Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  Several commercial diagnostic tests available to detect BRSV antibodies or diagnosis via RT-PCR.

  List of commercially available diagnostics. (Diagnostics for Animals).

• Diagnostic kits validated by International, European or National Standards

  GAPS :

  Lack of international and national standards to evaluate the characteristics of the BRSV diagnostic tests on the market.

• Diagnostic method(s) described by International, European or National standards

  No.

• Commercial potential for diagnostic kits worldwide

  If voluntary/compulsory control programmes start, diagnostics would become very profitable but this seems unlikely except in some Nordic countries (e.g. voluntary control programme in Norway, voluntary surveillance in Sweden).

  GAPS :

  Penside test to detect BRSV and could also detect simultaneously other respiratory pathogens.

• DIVA tests required and/or available

  None available yet.

  An N protein-based ELISA, combined with an appropriate companion vaccine, would be a possible option, since all animals infected with BRSV develop antibodies against this protein and the N-specific antibody response is long lasting.

  For a live, attenuated BRSV mutant vaccine, non-essential viral proteins such as SH, M2, G, NS1 and NS2, are possibly suitable for DIVA test development, depending on their capacity to induce antibodies in the BRSV infected host.

  Currently, vaccination makes us blind regarding the monitoring of the epidemiological situation of BRSV, and a DIVA would enable a better understanding of the epidemiological situation of BRSV infection in vaccinated areas. Furthermore, a DIVA approach is not only interesting for control programmes but it will also enable monitoring the vaccine efficacy. Indeed, the efficacy and the duration of protective immunity of a DIVA vaccine could be evaluated through the reduction of BRSV spread in vaccinated populations, by monitoring the seroprevalence of antibodies targeted in the DIVA test.

  GAPS :

  Further research into the antibody response induced by individual BRSV proteins would be needed in order to select which of the proteins would be most suitable for BRSV DIVA vaccine-test combinations.

  Evaluation of the specificity of N antibodies if the DIVA test is based on the detection of N antibodies to make the difference between vaccinated and infected animals.

• Vaccines availability

• Commercial vaccines availability (globally)

  There are many modified-live or inactivated BRSV vaccines currently on the market, globally, for intramuscular, subcutaneous and intranasal administration in cattle. The majority are multicomponent vaccines. Current vaccines include e.g.:

  EU

  Live

  • Nasym, Hipra, (IN and IM route)
  • Bovalto Respi 2, Boehringer Ingelheim Animal Health (lN route)
  • Bovilis INtranasal RSP live, MSD Animal Health (IN route)
  • Hiprabovis 4, Hipra (IM route)
  • Rispoval RS, Zoetis, Intramuscular application
  • Rispoval RS+Pi3 Intranasal, Zoetis

  Inactivated

  • Bovilis® Bovipast vet., MSD Animal Health (SC route)
  • Bovalto respi 3,4 Boehringer Ingelheim Animal Health (SC route)

  US

  Live

  • Bovilis Vista Once SQ: Merck-AH (SC route)
  • Bovilis Vista 5 SQ: Merck-AH, (SC route)
  • Bovilis Nasalgen 3-PMH: Merck-AH, (IN route)
  • INFORCE^TM 3 Respiratory vaccine: Zoetis (IN route)
  • Pyramid 5: Boehringer Ingelheim Animal Health (SC route)
  • Express 5 HS: Boehringer Ingelheim Animal Health (SC route)
  • Titanium: Elanco (SC route)
  • Master Guard: Elanco (SC or IM route)
  • Cattlemaster Gold FP 5: Zoetis (SC route)
  • Bovishield 5: Zoetis (SC route)

  Inactivated

  • Vira-Shield 6: Elanco (SC route)
  • Bovi- Shield, Zoetis
  • Bayovac (BRSV), Zoetis
  • Triangle (Boehringer Ingelheim )
  • Hiprabovis: Hipra, Nasym

  European pharmacopoeia specifies the requirements for the freeze-dried BRSV vaccine (live).

  GAPS :

  In humans, subunit vaccines based on the prefusion protein of human RSV (HRSV) have been approved by FDA and EMA-as the first HRSV vaccines to be on the market (such as Arexvy for elderly (GSK) and Abrysvo (for elderly and maternal immunization).

  How about acceptance of the use of other vaccine platforms incl. GMO in the veterinary field? (RNA platform, vectors).

• Marker vaccines available worldwide

  None.

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Protection (virological and clinical) induced by BRSV vaccination is probably short-lived. Therefore, frequent vaccination may be necessary to control infection. Following BRSV infection, protection is also short-lived but partial clinical and virological protection is still observed 4 years after a primary infection. If calves with BRSV-specific maternal antibodies experience BRSV infection or vaccination, the ensuing clinical and virological protection tends to be shorter and weaker. However, host resistance increases following repeated infection. The reasons for the short duration of full protection against BRSV, and its human counterpart Human RSV (HRSV), are not known, but may explain the common occurrence of recurrent infections in vaccinated and unvaccinated individuals.

  Some inactivated vaccines have induced exacerbated disease following BRSV infection, possibly linked to weak CTL responses and a strong Th-17 memory.

  As young calves are at greatest risk of severe BRSV disease, calves should be vaccinated when maternally-derived antibodies (MDA) are still present. However, MDA interfere with humoral immune responses following vaccination or infection.

  Intranasal vaccination with live attenuated BRSV vaccines induces rapid protective immunity, which is useful when disease occurs in very young calves (3 to 6 weeks old). For vaccines licensed in the EU, reversion to virulence is tested prior to licencing. However, since the live virus vaccine is excreted there remains a theoretical possibility that on transmission between calves, reversion to virulence could occur.

  Heterologous prime-boost strategy can help to improve the duration of protection: IN prime at very young age in presence of MDA (fast, local / mucosal immunity, and short-living) and IM boost at >2-3 months of age (systemic immunity).

  Current vaccines induce poor or variable protection against viral shedding allowing the virus circulation to continue. Furthermore, the cost of vaccines is high and vaccination is therefore limited to some animals that are considered to be clinically at risk. Therefore, the current use of vaccination has probably little impact on BRSV circulation between (and probably within) herds.

  GAPS :

  Demonstration of efficacy of currently available BRSV vaccines in a field setting, via properly designed field trials with adequate study power to identify clinically meaningful benefit, is needed. Currently vaccine efficacy is usually confirmed in challenge studies which may not represent effects in the field.

  Field trials should demonstrate efficacy when BRSV is confirmed to be present. Some trials evaluate only effects on undifferentiated respiratory disease.

  Demonstration of efficacy in calves with passively acquired (maternal) antibody should be required of vaccine manufacturers. In many cases vaccine efficacy is demonstrated only in seronegative calves, whereas in the field it is desirable to vaccinate calves before maternal antibodies have completely disappeared.

  Knowledge about calf neonatal antibody repertoire to reduce the risk of interference with maternally derived antibodies. Selection of the best epitopes to induce neutralizing antibodies in calf (taking advantage of neutralizing site- mapping of preF from human RSV (HRSV).

  Added value of dam vaccination with BRSV vaccine (inactivated and MLV) to passively protect calves against BRSV.

  Better knowledge of the true differences and relative benefits of intranasal vs parenteral vaccination.

  Knowledge about if vaccines can be used to decrease the level of BRSV transmission intra and inter-herd.

  Transparency of the number of sold vaccine doses at regional and national level (impact of age and level of MDA)

  Efficacy and safety of new vaccine platforms (i.e. RNA vaccine) should be tested in cattle.

• Commercial potential for vaccines

  A highly effective BRSV vaccine with documented effect on calf pneumonia in general would have a good market. Furthermore, the increasing pressure on the reduction of antibiotic use in livestock supports the use of vaccines.

  GAPS :

  More studies to evaluate the direct and indirect economical impact of BRSV outbreaks at short and long terms in different types of cattle productions to justify BRSV vaccination and to increase vaccination rate / vaccine compliance.

• Regulatory and/or policy challenges to approval

  None unless genetically manipulated vaccines which may pose a problem in some countries. Some countries may be reluctant to use live virus vaccines that may spread within the calf population.

  Voluntary control programmes of BRSV based on biosecurity and trade between herds in which BRSV does not circulate, have been implemented in Norway and voluntary regular antibody monitoring is performed in Sweden.

• Commercial feasibility (e.g manufacturing)

  Feasible.

  GAPS :

  Different types of vaccines could be commercially available

• Opportunity for barrier protection

  Not applicable.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  As with other viruses, antibiotics have no effect on BRSV infection. However, antibiotic treatment is indicated in attempts to control secondary bacterial infections. As there is a need to reduce antibiotic usage, antibiotic treatment should be linked to development of rapid diagnostic tools to show presence of pathological bacterial infection in the lungs.

  Anti-inflammatory or other compounds are used in some countries. The efficacy and adverse effects of these drugs need to be further investigated.

  GAPS :

  Demonstration that an efficient BRSV vaccination leads to reduced antibiotics usage (less secondary bacterial infection when less RSV infection).

  Larger studies including controlled field trials on clinical effect of corticosteroids and NSAID, which are commonly used in BRSV outbreaks in the field.

  Improvement of NSAIDs, e.g. by preserving the anti-inflammatory and pro-resolving effect of prostaglandins in the lung. An increased understanding of the pathogenesis of BRSV infection would lead to the development of therapeutics that specifically target BRSV-induced pathology.

  Biomarkers to predict severity outcome of infection (to identify at an earlier stage which animals need treatment and which not)?

  Identification of new innate immune molecules as a basis for antiviral, antioxidant and anti-inflammatory treatments.

  Screening for molecules limiting the detrimental effect of neutrophils.

  Characterisation of the lung microbiota, to identify occurrence of dysbiosis in severe disease and try to prevent-restore it with a probiotic treatment.

  Evaluation of the potential benefit of the immunomodulatory therapy.

• Future therapy

  None.

• Commercial potential for pharmaceuticals

  An antiviral may have a place in future as well as other agents that have a disease mitigating effect at low cost, in combination with antibiotics or anti-inflammatories.

  GAPS :

  Identification of safe and effective anti-viral compounds (as inexpensive as possible) usable in field conditions in food producing animals.

• Regulatory and/or policy challenges to approval

  None.

• Commercial feasibility (e.g manufacturing)

  Not applicable at present.

• New developments for diagnostic tests

• Requirements for diagnostics development

  F protein antibody Elisa’s are available (see above).

  Lab-based (real time) PCR’s have been described by several research groups. Real time RT-PCR kit (LSI, Thermo Fisher) is available for vet labs.

  GAPS :

  Alternative sampling procedures (like chewing cords as used for diagnostics of pig pathogens).

  Cheap penside test to detect multiple respiratory viral and bacterial pathogens.

  Penside test as support tool for the necessity to treat bacterial superinfection in BRSV infected animals.

  Assays to detect detrimental inflammation, for initiation of targeted anti-inflammatory treatment.

  Potential for a DIVA vaccine and accompanying diagnostic test.

• Time to develop new or improved diagnostics

  Can be fast, depending on approach and availability of reagents within weeks (PCR’s) or months (ELISA).

  GAPS :

  The development of cowside multiplex LFTs will depend on the availability of mAbs specific for the respiratory pathogens to be detected. Development of multiplex LFTs could take a while if mAbs are not already available.

• Cost of developing new or improved diagnostics and their validation

  If enough samples for validation of tests are available, costs are low. If field experiments are necessary for sample generation development may get costly.

• Research requirements for new or improved diagnostics

  GAPS :

  See Section “Time to develop new or improved diagnostics” above.

  Test enabling the veterinarian to decide if antibiotherapy is needed due to bacterial superinfection (e.g. C-reactive protein).

  On-site biomarker assay to predict severity outcome (eg cytokine, acute phase protein)?

  Research to determine the cost vs benefit of diagnostic testing in different types of production settings. Currently, it is not easy to determine when testing is worth the cost.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  BRSV vaccine to provide durable immunity against BRSV infection of the lower respiratory tract, which prevents viral shedding and is effective in calves with maternal antibodies. Recent data obtained with a PreF-based experimental vaccine indicate that some of these requirements might be fulfilled.

  Development of an efficacious DIVA vaccine (single shot; duration of protection > 1 year in young calves) with an accompanying ELISA based diagnostic test.

  Most promising approaches seem to be Vector based- and genetically modified live virus vaccines and subunit vaccines with ISCOMs or water-in-oil adjuvants.

  A device for intranasal application that allows an easy delivery of a precise amount of vaccine.

  Other adjuvants (CpG, commercial adjuvants) could be tested for their capacity to induce a strong immune response (TH1 cell response, long-lived plasma cells and B-cell memory).

  GAPS :

  Determine the “best” time and route to vaccinate against BRSV to balance between the desire to vaccinate calves as young as possible and the fact that the immune response is not optimal if the calves are vaccinated when they are transitioning from intrauterine to post-natal life and stressed by all sorts stress factor s (movement, mixing…).

  Study of immunological markers/mechanisms associated with protection (connection to human research).

  Development of stabilized mRNA vaccine for BRSV may be of value.

  Knowledge about calf neonatal antibody repertoire to reduce the risk of interference with maternally derived antibodies. Selection of the best epitopes to induce neutralizing antibodies in calf (taking advantage of neutralizing site- mapping of preF from HRSV).

  More knowledge sharing between human and veterinary RSV field.

  Understanding of vaccination approaches that induce protection of long duration without stimulating potentially harmful (i.e., virus-specific IgE) responses.

  Understanding of the true comparative benefits/risks of intranasal versus parenteral vaccines for BRSV.

  Impact of the genetic of the host (e.g. response to vaccination, clinical signs, etc).

• Time to develop new or improved vaccines

  Up till licensing at EMEA, 5-10 years.

• Cost of developing new or improved vaccines and their validation

  Hard to estimate, but can be high, especially for GMO’s; mainly depends on safety study requirements of EMEA.

  GAPS :

  Vaccine efficacy will need to be evaluated i n calves with MDA.

  Good and repeatable BRSV challenge models that induce clinical disease should be used to evaluate vaccine efficacy and safety.

  Because many challenge models use lung lavage fluid from BRSV-infected calves for challenge, it would be beneficial to know the relative effect of the virus vs host proteins/cytokines/other mediators in the lung lavage fluid for experimental disease induction.

  Animal trials still need to be used to evaluate vaccine safety and efficacy. Identification of correlates of protection to decrease the number of animal experiments.

• Research requirements for new or improved vaccines

  The development of safe and effective RSV vaccines has been hampered by the need to induce protective immunity within the first month of life, at a time when the calf's immune response capacity is reduced and when maternal antibodies can pose a major obstacle to successful vaccination; and the observation that vaccination can exacerbate RSV disease for one commercialised BRSV vaccine. Since vaccine-augmented disease has been associated with whole-inactivated virus, it has been proposed that a live, attenuated virus administered intranasally would make a safer and more effective vaccine.

  Recent advances in the molecular biology of negative-sense RNA viruses have provided a means to manipulate the genome of BRSV and opened the way for producing genetically stable, attenuated BRSV vaccine candidates.

  Development of gene deleted or recombinant BRSV vaccines would have the advantages of allowing the development of diagnostic kits, which could differentiate infected form vaccinated cattle.

  Specific research requirements for future vaccine include:

  • Effective antigen delivery systems.
  • Adjuvants for inactivated vaccines or attenuated vaccines (insertion of immunomodulatory genes).
  • Combination vaccines.
  • Route of administration.
  • Research into mechanisms of exacerbated disease induced by some vaccines.
  • Vaccines that induce durable protective immunity.

  GAPS :

  Reproducible model to evaluate both vaccine efficacy and safety.

  Better understanding of whether limiting viral replication or modifying the host immune/inflammatory response is the most beneficial outcome of vaccination.

  Better understanding of the best measurable correlate of vaccine-induced protection.

  Understanding of the role of defective virus genomes in BRSV challenge material on severity of resulting experimental disease.

  Better understand the added value (duration of immunity, efficacy) of heterologous vaccination (mucosal and then parenteral with modified live or inactivated).

  Use of unified BRSV challenge stocks in order to compare results from different challenge studies performed in different establishments.

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  None apart from the generic approach to antivirals for most viral diseases. Main effort is currently directed at development of antivirals effective against HRSV. Such products could be validated against BRSV in calves.

  Use of antivirals could cause problems with emergence of antiviral resistance.

  GAPS :

  A greater understanding of the role of the host response in the BRSV pathogenesis could lead to the development of more targeted immunomodulators to treat excessive inflammatory response associated to BRSV disease.

  Modulator of immune system to prevent immunosuppressive effect of stress.

• Time to develop new or improved pharmaceuticals

  Depends upon the nature of the product.

• Cost of developing new or improved pharmaceuticals and their validation

  Depends upon the nature of the product.

• Research requirements for new or improved pharmaceuticals

  A greater understanding of the role of the host response in the pathogenesis of BRSV could lead to the development of immunomodulators to treat disease.

  GAPS :

  Better understanding of the interplay between nasal-lung microbiota and immuno-pathology upon virus infection (is there a dysbiosis?). Mitigation by probiotics?

Disease details

• Description and characteristics

• Pathogen

  Bovine respiratory syncytial virus (BRSV or bovine Orthopneumovirus) is an RNA virus classified as Orthopneumovirus in the Pneumoviridae family. It is a negative single-stranded, non-segmented RNA genome of about 15 kilobases. The genome encodes for two non-structural proteins NS1 and NS2 and the 8 structural proteins,N, P, M, SH, G, F, M2-1, M2-2 and L. The G protein is the viral attachment protein. However, it is dispensable for viral infection and protection. The F or fusion protein and particularly the preFusion form is essential for viral infection and induces neutralising antibodies and CTL’s. Virions have various shapes, often rod-shaped and surrounded by a lipid envelope into which the G, F & SH are inserted.

• Variability of the disease

  BRSV exist as a single serotype, with four antigenic subtypes and at least 10 phylogenetic groups on the G protein-coding gene, which cluster temporally and spatially. BRSV is species specific although sheep may be infected experimentally with BRSV. Natural infections of sheep and goat occur with closely related RS viruses. BRSV is also structurally and antigenically related to human (H)RSV, which is the single most important cause of bronchiolitis and pneumonia in infants. The high degree of similarity between HRSV and BRSV indicates that comparative studies of the immunobiology of these viruses will yield important insights that should benefit both man and cattle.

  Whole genome sequencing data can be used to identify characterised strains at the regional level. However, the lack of genetic changes in the whole genome does not allow a precise tracing of a transmission of a strain between herds.

  GAPS :

  What is the role of genetic variation in calves and adult cattle on disease severity?

  Factors that affect colostrum uptake including genetic of the host.

  What is the role of production parameters, such as milk yield, stage of gestation (adult cattle) and growth (young stock, beef) on disease severity.

  What is the role of nutrition of cattle on inflammation induced by BRSV?

  What aspects of the virus determine virulence?

  How relevant are subtypes and genotypes for –selection of vaccine strains.

  What is the effect of virus variation on the duration of protection?

  What is the role of defective viral genomes in disease severity?

• Stability of the agent/pathogen in the environment

  BRSV does not survive very long in the environment. The fragility of the virus makes it difficult to isolate in the laboratory; therefore, BRSV infection is difficult to diagnose by virus isolation. However, by the use of antigen detection (IIF, ELISA) conventional or real time RT-PCR, the virus can be detected in clinical specimens such as nasopharyngeal swabs, bronchoalveolar lung lavage or lungs.

  GAPS :

  How long can BRSV persist in the environment?

  The survival of BRSV in the environment is not really known i.e. water, teats, feeders even if it is probably short. Nevertheless, outbreaks can occur without animal introduction suggesting that the virus is resistant enough to enable indirect transmission.

• Species involved

• Animal infected/carrier/disease

  In addition to cattle, sheep and goats can also be infected by respiratory syncytial viruses. BRSV infections associated with respiratory disease occur predominantly in young beef and dairy cattle. BRSV can be detected in cattle with mild to severe respiratory signs. Virus has been detected from lymph nodes of calves 71 days after experimental infection. However, viral excretion from persistently infected animals has not been documented. BRSV can also be detected in cattle without clinical signs of disease.

  GAPS :

  Existence of carrier and can they excrete BRSV?

• Human infected/disease

  Although there are many similarities in antigenic epitopes, epidemiology and disease pathogenesis with HRSV, BRSV is not known to be infectious to humans. Although calves can be experimentally infected with HRSV, replication of BRSV in chimpanzees is highly restricted.

  GAPS :

  Existence of carrier and can they excrete BRSV.

• Vector cyclical/non-cyclical

  None.

• Reservoir (animal, environment)

  Following an outbreak, the virus can disappear from herds. However, in some cases, it may persist in a herd from outbreak to outbreak through subclinical or mild infections in a few infected animals that may transmit virus to younger susceptible cattle, but this has not been definitely proved. Neither can excretion by persistently infected animals be excluded. BRSV also circulates between herds, probably by indirect as well as direct transmission to susceptible animals. The existence of a wildlife reservoir cannot be excluded but has not been confirmed to play a major role in the epidemiology.

  GAPS :

  How long does BRSV circulate in closed herds after an outbreak?

  At the individual level, how long does virus excretion persist after natural infection in animals of different age and immunity?

  Do BRSV reservoirs exist?

• Description of infection & disease in natural hosts

• Transmissibility

  The transmissibility of BRSV is high: the spread of the virus between immunologically naive animals within herds and between herds is very rapid in small and medium sized herds. BRSV gains entry to susceptible cattle through the respiratory tract where it replicates and causes disease. Based on recent epidemiological data and whole genome sequencing, humans are potential passive vectors between infected and susceptible herds.

  Previously infected animals can shed virus at reinfection, although less than primary infected animals.

  GAPS :

  How does BRSV spread? An understanding of the mode of transmission will aid the development of biosecurity measures.

  Can vaccinated or previously infected cattle, which do not show clinical signs of disease, play a role in virus transmission within and between herds?

• Pathogenic life cycle stages

  Not applicable.

• Signs/Morbidity

  Major respiratory pathogen in young and older calves, as well as in seronegative adults (particularly in highly productive dairy cows), causing severe bronchiolitis, pneumonia, and upper- and lower respiratory tract disease. The clinical signs range from hyperthermia +/- cough with serous nasal and ocular discharge to severe broncho-interstitial pneumonia with abdominal dyspnoea, raised temperature, and death following acute respiratory distress caused directly by the virus and virally-induced inflammation, or by bacterial superinfection. Clinical signs of respiratory disease can be observed for several weeks after the virus has disappeared from the respiratory tract.

  Some variations are observed:

  • Morbidity is highest in calves 1 to 6 months of age in areas where the virus is endemic. However, the severity of the disease is variable among calves in one herd.
  • In feedlots, BRSV may cause severe respiratory diseases in cattle between 6 months to 1 year, with or without superinfection by other viruses, mycoplasmas &/or bacteria. This justifies the wide range of BRSV vaccination in this type of production.
  • A primary infection in older cattle is also associated with high morbidity.
  • Re-infection of older cattle is associated with little clinical disease if animals are regularly reinfected.

  GAPS :

  What determines differences in disease severity? (HRSV disease severity in infants is influenced by host genetics)

  • Influence of host genetics on virus replication as well as on inflammation and clinical signs of disease?
  • Role of co-infection with viruses and/or bacteria and/or parasites and how does BRSV infection predispose to secondary bacterial infection?
  • Does BRSV infection or vaccination predispose to exaggerated inflammation upon specific or unspecific stimulation of memory lymphocytes?
  • Does BRSV infection impact the pulmonary function with long term consequences on, for example, production?
  • Genetic background of virus?
  • Role of other environmental exposure (e.g., fungus in hay) on host response to primary infection or reinfection?

• Incubation period

  3-5 days after exposure to the virus.

• Mortality

  Usually less than 5% in young calves. Deaths may result from BRSV infection alone or as a result of secondary bacterial pneumonia. However, severe outbreaks of BRSV with 15-20% mortality can be seen. In dairy herds, some mortality can be observed in highly productive, BRSV-seronegative dairy cows.

  GAPS :

  What is the role of co-infections and differences in virulence of BRSV isolates in severity of disease?

  What is the relative importance of host response versus viral characteristics in BRSV case fatality? What is the influence of production on mortality?

• Shedding kinetic patterns

  Excretion in droplets and nasal secretions.

• Mechanism of pathogenicity

  Much like HRSV, BRSV replicates predominantly in ciliated airway epithelial cells and type II pneumocytes inducing an array of pro-inflammatory chemokines and cytokines that recruit neutrophils, macrophages and lymphocytes to the respiratory tract resulting in respiratory disease. Neutrophils release NET and enzymes that have a defensive role against BRSV but, when excessive, have a negative effect on the respiratory function and respiratory tissues with short and long term consequences. In tissue outside the respiratory tract and regional lymph nodes neither BRSV antigen nor replication of BRSV could be demonstrated.

  GAPS :

  A greater understanding of the mechanisms of pathogenicity, including relative importance of virus variation versus the nature of the host response, is needed.A greater understanding of the long-term consequences on lung and respiratory function is needed.

• Zoonotic potential

• Reported incidence in humans

  Does not infect humans.

  GAPS :

  Better understanding of factors playing a role in the species barrier is needed.

• Risk of occurence in humans, populations at risk, specific risk factors

  Not known.

• Symptoms described in humans

  Not known.

• Likelihood of spread in humans

  Minimal.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  Respiratory disease in young calves, and sometimes in adult animals, is a major animal welfare problem. BRSV is a major primary pathogen in the respiratory disease complex of calves. Respiratory disease in young calves has been shown to have an effect on growth and age of first calving, and as a consequence, also on risk of culling before first parturition, as well as milk yield.

  GAPS :

  No specific and effective treatment limiting the short and long-term consequences of BRSV infection on health and suffering are available on the market.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  No.

• Slaughter necessity according to EU rules or other regions

  No.

• Geographical distribution and spread

• Current occurence/distribution

  Worldwide/ubiquitous-endemic character of infection in dairy and especially beef cattle.

  GAPS :

  Up-to-date prevalence studies based on sensitive detection methods in animals at the acute stage of disease, (when BRSV is present as primary pathogen) are needed.

  Although BRSV is already considered as a major pathogen in the respiratory disease complex of calves, prevalence studies based on virus isolation and chronic cases might give an underestimation of BRSV importance.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Endemic.

• Speed of spatial spread during an outbreak

  Rapid within a herd. Rapid between herds with low herd immunity. However, the spread in large herds with several hundreds of animals located in several buildings can take several weeks. Spread of BRSV seems to be less efficient and clinical signs appear milder in animals kept outdoor in hutches/igloo compared to indoors in groups with a high density of animals.

  GAPS :

  What is the relation between infectious dose in the air or by contact and the effectiveness of spread of the virus between animals and its impact on the clinical expression of the infection?

• Transboundary potential of the disease

  Can be easily spread by movement of cattle. Aerogenic transmission of BRSV at short distance has also been suggested.

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  Transmission from one animal to another is thought to be via aerosol droplets from the nose and throat, or direct contact with virus on recently contaminated surfaces or fomites. However, aerosol transmission has also been described. Due to the mode of transmission, the length of time for the disease to progress through an exposed herd depends upon the confinement status of the herd. In feed yards and dairies, where cattle are in close confinement, the disease can spread rapidly through the cattle in 3 to 10 days. However, in pastured cattle or in very large herds (with several buildings), it may take several weeks or months to move through the entire herd. Once exposed, it requires 2-4 days for a susceptible animal to begin showing clinical signs of the disease. In susceptible herds undergoing a BRSV outbreak, one can expect 100% of the animals to become infected with the virus, 20-50% to show clinical signs, and generally less than 5% to die. Indirect transmission between herds via humans or other passive vectors is likely to occur but has never been documented. Transmissibility (and consequently disease progress) also depends on the immune status of animals, since immunity is known to reduce the nasal BRSV excretion. The infectious dose probably affects both incubation time and load of virus shedding, as shown for HRSV in humans.

  Based on epidemiological data and whole genome sequencing, humans are potential passive vectors between infected and susceptible herds.

  GAPS :

  What is the route of transmission of BRSV within and between herds?

  What is the importance of passive vectors?

  What are the biosecurity measures needed to prevent introduction of BRSV in herds that are closed with regard to animal introduction?

• Occasional mode of transmission

  Not known. However, other animal species may play a role as BRSV-specific antibodies have been detected in dogs , elk, as well as sheep and goats.

• Conditions that favour spread

  Close confinement of animals and close contact between calves and older animals. Mixing of animals from multiple origins.

  GAPS :

  What is the effect of specific immunity on spread?

  How does vaccination influence spread?

• Detection and Immune response to infection

• Mechanism of host response

  Both cell-mediated (innate and adaptive) and antibody–mediated immune responses contribute to efficient protection of animals. Antibody to the F and G proteins are important in mediating protection. However, antibody to the G protein is mainly sub-type specific. MHC class I restricted CD8+ CTL’s play an important role in clearing the virus from lungs and nasopharynx. Bovine CD8+ T cells recognise predominantly the N and P proteins, although other viral proteins such as F are also recognised in cattle with different MHC class I haplotypes. In addition to the F and G proteins, the N protein can also induce some protection against challenge.

  Mucosal immunity also plays a role against BRSV infection.

  There is evidence of vaccine-augmented disease, possibly related to a Th2- and/or Th17-biased immune response. Whereas a balanced neutrophil response may be protective, exaggerated neutrophil activity is related to immune-mediated pathology.

  GAPS :

  Immunological basis of vaccine-augmented disease in cattle needs clarifying further.

  What is the role of the immune response in the pathogenesis of primary infection or secondary infection?

  What is the duration of protective immunity?

  What influences the duration of immunity?

  What is the role of airway-resident T cells in protection and what factors influence their activation and longevity?

• Immunological basis of diagnosis

  Antibody detection using paired samples. However, the high levels of maternally-derived antibodies (MDA) in young calves can mask antibody response. MDA affects the detection of IgG antibodies to a greater extent than IgM or IgA antibodies.

  GAPS :

  Development of an immunological test based on detection of BRSV-specific IgM or IgA antibodies.

• Main means of prevention, detection and control

• Sanitary measures

  Introduction of animals into herds through quarantine, if possible at pasture. Hygiene of visitors and material that are in contact with several herds. Keeping the density of animals and calf group size low. Ensuring adequate colostrum-intake. Implementation of calf hutches outdoors. Avoiding mixing of calves from several herds and without quarantine. Separating young naive calves from older cattle is a simple management tool that can be used to reduce BRSV exposure and disease in calves that are usually most susceptible to severe BRSV infections. However, this is often not practical.

  BRSV is also diagnosed in feedlots, where it is difficult to apply sanitary policies. In the veal production industry, calves are collected at 10-14 days of age and taken to a farm where they will be fattened together with a few hundred calves from multiple dairy farms. A “system innovation” instead of a technical innovation to prevent calves being brought together in a period when they are most vulnerable may reduce respiratory disease.

  GAPS :

  Designing efficient and applicable biosecurity measures that include resilience aspects to limit the spread of the virus.

  What length of quarantine is adequate to prevent introduction into a herd?

  What management practices best limit introduction of BRSV into a herd? What practices, if any, can keep a herd free from BRSV?

  Political decisions against antibiotic resistance: strategies to prevent mixing many susceptible animals from different origins and keeping many susceptible animals in a confined area. Can more dairy systems keep their own calves until slaughter? Would this improve the management (health and welfare) of the young dairy bull calf?

• Mechanical and biological control

  Vaccination.

  GAPS :

  Determine the optimum time for vaccination – maternal BRSV vaccination with good colostrum management on the dairy farm, neonatal vaccination, vaccination preweaning and delayed /abolished shipment of calves, or when calves are moved and arrive at rearing/fattening farms?

• Diagnostic tools

  The clinical and epidemiological picture in major BRSV outbreaks is quite distinctive; however, the symptoms and lesions noted are generally not specific enough for diagnostic purposes. Diagnosis must be based on laboratory findings.

  Virus detection

  Virus detection in (deep) nasal swabs, tracheal wash, bronchoalveolar lavage or lung homogenates. A diagnosis of BRSV requires laboratory confirmation. BRSV has proved to be a difficult virus to detect by isolation procedures. Chances of isolation may improve by sampling animals that are in the incubation or acute phase of infection (hyperthermia phase). However, the sensitivity of these assays is often low. Other procedures that have proved useful in detection of BRSV virus antigen are fluorescent antibody and immunoperoxidase staining. PCR-based tests are more sensitive and are used in routine diagnostics as well as for research purposes.

  Identification of antibodies

  Paired serum samples can be used to establish a diagnosis of BRSV infection. Calves that become infected with BRSV in the presence of passively derived maternal antibody may not seroconvert, and serum antibody titres may even decrease between sampling. The duration of BRSV maternal antibodies in calves is usually between 3 to 6 months.

  GAPS :

  Penside tests with increased sensitivity.

  Tests to detect multiple pathogens in a single respiratory sample.

  Tests to detect BRSV-specific antibody response in calves with high levels of maternally-derived serum antibodies.

• Vaccines

  The majority of commercially available BRSV vaccines are multicomponent vaccines with BRSV as one of the components. These vaccines contain either inactivated or live attenuated virus. These induce different responses depending upon the route of vaccination, dose and adjuvant.

  • Modified live virus (MLV) vaccines can induce virus neutralizing serum antibodies, although these may not be high following intranasal vaccination. In general, inactivated vaccines induce significantly lower levels of virus neutralizing antibodies and some (not commercialised) stimulated Th-2 responses, which may, also very seldom, have a disease enhancing effect following exposure to live virus.
  • BRSV infections are often recurrent despite the presence of neutralizing serum antibodies, suggesting the importance of cytotoxic T cells (CTL) and/or IgA responses in protection.
  • Young calves (<6 months) may be difficult to immunise effectively and maternally-derived antibodies may compromise vaccine efficacy.

  Young calves may need a different type of vaccine than older calves (heterologous prime-boost strategy).

  However, numerous published challenge studies support vaccine efficacy for decreasing disease following experimental challenge. In contrast, only a very small number of clinical trials have tested field efficacy for decreasing disease specifically due to BRSV, and most of the available trials are quite old and do not test recent vaccines.

  GAPS :

  An effective BRSV DIVA vaccine that will:

  • be convenient to administer
  • be safe and rapidly induce clinical and virological protection when administered to calves with maternal antibodies
  • be effective in neonatal calves
  • require a minimum number of dose administration to obtain a long duration of protection
  • enable the distinction between vaccinated and infected animals (DIVA)
  • be suitable for large scale production and have a cost compatible with its use in livestock production
  • can be combined with other respiratory pathogens or is compatible with vaccines against other respiratory pathogen

  Identification of immune correlates of protection.

  Lack of high-quality field trials confirming field efficacy of currently available vaccines to decrease clinical disease and related impacts. Good estimates of the value of currently available vaccines in modern production settings are lacking.

• Therapeutics

  None specifically for BRSV and only the use of antibiotics to control secondary bacterial infection. In case of respiratory distress syndrome, non-steroidal anti-inflammatories, corticoids and a mucolytic drug are currently used in the field. The efficacy of these treatments is not proved to date.

  Furthermore, non-steroid anti-inflammatory drugs (NSAIDs) that are widely used might have a negative effect on lung healing. NSAIDs reduce prostaglandins, which have anti-inflammatory and pro-resolving effects in the lung.

  GAPS :

  Identify efficient therapeutics to limit animal losses, short- and long-term consequences on lung function, and impact on the welfare. Identification through a better understanding of the pathogenesis of BRSV infection?

  Development of NSAIDs targeted to resolve the inflammation in the lung.

• Biosecurity measures effective as a preventive measure

  Closed herds with regard to introduction of cattle and visits by humans with cattle contacts. However, introduction of virus into closed herds has been described.

  GAPS :

  Scientifically based evidence on BRSV route of transmission and effective methods to prevent introduction into herds is needed.

• Border/trade/movement control sufficient for control

  None as not a listed disease.

• Prevention tools

  Since disease caused by BRSV and secondary bacterial infections can be difficult to treat, especially in young calves, control of the disease should be aimed at prevention. Due to the widespread occurrence and lack of detailed knowledge of disease transmission and persistence of virus in the population, eradication is not realistic in high cattle density areas. However, eradication in such areas might be possible if a vaccine that induces full virological protection with long duration was developed and used in combination with biosecurity measures.

  Very strict biosecurity measures might be sufficient to stop BRSV introduction in a herd (if animals are confined without direct or indirect contact with animals from other herds). However, when naïve herds are infected, losses are higher in highly valuable adult animals and the virus shedding (thus the risk of transmission) is higher. Therefore, the creation of large populations of BRSV-naïve adult animals should be combined with the development of effective DIVA vaccines, for emergency ring vaccination (as demonstrated for equine influenza, Australia 2007). Norway has now officially started a control programme against BRSV and Coronavirus. This programme is based only on commercialisation of animals from herds in which the virus has not circulated recently. http://storfehelse.tine.no/hjem/kontrollprogramme-brsv-og-bcov

• Surveillance

  Serology when required. BRSV-naïve dairy herds can be identified by absence of BRSV-specific IgG in bulk tank milk. Or by monitoring the level of specific antibodies in animals older than 6 months of age.

  Multiplex PCR can be used for surveillance to detect BRSV RNA during the acute phase of disease.

  GAPS :

  In case of eradication programmes and in the absence of a marker vaccine, a sensitive virus detection assay (of antigen or genome) may be helpful.

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  Variable. BRSV is a component of bovine respiratory disease (BRD) complex caused by a wide range of viruses and bacteria. Reports exist of BRSV vaccine failure. However, it is difficult to estimate a BRSV vaccine failure as it could be either vaccine failure, failure of vaccination procedure, or that BRSV is not involved in the outbreak.

  GAPS :

  Improved methods to rapidly and inexpensively identify BRSV in cattle would support improved understanding of when control methods fail.

  Early warning system to increase the level of biosecurity to stop or decrease BRSV spread in an area.

• Costs of above measures

  Costs of treatment of infected animals. Costs of purchase and application of vaccine when used.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  No.

  BRSV is non-notifiable to the WOAH.

• WOAH disease card available

  N.A

• WOAH Terrestrial Animal Health Code

  N.A.

• WOAH Terrestrial Manual

  N.A.

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  None.

• Zoonosis: cost of treatment and control of the disease in humans

  None.

• Direct impact (a) on production

  BRSV is a major cause of respiratory disease in calves resulting in a substantial economic loss for the cattle industry worldwide. No specific figures are available for all EU member states, but must be significant given BRSV infection is a major respiratory disease in cattle below 6 months of age. Approximately 1.9 million calves in the UK affected by respiratory disease each year, at a cost of £54 million. Furthermore, approximately 160,000 calves, which have a potential market value of £100 million, die annually as a result of pneumonia and related illnesses in the U.K. In the Netherlands, losses due to BRD have been estimated to be 33.5 euros per calf in the fattening period. However, this is an underestimate as it does not include losses due to calf mortality, medicines, extra labour to take care of diseased calves, and growth retardation in apparently healthy but perhaps subclinically-infected calves. BRSV is the single most important respiratory viral pathogen of calves.

  GAPS :

  The cost of losses due to BRSV infection in different types of production systems is needed to estimate more precisely the economic impact of this infection.

• Direct impact (b) cost of private and public control measures

  Costs of diagnosis and treatment (medicine, manpower), mortality, decrease of milk production and growth, non-commercialisation of milk obtained from treated milking cows (withdrawal delay for antibiotic or other medicine).

• Indirect impact

  Disruption to production and mortality of young calves with a knock-on effect on livestock production. The non-commercialisation of milk and animals from a farm undergoing an outbreak (sometimes for more than one month) has consequences for the farm as a result of increased workload, food, accommodation. Dairy cows are commonly treated with antibiotics during severe BRSV outbreaks – their milk is not sold until the withdrawal period is over. Thus, for each antibiotic-treated cow, the milk can be lost for ~10 days. As a single diagnosis, BRSV is the main cause of insurance reimbursement to Swedish farmers.

  Farmers buying calves can be affected by BRSV outbreaks either by introducing BRSV in their herd or by not filling up their installations with animals and therefore being economically affected.

  GAPS :

  Increase knowledge on long-term effect of calf-hood diseases on productivity later in life (including reproduction and milk yield).

• Trade implications

• Impact on international trade/exports from the EU

  None.

• Impact on EU intra-community trade

  None.

• Impact on national trade

  Has some impact. Farmers are asked by adviser organisations not to commercialise animals if an outbreak occurs in their herd.

• Links to climate

• Seasonal cycle linked to climate

  There is some evidence that climatic conditions may affect the occurrence of BRSV infections, which tend to be more prevalent in the autumn and winter. It is speculated that BRSV outbreaks may be precipitated by changes in the weather, such as a drop in temperature or a decrease in atmospheric pressure.

  GAPS :

  Is there a link with day-light length, change in environmental temperature, &/or absolute humidity?

• Distribution of disease or vector linked to climate

  No.

• Outbreaks linked to extreme weather

  No.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  No.

• Main perceived obstacles for effective prevention and control

  Lack of evaluation of economic impact of BRSV, and the cost benefit of preventive measures.

  Much of what is known about BRSV comes from experimental challenge studies and observational research.

  There is currently poor understanding of the degree to which genetic and antigenic characteristics of the virus are related to transmissibility or disease severity. Although many experimental challenge studies support vaccine efficacy, few data are available to determine whether currently available vaccines decrease disease in the field. Most published field trials of BRSV vaccines are several decades old, tested vaccines no longer available, or only test effects on undifferentiated BRD, and not BRSV specifically. Some concepts widely believed to be true, such as the idea that intranasal vaccination is more effective than parenteral vaccination in young calves, are actually not supported by very much high-quality data.

  GAPS ;

  Evaluation of the benefit to implement preventive measures such as biosecurity and vaccine measures to stop BRSV transmission.

  Lack of vaccine inducing a long duration of virological protection against BRSV infection in calves or adult cattle.

  Lack of data confirming the most effective ways to use currently available vaccines to decrease disease and maintain production in modern cattle production settings.

  Need of effective treatment against the severe respiratory form of BRSV infection.

  Lack of understanding of the degree to which antigenic/genetic changes in the virus versus characteristics of the immune/inflammatory response of infected cattle, impact transmission and disease severity.

• Main perceived facilitators for effective prevention and control

  GAPS :

  A system that promotes the conduct of good quality field trials to confirm field efficacy of BRSV vaccines in modern production settings would help to confirm whether vaccines actually have practical value in field settings. It might be that vaccines are helpful in certain cattle production settings but not in others. Perhaps other management practices such as within-farm biosecurity is more effective in some settings.

  Clinical trials in veterinary medicine are often underpowered due to small numbers of animals or farms studied. Resources to support more and larger clinical trials of different practices could improve understanding of the true effects of BRSV prevention and control measures.

Global challenges

• Antimicrobial resistance (AMR)

• Impact of AMR on disease control

  Non applicable.

• Established links with AMR in humans

  Non applicable.

• Digital health

• Precision technologies available/needed

  Early BRSV detection could improve at

  • the herd level: animal welfare by giving extra-care to affected animals as well as the implementation of earlier interventions with supportive care, for example by administering anti-inflammatory/pro-resolving.drugs (if developed and proven to be beneficial).
  • Between herds: early warning to increase the level of biosecurity.

  GAPS :

  Since BRSV is a major contributor to the BRD complex, precision technologies supporting rapid and earlier detection of BRD-affected cattle through remote detection of decreased food and water intake, or decreased movement, could decrease impact of BRSV infection.

• Data requirements

  GAPS :

  Reliable and accurate remotely detected evidence of BRD.

• Climate change

• Role of disease control for climate adaptation

  Non applicable.

• Effect of disease (control) on resource use

  BRSV is a common contributor to the BRD complex, and the BRD complex is a leading cause of bovine sickness and death worldwide. Because some cattle die or experience decreased production due to BRD complex, more cattle and thus more resources are needed to provide the same amount of meat and milk.

  GAPS :

  Improved knowledge of the true impact of BRD complex on resource utilization in cattle production.

  Gaps noted in previous sections should improve control of infection and disease due to BRSV, leading to less BRD complex and more efficient use of resources.

• Effect of disease (control) on emissions and pollution (greenhouse gases, phosphate, nitrate, …)

  Increase the fattening period for beef production which imply more food consumption to reach the same final weight

• Preparedness

• Syndromic surveillance

  Possible.

  GAPS :

  Regroup data from diagnostic laboratories at regional/national level.

  Better rapid and cost-effective BRSV detection methods could improve knowledge of how often BRSV contributes to outbreaks of respiratory disease in different cattle production settings. Could also improve understanding of what clinical syndromes are most likely due to BRSV.

• Diagnostic platforms

  GAPS :

  Rapid and inexpensive viral detection methods could improve preparedness by improving understanding of when BRSV is likely to be involved in outbreaks.

• Intervention platforms

  GAPS :

  DIVA vaccines as described above could improve control of BRSV if partnered with rapid detection methods.

• Communication strategies

  GAPS :

  Early warning system to warn farmers/animal workers to increase biosecurity/vaccination measures to limit the spread of virus between herd

Main critical gaps

• Understanding of the relationship between virus characteristics and disease severity/transmissibility.

  Understanding of the true effects of vaccination and other control measures in field settings.

  Vaccine compliance.

  Development of effective treatments.

Conclusion

• BRSV is still a major cause of respiratory disease in calves and causes considerable economic losses worldwide. More effective vaccines, especially of the DIVA type, combined with biosecurity measures based on identified routes of virus introduction in herds are needed to combat the disease successfully in a well-controlled manner in endemic areas.

  However, BRSV infections are not notifiable to the OIE and there is no compulsory control programme being considered.

  Large volumes of antibiotics are used in the veal production sector to try and control respiratory disease. Following the request of Governments to significantly reduce the use of antibiotics in livestock the use of BRD vaccines is increasing.

  Targeted anti-inflammatory drugs with increased efficacy against pneumonia would reduce clinical disease and antibiotic consumption.

  Increased funding for research and development is needed, especially for well designed field trials on modern cattle production operations, as the level of funding for endemic diseases is decreasing in many EU countries.

  BRSV in calves is an excellent model for development of HRSV vaccines and pharmaceutical products.

Sources of information

• Expert group composition

  Expert group members are included where permission has been given

  Jean François Valarcher, Swedish University of Agricultural Sciences (SLU), Sweden – [Leader]

  Rineke de Jong, Wageningen University & Research, The Netherlands

  Sara Hägglund, Swedish University of Agricultural Sciences (SLU), Sweden

  Birgit Makoschey, MSD Animal Health, The Netherlands

  Gilles Meyer, Toulouse Veterinary School (ENVT), France

  Sabine Riffault, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), France

  Geraldine Taylor, The Pirbright Institute (PIR), UK

  Edouard Timsit, Ceva Santé Animale, France

  Amelia Woolums, Mississippi State University, U.S.A.

• Date of submission by expert group

  28 March 2024