The NS2 deletion mutants, however, yielded only small pinpoint foci in MDBK monolayers, consisting of a small number of infected cells Fig. Due to their very slow growth in MDBK, cells had to be split every three days in a ratio to keep the infection going on. To our knowledge, this is the second species of the genus Pneumovirus for which the entire genome sequence has been determined and which has been made amenable to genetic manipulation. Compared to the published sequences of strain A, a marked divergence was observed.
The parental virus was therefore designated ATue GenBank accession no. The approach used to rescue cDNA derived from ATue into infectious BRSV follows the principles shown to be successful for recovery first of recombinant rabies virus 40 and then of a variety of negative-strand RNA viruses from the rhabdovirus, paramyxovirus, and bunyavirus families 8.
The expression systems most widely used rely on infection of cells with recombinant vaccinia viruses vTF or MVA 2 — 4 , 10 , 13 , 17 , 18 , 23 , 45 providing T7 RNA polymerase, which is needed for expression of proteins and RNAs from transfected plasmids.
This, however, requires coping with vaccinia virus-induced CPEs which limit the window for recovery, vaccinia virus-induced recombination of transfected plasmid DNA 13 , 18 , and separation of different viruses by biophysical 40 , biochemical 45 , or biological 13 means. We describe here the establishment of a BHK-derived cell line stably expressing T7 RNA polymerase, as first reported for measles virus 32 , obviating the use of vaccinia helper virus.
Especially for recovery of BRSV, the availability of a vaccinia virus-free system was regarded as crucial, since BRSV replicates very slowly and to low titers in cell culture and is highly cell associated, like vaccinia virus, and since virions are pleomorphic in size and shape, with some particles comparable in size to vaccinia virus.
Moreover, a general advantage of the T7 polymerase-expressing cell line in combination with IRES-containing support plasmids 11 was confirmed in the rabies virus recovery system.
Compared to the vaccinia virus-driven expression system, the recovery rates were increased at least fold 12a. In contrast to other paramyxoviruses or rhabdoviruses, where N, P, and L proteins are sufficient to support encapsidation of antigenome RNA and to initiate an infectious cycle, recovery of the pneumovirus HRSV has been shown to require the additional expression of the M2 gene ORF 1 , which encodes a transcription elongation factor 5 , Both viruses corresponding to ATue, chimeric viruses possessing the leader region of HRSV, and considerably attenuated NS2-deletion mutants could be isolated from every transfected cell culture dish.
The recovery rate thus exceeds by far 1 in 10 6 transfected cells. The successful recovery of recombinant BRSV indistinguishable in phenotype from the parental virus ATue confirmed the authenticity and the functionality of the determined nucleotide sequences.
A particular focus was laid on the functional characterization of BRSV sequences previously not available, namely, the gene ends and the L gene. The amino acid differences were distributed over the entire protein, indicating rather identical functions of the two proteins. In the case of HRSV minigenomes, the promoter function was highly sensitive to insertion of nucleotides into the terminal 10 residues and into the stretch of residues 21 to 25 6 , 7. Interestingly, the eight nucleotide differences of the BRSV leader region are all located outside of these functionally critical regions.
The chimeric viruses could be rescued with the same efficiency as rBRSV and replicated with the same speed to the same titers and produced the same type of CPE.
The same applied to the chimeric and authentic NS2 deletion mutants see below. The observed nucleotide differences apparently do not specify genetic information that may account for species specificity, further confirming the close relationship of BRSV and HRSV.
Members of the genus Pneumovirus show particular features that distinguish them from other paramyxovirus genera, such as the lack of P gene RNA editing. Apparently, this is also true for BRSV. Neither the parental virus ATue nor any of the recombinants have a genome consisting of multiples of 6 nt. The recombinant BRSV genome lacks five residues compared to the ATue genome but replicated with the same efficiency.
Again, they were found to replicate at identical rates. Another peculiarity of pneumoviruses is the high number of encoded genes, some of which do not have counterparts in other paramyxoviruses, such as SH, M2, and the nonstructural genes NS1 and NS2. A role for the M2 protein as a transcription elongation factor has also been established 5 , 16 , but the function of the two nonstructural proteins NS1 and NS2 has remained rather obscure.
Only revertants of HRSV NS2 knockout viruses, in which tandem stop codons were introduced in such a way that the NS2 protein would not be expressed, could be isolated from plaques observed in transfection experiments 42 , indicating an important function of HRSV NS2 in the virus life cycle.
Strikingly, in the avian pneumovirus TRTV, both nonstructural genes are absent, emphasizing the question of whether they represent essential genes in mammalian pneumoviruses such as BRSV. The pattern and the relative amounts of mRNAs and full-length virus RNA produced in infected cells were not markedly changed, except for the lack of an NS2 transcript.
Moreover, maximum titers were reached in MDBK cells infected with NS2 deletion mutants by 15 days after infection, compared to 8 days after infection with standard ATue As the cDNA constructs used for recovery of nondeficient rBRSV were made by completion of the NS2 deletion cDNA, the observed slower growth and the reduced virus titers are due to the lack of NS2 rather than to putative differences in other parts of the genome. Thus, although not essential, NS2 is an accessory factor able to substantially support virus growth, by a thus far unknown mechanism.
Further experiments using modified virus mutants are now feasible and should help to reveal the mechanisms of NS2 involved in facilitating virus growth in different cell types.
The successful recovery of the first BRSV strain from which an entire gene has been deleted is important not only for studying the molecular biology and genetics of the virus but also because it provides a severely attenuated virus with an unequivocal serological marker. Further manipulation of NS2-deficient viruses may lead to the development of attenuated marker vaccines, easily distinguishable from wild-type virus. For the prevention of respiratory diseases, live vaccines appear to be best suited due to their ability to confer local immunity in addition to humoral immune response.
It will also be of interest to determine whether foreign epitopes or proteins can be incorporated into the virion in order to design vaccines for other respiratory pathogens or vectors for transient gene therapy. National Center for Biotechnology Information , U.
Journal List J Virol v. J Virol. Ursula J. Author information Article notes Copyright and License information Disclaimer. Phone: 49 Fax: 49 E-mail: ed. Received Jul 2; Accepted Oct 8. This article has been cited by other articles in PMC. Try out PMC Labs and tell us what you think. Learn More. Language: English French. Acta vet. The study of the virus has been difficult because of its lability and very poor growth in cell culture.
However, during the last decade, the introduction of new immunological and biotechnological techniques has facilitated a more extensive study of BRSV as illustrated by the increasing number of papers published. Despite this growing focus, many aspects of the pathogenesis, epidemiology, immunology etc.
The course and outcome of the infection is very complex and unpredictable which makes the diagnosis and subsequent therapy very difficult. BRSV is closely related to human respiratory syncytial virus HRSV which is an important cause of respiratory disease in young children. The present paper contains an updated review on BRSV covering most aspects of the structure, molecular biology, pathogenesis, pathology, clinical features, epidemiology, diagnosis and immunology based on approximately references from international research journals.
These references are in PubMed. This may not be the complete list of references from this article. National Center for Biotechnology Information , U.
Journal List Acta Vet Scand v. Acta Vet Scand. Published online Mar 1. Author information Article notes Copyright and License information Disclaimer. Larsen, Email: kd. Corresponding author.
Received Feb 10; Accepted Dec This article has been cited by other articles in PMC. Functional diversity of helper T lymphocytes. Experimental infection of lambs with bovine respiratory syncytial virus and Pasteurella haemolytica: clinical and microbiologic studies. Serological evidence for pneumovirus infections in pigs.
Distinct patterns of T- and B-cell immunity to respiratory syncytial virus induced by individual viral proteins. Polylactosaminoglycan modification of the respiratory syncytial virus small hydrophobic SH protein: a conserved feature among human and bovine respiratory syncytial viruses.
The NS1 protein of human respiratory syncytial virus is a potent inhibitor of minigenome transcription and RNA replication. Viral-bacterial synergistic interaction in respiratory disease. Virus Res. Seroepizootiologic study of bovine respiratory syncytial virus in a dairy herd.
Seroepizootiologic study of bovine respiratory syncytial virus in a beef herd. Study on the etiologic role of bovine respiratory syncytial virus in pneumonia of dairy calves. Gene expression of nonsegmented negative strand RNA viruses. Transcription of human respiratory syncytial virus genome RNA in vitro: requirement of cellular factor s.
Sequence of the major nucleocapsid protein gene of pneumonia virus of mice: sequence comparisons suggest structural homology between nucleocapsid proteins of pneumoviruses, paramyxoviruses, rhabdoviruses and filoviruses.
Application of the polymerase chain reaction PCR in veterinary diagnostic virology. Electron microscopic evidence for bridges between bovine respiratory syncytial virus particles.
Experimental respiratory syncytial virus infection in calves and lambs. Comparative structure, morphogenesis and biological characteristics of the respiratory syncytial RS virus and the pneumonia virus of mice PVM.
A microbiological study of pneumonic calf lungs. Ultrastructural features of alveolar lesions in induced respiratory syncytial virus pneumonia of calves. Observations on outbreaks of respiratory disease in housed calves. Respiratory syncytial virus pneumonia in young calves: clinical and pathologic findings. The G protein can also modulate components of the innate and adaptive immune response, leading to a reduction in the BRSV specific immune response [ 10 , 64 ]. These immunomodulating properties might explain why deletion of the genes coding for either of the two proteins leads to attenuation in calves [ 7 , 11 ].
The complex interaction between virus and immune system is depicted in Fig. Virus infection and interaction with the innate immune system. The protective immune response against BRSV and BPIV3 involves both humoral antibody and cell-mediated immunity with different roles for the two branches.
While neutralizing antibodies seem to be a correlate of protection against severe disease, cell-mediated immunity is considered to be essential for virus clearance following acute infection [ 44 ] Fig. Infected cattle develop antibodies directed against these glycoproteins as well as some of the minor viral proteins [ 30 , 63 ]. Results with HRSV in mice, suggest that G-specific antibodies might be neutralizing the virus, and might be involved in antibody-mediated cellular immune functions [ 67 ].
On the other hand, the soluble form of the HRSV G protein has been shown to antagonize antibody-mediated inhibition of virus replication [ 68 ]. Both, under field and experimental conditions it has been shown that presence of neutralizing antibodies either maternally derived or due to previous infection does not fully prevent disease but reduces the severity of the disease, both for BRSV [ 72 , 73 ] and BPIV3 [ 30 , 74 ].
In an epidemiological study with antibody positive calves, neutralizing antibody levels were inversely related to the severity of disease after infection with BRSV [ 75 ]. The mucosal antibodies decline to low levels after 6 to 8 weeks, whereas the serum antibodies persist for 3 to 5 months. It was noted that high concentrations of mucosal antibodies protect against disease, whereas the serum antibodies reduce the severity of disease once it has occurred [ 30 ].
Colostral antibodies provide partial protection against clinical disease. On the other hand, they can hamper the induction of an active humoral immune response after infection or vaccination, but they do not suppress priming of the humoral and cellular immune system as indicated by a rapid response systemic and mucosal IgA response after secondary infection [ 75 ].
In several studies, clear antibody responses were measured after vaccination [ 38 , 78 ], yet no information is available, whether these responses was directly correlated with protection. Moreover, the immune response and level of protection may differ between vaccines depending on the type of vaccine and the route.
Results from efficacy studies with live BRSV and BPIV3 vaccines suggest that animals with a low or even undetectable antibody response can be protected [ 38 , 79 — 81 ], Makoschey et al. Cell mediated responses can be induced by modified-live, conventional vaccines as well as some inactivated BRSV vaccines [ 83 — 85 ]. The mechanisms for initiation of cell mediated immunity against BRSV have been studied quite extensively and comprehensive reviews are available [ 44 , 62 ].
Similar observations were made after BPIV3 challenge of previously vaccinated calves: the production of neutrophil chemotactic factors by alveolar macrophages and the resulting neutrophil influx into the lungs occurred more rapidly than in the control animals resulting in a more rapid clearance of the virus [ 91 ].
Numerous studies, both with HRSV and BRSV suggest that a disbalanced cellular immune response is involved in the pathogenesis of this phenomenon, yet the immunological mechanisms are still not completely understood [ 44 ]. Such an immunopathological phenomenon has never been reported for BPIV3.
The importance of early BRD detection is generally acknowledged. Measuring of the body temperature [ 96 , 97 ], auscultation, ultrasonography [ 98 ] and detection of acute phase protein [ 99 ] have been described as suitable methods for diagnostics based on clinical signs, yet they do not enable distinction between different respiratory pathogens.
Regarding virus detection, it is important to realize that the viruses are only shed during a limited timeframe. BRSV RNA was detected in nasal swab samples starting on day one to day five after experimental infection for up to 4 weeks [ ], while previous studies have concluded that viral shedding usually begins later, and lasts for a shorter period [ 38 , 79 , 81 , , ]. The explanation for this discrepancy is likely related to the difference in detection methods i.
RNA detection by polymerase chain reaction PCR as opposed to virus titration assay in tissue culture in the latter studies. Also, for BPIV3, virus detection in nasal swab samples was positive at an earlier time point and continued for a longer period when tested by PCR as compared to the results of the virus titration in tissue culture Makoschey et al.
In the culture method, which could be considered the gold standard, samples are incubated on susceptible cells and virus infection is determined by cytopathic effect or immunostaining using labelled specific antibodies or antiserum.
In the case of BPIV3, the culture plates can also be incubated with erythrocytes and subsequently read for haemadsorption. Due to the nature of the test, the titration method only detects infectious virus particles, while also non-infectious virus particles can lead to a positive PCR result.
As both viruses are very labile and easily killed, samples might lose infectivity during transport and storage. Those samples are then found false negative in the virus titration assay, but positive in the PCR test.
As the pattern of values obtained from the two assays over the infection time course correlated closely, the results suggest that, incomplete viral genomes that occur during virus replication might also contribute to the difference between infectious virus titer and RNA copies.
Some of those are commercially available [ — ]. The testing is commonly applied on nasal swab samples, transtracheal aspiration or bronchoalveolar lavages BAL. When comparing different sampling methods, results obtained from nasal swabs or BAL were in moderate agreement [ ]. BRSV levels in BAL samples from experimentally infected animals were found to be slightly higher than levels in nasal swab samples taken at the same day Makoschey et al.
Moreover, BAL samples might provide more reliable results for diagnostics of bacterial infections [ ]. When testing calves that have been administered an intranasal vaccine, caution must be taken for the interpretation of results as the virus can be detected for more than a week after vaccination [ , ] and the signal can be derived from vaccine virus or from a mix of wild type and vaccine virus.
The ELISA technique is fast, cost-effective, large numbers of samples can be handled, the method can be standardized and as opposed to virus neutralization test, an antibody ELISA does not require handling of live virus. Moreover, the isotype- and subclass of the antibodies can be determined using the ELISA technique [ 76 , 77 , ].
However, as the viruses are endemic in most herds, the diagnostic value of single serum samples are highest for IgM and IgA that are indicative of a recent re- infection [ 76 ]. Several commercially available ELISAs used in routine diagnostics and research can be used in serum or milk, and levels of antibodies in serum correlates well with levels of antibodies in milk in individual cows, although the antibody titers are generally lower in milk than in serum [ ].
However, the levels of antibodies in bulk tank milk can remain high for several years, and this limits the ability to use the bulk tank milk to determine evolution of disease within a farm [ ]. In herds with recurrent disease, paired samples might be useful to establish a diagnosis. An increase in titer of at least four-fold is considered indicative for an infection. The fact that calves that become infected in the presence of passively derived antibody may not seroconvert [ 75 ] should be taken into consideration for the interpretation of results.
In addition to the diagnostic purposes, antibody testing of serum samples taken from calves at the arrival in a fattening unit can provide useful information for the prediction of the risk to develop BRD later in life [ , ].
Another application might be the monitoring of the immune response after vaccination. In this case, the type of vaccine must be taken into account. Also, the route of vaccination influences the antibody response. As mentioned earlier, especially live BRSV vaccines applied via the intranasal route have been shown to be efficacious even in the absence of detectable levels of serum antibodies [ 38 , 79 — 81 ], Makoschey et al.
Last but not least, it should be mentioned, that metabolomic profiling might offer new approaches to determine markers for the systemic immune response [ ] following virus infection or vaccination. As for other virus infections, treatment of BRSV and BPIV3 infected animals is mostly limited to supportive measures to keep the affected animals well hydrated and to maintain proper energy and electrolyte balance.
If the affected animals do not recover, and the involvement of secondary bacterial infections has been diagnosed, treatment with antimicrobials, for which the bacteria are susceptible, may be required.
Corticosteroids are not recommended for use in the treatment of BRD due to their immunosuppressive nature. Promising results with a combination of antiviral and nonsteroidal anti-inflammatory treatment have recently been obtained in a bovine model of respiratory syncytial virus infection [ ].
In addition, general measures should be taken to minimize risk factors for the development of BRD including ensuring optimized environmental conditions [ ] and reduction of stress factors [ ].
Basic cleaning and hygiene procedures should be applied to prevent or at least reduce the infection pressure. As both viruses have a low tenacity, they are readily inactivated with common disinfectants.
Direct transmission from infected animals, indirect transmission by individuals visiting farms vectoring the viruses [ ] or not providing boots for visitors [ ] have been identified as risk factors for inter-herd transmission of BRSV. On the other hand, herds can remain seronegative despite proximity to seropositive herds if herd biosecurity is appropriate [ ]. Good colostrum management is an important preventative measure as low levels of IgG in general and low levels of BRSV specific antibodies were found to be associated with a higher risk of BRD [ ].
Novel approaches to BRD disease control and prevention that are currently investigated are innate immunomodulation [ ] and the identification of genes and chromosomal regions that underly genetic variation in disease resistance and response to vaccination.
Analysis of the genetic variation of animals in a BRSV infection trial suggest that certain motifs in genes related to immunity were associated with high or low antibody and T cell responders [ ]. Eventually, this research could lead to selection of animals that are more resistant to disease caused by BRSV and BPIV3 and open new ways to improve vaccine efficacy. Shortly after the discovery of BPIV3, the first inactivated vaccines against this virus were developed [ ] followed some years later by modified live virus MLV vaccines [ ].
Due to the observation of disease enhancement in children vaccinated with a formalin-inactivated HRSV vaccine [ ] attempts to develop a BRSV vaccine initially focused on live vaccines [ ]. Some years later, promising results were achieved with a BRSV vaccine derived from glutaraldehyde-fixed cells, which did not cause disease enhancement, but even provided better protection than two live-attenuated vaccines tested in the same study [ ]. Several inactivated BRSV vaccines have been available and widely used since then, and only incidentally severe courses of BRSV infection have been reported in calves that had previously been vaccinated with formalin-inactivated vaccines [ 93 , ].
An incident of vaccine associated disease enhancement has also been reported for a beta-propriolactone-inactivated, alum- and saponin-adjuvanted BRSV vaccine [ 92 ]. It should be noted that vaccination with a modified live vaccine during the course of a natural infection may also enhance the severity of disease [ ]. The immunological mechanisms have not been fully unraveled, but it has been proposed that the inactivation process is able to alter BRSV epitopes and thus the induction of cytotoxic T lymphocyte activity [ ] and functional antibodies [ ].
This can lead to high levels of non-neutralising antibodies in combination with relatively low levels of neutralising antibodies [ , ] and increased levels of IgE [ ]. Moreover, it has been observed that Interferon gamma production following BRSV infection is reduced in calves previously vaccinated with formalin-inactivated BRSV [ ].
Several commercially available live attenuated BRSV and BPIV3 vaccine strains have been obtained using traditional approaches such as passaging in cell culture [ ] or selection of temperature-sensitive mutants [ 78 , ].
In general, the mechanisms of attenuation are unknown, but in a recent study it was shown that transcriptions of cytokines related to fever and inflammation were not upregulated in the nasopharyngeal mucosa after vaccination with a new live attenuated intranasal BRSV-BPIV3 combination vaccine, while these factors were upregulated after infection with BPIV3 field virus [ 47 ].
Multiple approaches using contemporary vaccine technologies have been investigated with the intention to develop better vaccines for use in cattle, or to use the bovine viruses in their natural host as model for vaccines against their counterpart in humans. Subunit vaccines based on the major glycoproteins of BRSV have been tested with good results, both for parenteral [ 80 , ] and intranasal application [ ].
After intranasal application of BPIV3 antigen formulated in nanoparticles, a mucosal IgA response was measured [ ], yet protection against infection was not tested. The development of a reverse genetic system for BRSV [ ] enabled the engineering of recombinant viruses. Several viruses lacking one or more proteins induced at least partial protection in calf models [ 7 , 11 , 17 , 80 ].
Such a virus might potentially be a bivalent vaccine against both, BRSV and BPIV-3, but to our best knowledge, this has not yet been demonstrated in calves. Promising results with human recombinant RSV-vaccine candidates in which the F glycoprotein is stabilized in its prefusion state could be reproduced with recombinant BRSV in the calf model initially in animals without maternal antibodies [ ] and more recently also in animals with maternal antibodies [ ].
Last but not least, chimeric vaccinia viruses [ , ] or bovine herpesviruses [ ] expressing BRSV proteins have been developed as vaccine candidates. One major advantage of these viruses for vaccine development would be that they grow much better in cell culture than the BRSV viruses. Another advantage is that some of these vaccines offer DIVA properties, which allow to differentiate between infected and vaccinated animals by serological testing.
Such vaccines would be helpful for monitoring efficacy of biosecurity measures or for countries with BRSV control programs such as Norway. Although the results obtained with several of the above-mentioned vaccine candidates were promising, none of them clearly outperformed the currently available commercial vaccines with regards to all the requirements for yields, process robustness, safety and efficacy. Completely novel approaches to vaccine development might become available in the future thanks to the progress in the understanding of host pathways involved in the innate anti-viral response, together with the capability to generate substances that can interfere with these processes [ ].
Prior to commercialization, the efficacy of any new vaccine must be demonstrated, under both experimental and field conditions as prescribed in relevant regulations. Given the multifactorial nature of the disease, it is rather demanding to reproduce clinical signs under experimental conditions [ ]. In the first infection studies with cell-culture-passaged BRSV only mild disease or no disease at all was observed in the unvaccinated control animals [ ], even in colostrum deprived or gnotobiotic calves.
The suggestion that the viruses attenuate rapidly upon culture in vitro has been supported by several studies in which clinical signs of respiratory disease were reproduced by inoculation of low-passage BRS virus [ 20 , ]. Early studies investigated different administration protocols for the BRSV and BPIV3 challenge strains including multiple application [ ] and invasive intratracheal routes [ , ], which are not representative of natural transmission.
Aerosolization, a delivery method that mimics the natural route of transmission, was found to produce more consistent results [ , , ].
The same method has also been successfully applied in BPIV3 infection studies [ ]. Many efficacy studies with commercially available BRSV and BPIV3 vaccines both under experimental and field conditions have been published and comprehensive reviews are available [ , ]. Most of these studies estimated clinical efficacy from results of experimental challenge studies. Interpretation of the results requires caution as some of the models are not representative for natural exposure.
An important requirement for live BRD vaccines is an early onset of immunity. Studies with a live marker vaccine against Bovine Herpesvirus have shown that the animals were protected as early as 3 days after intranasal vaccination [ ]. Studies to determine the onset of immunity of the currently available BRSV and BPIV3 vaccines were hampered by the fact that the commonly applied methods for virus detection in nasal discharge do not discriminate between vaccine and field strains.
By consequence, vaccine virus interferes with the detection of wild-type virus if the experimental infection is done too shortly after vaccination. A single dose was shown to prime the cellular immune response in calves around 2 weeks of age with maternal antibody [ 85 ] and provided partial protection against experimental BRSV infection [ ], yet complete protection can only be expected after completion of the two-dose vaccination course. In field studies, efficacy is typically evaluated by general parameters for disease such as mortality, morbidity, treatments and growth rate while no or only limited information is available about the involvement of specific pathogens in the disease outbreak.
Several studies in which commercially available MLVs with and without BRSV were compared, indicated a reduction of respiratory disease [ , ], or improved milk production and reproductive parameters [ ] in the groups vaccinated with BRSV. In our current production systems young calves are assembled under stressful conditions in high numbers, which at the same time increases the infectious pressure and weakens the immune system of the calves.
Early in live, calves depend on the colostral immunity for protection against infectious agents. Unfortunately, the amount of specific maternal antibodies is very variable and the duration of protection by colostral antibodies is difficult to predict.
By consequence, vaccines must be applied early in live and have an early onset of immunity to protect those calves that have received low levels of colostral antibodies. On the other hand, the vaccines should also be efficacious in the face of maternal antibodies IFOMA to provide immunity to those calves that have received high levels of colostral antibodies.
They concluded that parental vaccination IFOMA is unlikely to result in seroconversion, and other immune responses are inconsistent, but the presence of antibodies may be prolonged and immunological memory might be induced. Moreover, reduction of clinical signs was reported by Chamorro and colleagues [ ]. The potential advantages of intranasal vaccination with a live vaccine IFOMA by stimulation of a local immune response and priming the systemic immune response prompted Ellis and colleagues to determine the efficacy of a live vaccine for parental delivery after intranasal administration [ 81 ].
That study suggested that similar levels of protection were provided by intranasal and parenteral administration. However, it should be noted, that the calves in that study had low levels of colostral antibodies. Typically, spraying devices generating a kind of aerosol are required for administration of these vaccines, however, in a recent study with a new BRSV-BPIV3 live vaccine, animals vaccinated without spraying device directly from the tip of the syringe were protected against experimental BRSV and BPIV3 infection [ ].
An alternative approach to protect the calf early in life is the vaccination of the pregnant dam to achieve higher and more homogenous levels of antibodies in the colostrum [ , ] and also specific memory cells in the calves [ ]. Calves fed colostrum from vaccinated dams were partly protected against BRSV infection [ 73 ]. Therefore, cow vaccination in combination with good colostrum management might be considered to complement an active immunisation program against BRD.
Given the involvement of multiple different pathogens in BRD, an important selection criterion for a vaccine is the range of antigens against which protection is provided. These observations illustrate the fact that BRD outbreaks in the field are often a combination of viral and bacterial pathogens. A general concern especially with BRSV vaccines is the rather short duration of immunity as compared to other viruses [ 79 , , , , ].
The observation that re-infections are common [ 65 ] suggest that also the immunity following field infection is of relatively short duration.
Therefore, re-vaccination of animals is advised to achieve lasting herd immunity [ ]. In the current complex economic structure of the cattle industry, cow-calf producers often do not have economic incentive to vaccinate the calves [ ].
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