstly, is it possible to reproduce clinical signs of acute bovine virus diarrhoea virus (BVDV) type 2 infection including signs of haemorrhagic disease under experimental conditions in cattle at 20 weeks of age? Secondly, what is the extent of the protection afforded by vaccination with an inactivated BVDV type 1 vaccine against BVDV type 2 infection? Calves were vaccinated at 12 and 16 weeks of age with a commercially available inactivated BVDV type 1 vaccine (Bovilis BVD). At 20 weeks they were challenge infected with BVDV type 2 virus together with unvaccinated control calves. The unvaccinated animals developed typical signs of respiratory disease, diarrhoea with erosions and haemorrhages along the whole length gastro-intestinal tract, and depletion of lymphocytes in lymphatic organs. These signs were either absent or markedly less severe in the vaccinated animals. The beneficial effects of vaccination were most striking in the haematological parameters thrombocytopenia and leukopenia. It can be concluded that vaccination with Bovilis BVD affords cross-protection against clinical effects of a challenge-infection with heterologous type 2 BVDV.     

Compatibility of a live infectious bovine rhinotraheitis (IBR) marker vaccine and an inactivated bovine viral diarrhoea virus (BVDV) vaccine

The target animals and vaccination regimes for vaccines against the bovine rhinotracheitis (IBR) and the bovine viral diarrhoea virus (BVDV) are very similar. Therefore, we have compared different schedules for the combined use of a live IBR marker vaccine and an inactivated BVD vaccine. The neutralizing antibody response against BVDV did not reveal any differences between the group vaccinated only with the BVD vaccine and the groups that were vaccinated simultaneously (together in the same syringe) or concurrently (two separate injections) with the IBR marker vaccine at the first or second dose and the third dose of the BVD vaccine. Likewise, the bovine herpesvirus 1 (BHV-1) neutralizing antibody titres did not exhibit any negative effect by the simultaneous or concurrent use of the two products as compared to the single IBR marker vaccination. These results indicate that the two vaccines can be applied at the same day for the first or second dose of the BVD basic vaccination and then at the booster vaccinations (third dose onwards).     

Evaluation of efficacy of mammalian and baculovirus expressed E2 subunit vaccine candidates to bovine viral diarrhoea virus

Bovine viral diarrhoea virus (BVDV) is a worldwide pathogen of cattle causing a wide spectrum of clinical disease. The major envelope glycoprotein of BVDV, E2, induces the production of neutralising antibodies. In this study we compared the protection afforded to cattle after BVDV challenge by two separate E2 vaccine candidates produced by different heterologous protein expression systems. E2 antigen was expressed using the baculovirus expression system (brE2) and a mammalian cell expression system (mrE2). In the first vaccination study the quantity of recombinant protein expressed by the two systems differed. Vaccination of cattle with a higher dose of brE2 or low dose mrE2 gave comparable protection from viral challenge. Immunised animals showed no pyrexia and reduced leucopaenia which contrasted to the unvaccinated controls. In addition virus shedding from the nasal mucosa was decreased in the vaccinated groups and strong humoral responses were evident post-challenge. However, the efficacy of the brE2 vaccine was greatly diminished when a reduced dose was tested, indicating the importance of assessing the type of expression system used in antigen production.     

Enhanced neutralising antibody response to bovine viral diarrhoea virus (BVDV) induced by DNA vaccination in calves

DNA vaccination is effective in inducing potent immunity in mice; however it appears to be less so in large animals. Increasing the dose of DNA plasmid to activate innate immunity has been shown to improve DNA vaccine adaptive immunity. Retinoic acid-inducible gene I (RIG-I) is a critical cytoplasmic double-stranded RNA pattern receptor required for innate immune activation in response to viral infection. RIG-I recognise viral RNA and trigger antiviral response, resulting in type I interferon (IFN) and inflammatory cytokine production. In an attempt to enhance the antibody response induced by BVDV DNA in cattle, we expressed BVDV truncated E2 (E2t) and NS3 codon optimised antigens from antibiotic free-plasmid vectors expressing a RIG-I agonist and designated either NTC E2t(co) and NTC NS3(co). To evaluate vaccine efficacy, groups of five BVDV-free calves were intramuscularly injected three times with NTC E2t(co) and NTC NS3(co) vaccine plasmids individually or in combination. Animals vaccinated with our (previously published) conventional DNA vaccines pSecTag/E2 and pTriExNS3 and plasmids expressing RIG-I agonist only presented both the positive and mock-vaccine groups. Our results showed that vaccines coexpressing E2t with a RIG-I agonist induced significantly higher E2 antigen specific antibody response (p < 0.05). Additionally, E2t augmented the immune response to NS3 when the two vaccines were delivered in combination. Despite the lack of complete protection, on challenge day 4/5 calves vaccinated with NTC E2t(co) alone or NTC E2t(co) plus NTC NS3(co) had neutralising antibody titres exceeding 1/240 compared to 1/5 in the mock vaccine control group. Based on our results we conclude that co-expression of a RIG-I agonist with viral antigen could enhance DNA vaccine potency in cattle.     

Bovine viral diarrhoea, bovine herpesvirus and parainfluenza-3 virus infection in three cattle herds in Egypt in 2000

This study reported field outbreaks of bovine viral diarrhoea virus (BVDV) infection, either alone or mixed with bovine herpesvirus-1 (BHV-1) and/or parainfluenza-3 virus (PI-3V) in Egypt during 2000. In Lower Egypt, young calves in three cattle herds in El-Minufiya Province, El-Fayoum Province and in governmental quarantine in El-Behira Province, showed symptoms of enteritis, either alone or accompanied by respiratory manifestations. The affected herds were visited and the diseased animals were clinically examined. Many epidemiological aspects, such as morbidities, mortalities and case fatalities, as well as the abortive rate, were calculated. Ethylenediamine tetra-acetic acid-blood samples, sterile nasal swabs and serum samples were obtained for virological and serological diagnosis. The laboratory investigations revealed that the main cause of calf mortalities in the three herds was infection with BVDV, either alone, as on the El-Minufiya farm, or mixed with PI-3V, as on the El-Fayoum farm, or mixed with both BHV-1 and PI-3V, as in the herd in governmental quarantine in El-Behira Province. A total of nine dead calves from the three herds were submitted for thorough post-mortem examination. Tissue samples from recently dead calves were obtained for immunohistochemical and histopathological studies. The most prominent histopathological findings were massive degeneration, necrosis and erosions of the lining epithelium of the alimentary tract. Most of the lymphoreticular organs were depleted of lymphocytes. In pneumonic cases, bronchopneumonia and atypical interstitial pneumonia were evident. The present study suggested that the immunosuppressive effect of BVDV had predisposed the animals to secondary infection with BHV-1 and PI-3V. This study concluded that concurrent infection with BVDV, BHV-1 and PI-3V should be considered as one of the infectious causes of pneumoenteritis and, subsequently, the high morbidities and mortalities among young calves in Egypt. Preventive and control measures against these infectious agents should therefore be adopted. All animals imported into Egypt should be free from BVDV infection. Control programmes for the detection and removal of BVDV-persistent cattle should be applied in cattle herds all over the country.     

Bovine virus diarrhoea virus: speculation and observations on current concepts

This final chapter highlights the advances and some of the unanswered questions concerning bovine virus diarrhoea virus (BVDV) presented in this Review by specialists from around the world. Persistently viraemic cattle play an essential role in the dissemination of BVDV but it is suggested that acute infections with the virus are also important. The role of latency is considered but, as yet, there is no evidence that it plays a part in pathogenesis. It is well established that BVDV, Border disease virus and hog cholera virus infect sheep and pigs. There is also some indication that pestiviruses may be involved in other infections of ruminants, such as syndrome X and hyena disease. They also infect other ruminants, such as deer, and human infections have been reported. It is now known that the pathogenesis of mucosal disease is due to the combined action of the two BVDV biotypes. However, the cause of death remains an enigma. It is suggested that, due to the importance of this syndrome, it may be an appropriate time to reconsider the use of "mucosal disease virus" to replace the ungainly name "BVDV".     

Protective effect of an ISCOM bovine virus diarrhoea virus (BVDV) vaccine against an experimental BVDV infection in vaccinated and non-vaccinated pregnant ewes.

Fifteen pregnant ewes were vaccinated twice with an experimental immunostimulating complex (ISCOM) subunit vaccine designed to contain the envelope proteins of a Danish cytopathic bovine virus diarrhoea virus (BVDV). The serological responses were measured in ELISA and virus neutralization (VN) tests. All ISCOM-vaccinated ewes developed high VN antibody titres to BVDV in contrast to the 14 non-vaccinated ewes. Both groups of ewes were challenged parenterally when 48-65 days pregnant with a Swedish cytopathic BVDV isolate. In the vaccinated group 26 fetuses out of 29 detected by ultrasound were liveborn, whereas only six out of 26 were liveborn in the non-vaccinated group. It is concluded that the ISCOM vaccine had the potential of eliciting high VN titres as well as protecting fetuses against transplacental infection after challenge with a virulent BVDV isolate.