Submitted Successfully!
Thank you for your contribution! You can also upload a video entry related to this topic through the link below:
Check Note
Ver. Summary Created by Modification Content Size Created at Operation
1 + 1372 word(s) 1372 2021-12-02 06:57:10 |
2 format correct Meta information modification 1372 2021-12-17 02:08:46 |
Limitations of Currently Available Bovine Respiratory Disease Vaccines
Upload a video

Ineffective vaccines, declining employment in the agricultural sector and increasing awareness of antimicrobial resistance has led policymakers to shift the focus onto the development of superior, more efficacious vaccines as a major contribution in reducing the pressure to intensify on the farming sector. Although many vaccines against BRD are currently available on the UK market, they have limitations. Only a few of the vaccines have been registered as suitable for use in pregnant or lactating cows and all require refrigeration. Additionally, all come with a strong recommendation for a booster to advance immunity and none have been tested for maternal antibody interference. Only eleven of the vaccines registered for use in the UK are multivalent and only four have been tested and deemed suitable for use alongside other veterinary treatments, frequently with those of the same manufacturer. However, multiple pathogens are considered threats during the neonatal stage and so it is impractical and ineffectual to have monovalent or incompatible medicines. Vaccination against BRD presents many challenges.

vaccination pathogens efficacy
Contributor :
View Times: 79
Revisions: 2 times (View History)
Update Time: 17 Dec 2021

1. Age of Administration

A major challenge to the development of a successful vaccines for BRD is the age at which calves must be vaccinated [1]. Peak viral infection occurs upwards from 1 month so vaccination must take place in the first few weeks of life to allow immunity to develop [2][3]. However, evidence shows a calf’s immune system to be immature at this time, thought to be a carryover from the immunotolerant state induced during pregnancy [1][4][5]. To compound this problem, several essential farm management practices (discussed earlier) occur during this period increasing corticosteroid levels [6] and essential maternally-derived antibodies (MDA) may interfere with the development of any vaccine-induced immunity [2][7].

2. Route of Administration

The majority of currently approved vaccines against BRD are to be used parenterally (i.e., sub-cutaneously or intramuscularly) and these have been demonstrated as producing protective immune responses [8][9][10][11]. However, parenteral vaccines are invasive, require trained personnel for sterile administration and often cause a ‘depot effect’ at the local site of injection; in cattle this can lead to carcass scarring and thus reduced price [12]. More recently, epicutaneous vaccination using skin patches, a non-invasive, needle-free delivery route, has been investigated in mice against RSV with encouraging results [13].
It has also been hypothesised that it might be more rational to vaccinate at the initial site of pathogen entry—intranasally—thereby potentially preventing infection at source. Many more intranasal vaccines are getting approved and coming onto the market. Intranasal vaccination induces more localised and protective mucosal immunity through activation of nasal-associated lymphoid tissues (NALT). Although mucosal immunity can also be generated as a consequence of vaginal, anal and oral inoculation, intranasal delivery is preferable due to its many advantages (discussed in context with disadvantages in Table 1). In support of this, a study by Ellis et al. showed that intranasal administration of BRSV vaccines intended for parenteral use did not reduce the protective efficacy of the vaccines [14]. Additionally, Rossi et al. [15] demonstrated strong bronchoalveolar cell-mediated and antibody responses after a single intranasal delivery of a multivalent BRSV, BHV-1 and BPIV-3 vaccine.
Table 1. Main advantages and disadvantages of intranasal vaccination in cattle.
More neutral pH and lower levels of enzymatic activity than digestive tract
Prime neonatal calf in the presence of MDA
Induction of systemic and mucosal immunity
User-friendly (potential use in herds/developing world/remote farms)
Rapid clearance of low affinity antigens
Potential antigen loss during inoculation (impact on cost)
Inefficient uptake
Lack of compatible adjuvants for mucosal vaccines

3. Type of Vaccines Available:

3.1. Modified-Live (MLV) Vaccines

Modified-live vaccines, also called attenuated vaccines, are those which employ live replicating whole pathogen that has been weakened in the laboratory. Attenuation of pathogenic strains can be obtained by modifying the molecular construction of the genome, using chemical mutagenesis, gene deletion or by extensive serial passaging in non-host cell culture or embryonated chick eggs. Chemical mutagenesis has also been coupled with low temperatures to develop a cold-adapted temperature-sensitive strain (ctss) of HRSV that can only replicate in the upper respiratory tract [16]. Only two diseases have been successfully eradicated across the globe—smallpox in humans [17] and rinderpest in cattle [18][19]—and both have been achieved using modified-live vaccines, thus illustrating their significant contribution to human and veterinary health.

3.2. Inactivated Vaccines

Inactivated vaccines, also known as killed vaccines, are those which do not contain any live replicating pathogenic material and cannot cause disease. For this reason they have a superior safety profile to their live counterparts [20] and are considered suitable for use in pregnant or lactating animals. The pathogenic agents are destroyed by heat, chemicals or radiation. Furthermore, inactivated vaccines do not require refrigeration and can be lyophilised for transport purposes [21].

3.3. Immunogenicity of Modified-Live and Inactivated Vaccines

As attenuated vaccines broadly mimic the immune response garnered from a natural infection, they are universally recognised for producing stronger, longer lasting and more robust immune responses for many pathogens [21][22][23][24]. Furthermore, it is surmised that modified-live vaccines can initiate cellular responses in a way that inactivated vaccines are not reported as doing [25][26]. Several studies report the benefits of using modified-live vaccines in calves [27][28][29][30]. However, several studies now indicate that evidence on this is conflicting [30][31] and even if this were conclusive, often the immunogenicity advantages gained from MLV are offset by the increased safety risks posed, particularly in neonates.
Conversely, the immune response garnered from using inactivated vaccines is considered by some as inadequate with suggestions that inactivated vaccines can effectively prime CD4+ T cells but encourage eosinophila [32] and others providing evidence that IFNγ expression is reduced [33]. A further study demonstrated a link between maternal vaccination for BVDV using inactivated vaccines and neonatal pancytopenia—a fatal autoimmune disease contracted from ingesting colostrum [34]. Further, although antibody titres can be high these are often found to be non-neutralising [35]. However, again, in contrast, several studies observed that using inactivated vaccines generated protection and they are at least as efficacious as using modified-live virus [32][36].

3.4. Vaccine-Enhanced Disease

Of particular note for BRSV is the observation that vaccination could actually augment disease. This was first noted in 1967 after a failed vaccine trail using a formalin-inactivated RSV (FI-RSV) vaccine against HRSV [37] which led to investigations in cattle where a similar pathology was reported [38][39]. In this study, one group was vaccinated with a FI-BRSV vaccine while the other was sham-vaccinated. Both groups were challenged with live BRSV post-vaccination. No significant difference in gross lung lesions and in lung function was noted between the two groups, indicating the failure of the vaccine to provide any protective immunity. Further, although two groups were challenged with the same amount of BRSV, the sham vaccinated cohort demonstrated lower mean clinical scores [39] indicating disease exacerbation arising from vaccination. High titres of non-neutralising antibodies have also been observed, which can be associated with a high IgE titres and an allergic, inflammatory Th2-type response [40] and it is hypothesised that disease escalation is attributed to FI-RSV generation of low affinity antibodies [41] targeted at non-protective epitopes. Consequently, apprehension surrounds trials employing inactivated vaccines and scientists are cautious about developing candidate vaccines using inactivated antigen. Although antibody titres generated from vaccination are not always correlated with reduced disease, vaccination against any other pathogen implicated in BRD does not appear to have had such a detrimental effect [6].

4. Storage Conditions

Incorrect vaccine storage is frequently cited as a main reason for vaccine failure [42]. Correct storage conditions are essential for conserving the three-dimensional structure of antigens, and thus essential for vaccines to retain their potency [43]. However, reliable vaccine storage is often not controlled for in a field setting. Vaccines which could potentially remain immunogenic outside of the cold chain (i.e., not refrigerated) would be greatly beneficial to remote regions, vast farms or areas lacking sufficient infrastructure [44]. Recently a candidate nanoparticle RSV vaccine derived from an Sf9 insect cell line has been trialled showing that, once re-suspended, the vaccine can remain stable for < 60 days [45]. In further support of this, another group demonstrated that dry ice storage for up to 30 days did not detriment stability for a vaccine against East Coast fever—a tick-borne disease of cattle in Eastern and Central Africa with high mortality rates [46]. More recently a study into vaccines for tuberculosis showed that desiccation of liquid vaccine antigen increased thermostability outside of the cold-chain and produced a vaccine antigen more adaptable for mucosal use [47].


  1. Chase, C.C.; Hurley, D.J.; Reber, A.J. Neonatal Immune Development in the Calf and Its Impact on Vaccine Response. Veter. Clin. N. Am. Food Anim. Pract. 2008, 24, 87–104.
  2. Niewiesk, S. Maternal Antibodies: Clinical Significance, Mechanism of Interference with Immune Responses, and Possible Vaccination Strategies. Front. Immunol. 2014, 5, 446.
  3. Richeson, J.T.; Falkner, T.R. Bovine Respiratory Disease Vaccination: What Is the Effect of Timing? Veter. Clin. N. Am. Food Anim. Pract. 2020, 36, 473–485.
  4. Cortese, V.S. Neonatal Immunology. Veter. Clin. N. Am. Food Anim. Pract. 2009, 25, 221–227.
  5. Tregoning, J.S.; Wang, B.L.; McDonald, J.U.; Yamaguchi, Y.; Harker, J.A.; Goritzka, M.; Openshaw, P.J. Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection. Proc. Natl. Acad. Sci. USA 2013, 110, 5576–5581, PMCID:PMC3619373.
  6. Taylor, J.D.; Fulton, R.W.; Lehenbauer, T.W.; Step, D.L.; Confer, A.W. The epidemiology of bovine respiratory disease: What is the evidence for preventive measures? Can. Veter. J. 2010, 51, 1351–1359, PMCID:PMC2978987.
  7. Ellis, J.; Gow, S.; Bolton, M.; Burdett, W.; Nordstrom, S. Inhibition of priming for bovine respiratory syncytial virus-specific protective immune responses following parenteral vaccination of passively immune calves. Can. Veter. J. 2014, 55, 1180–1185.
  8. Gershwin, L.J.; Behrens, N.E.; McEligot, H.A.; Carvallo-Chaigneau, F.R.; Crum, L.T.; Gunnarson, B.M.; Corbeil, L.B. A recombinant subunit vaccine for bovine RSV and Histophilus somni protects calves against dual pathogen challenge. Vaccine 2017, 35, 1954–1963.
  9. Van der Sluijs, M.; Kuhn, E.; Makoschey, B. A single vaccination with an inactivated bovine respiratory syncytial virus vaccine primes the cellular immune response in calves with maternal antibody. BMC Veter. Res. 2010, 6, 2.
  10. Blodörn, K.; Hägglund, S.; Fix, J.; Dubuquoy, C.; Makabi-Panzu, B.; Thom, M.; Karlsson, P.; Roque, J.-L.; Karlstam, E.; Pringle, J.; et al. Vaccine Safety and Efficacy Evaluation of a Recombinant Bovine Respiratory Syncytial Virus (BRSV) with Deletion of the SH Gene and Subunit Vaccines Based On Recombinant Human RSV Proteins: N-nanorings, P and M2-1, in Calves with Maternal Antibodies. PLoS ONE 2014, 9, e100392.
  11. Fulton, R.W.; E Briggs, R.; E Payton, M.; Confer, A.W.; Saliki, J.; Ridpath, J.F.; Burge, L.J.; Duff, G.C. Maternally derived humoral immunity to bovine viral diarrhea virus (BVDV) 1a, BVDV1b, BVDV2, bovine herpesvirus-1, parainfluenza-3 virus bovine respiratory syncytial virus, Mannheimia haemolytica and Pasteurella multocida in beef calves, antibody decline by half-life studies and effect on response to vaccination. Vaccine 2004, 22, 643–649.
  12. Richeson, J.T.; Hughes, H.D.; Broadway, P.R.; Carroll, J.A. Vaccination management of beef cattle: Delayed vaccination and Endotoxin stacking. Veter. Clin. Food Anim. 2019, 35, 575–592.
  13. Poulet, H.; Minke, J.; Pardo, M.C.; Juillard, V.; Nordgren, B.; Audonnet, J.-C. Development and registration of recombinant veterinary vaccines: The example of the canarypox vector platform. Vaccine 2007, 25, 5606–5612.
  14. Ellis, J.; Gow, S.; West, K.; Waldner, C.; Rhodes, C.; Mutwiri, G.; Rosenberg, H. Response of calves to challenge exposure with virulent bovine respiratory syncytial virus following intranasal administration of vaccines formulated for parenteral administration. J. Am. Veter. Med Assoc. 2007, 230, 233–243.
  15. Rossi, P.S.; Mattei, R.I.; Schllemer, N.R.; Thomaz, G.R.; Antunes, A.V.; Virmond, M.P.; Taube, M.J.; Bertagnon, H.G. The effect of bovine vaccines against respiratory viruses administered either intranasal or intramuscular on broncho-alveolar fluid cells of heifers. Veter. Q. 2021, 41, 97–106.
  16. Wright, P.F.; Karron, R.A.; Belshe, R.B.; Thompson, J.; Crowe, J.; Boyce, T.G.; Halburnt, L.L.; Reed, G.W.; Whitehead, S.S.; Anderson, E.L.; et al. Evaluation of a Live, Cold-Passaged, Temperature-Sensitive, Respiratory Syncytial Virus Vaccine Candidate in Infancy. J. Infect. Dis. 2000, 182, 1331–1342.
  17. Henderson, D.A. The eradication of smallpox—An overview of the past, present, and future. Vaccine 2011, 29 (Suppl. 4), D7–D9.
  18. Anderson, J.; Baron, M.; Cameron, A.; Kock, R.; Jones, B.; Pfeiffer, D.; Mariner, J.; McKeever, D.; Oura, C.; Roeder, P.; et al. Rinderpest eradicated; what next? Veter. Rec. 2011, 169, 10–11.
  19. Roeder, P.L. Rinderpest: The end of cattle plague. Prev. Veter. Med. 2011, 102, 98–106.
  20. Sanders, B.; Koldijk, M.; Schuitemaker, H. Inactivated Viral Vaccines. In Infectious Disease and Vaccines Therapeutic Area; Springer: Berlin/Heidelberg, Germany, 2015; pp. 45–80.
  21. Clem, A.S. Fundamentals of vaccine immunology. J. Glob. Infect. Dis. 2011, 3, 73–78.
  22. Ficht, T.A.; Kahl-McDonagh, M.M.; Arenas-Gamboa, A.M.; Rice-Ficht, A.C. Brucellosis: The case for live, attenuated vaccines. Vaccine 2009, 27, D40–D43.
  23. Goldsby, R.A.; Kindt, T.J.; Osborne, B.A.; Kuby, J. Immunology, 5th ed; Freeman: New York, NY, USA, 2003.
  24. National Institute of Allergy and Infectious Disease. Vaccine Types. Available online: (accessed on 10 October 2021).
  25. Stevens, E.T.; Brown, M.S.; Burdett, W.W.; Bolton, M.W.; Nordstrom, S.T.; Chase, C.C.L. Efficacy of a Non-adjuvanted, Modified-live Virus Vaccine in Calves with Maternal Antibodies against a Virulent Bovine Viral Diarrhea Virus Type 2a Challenge Seven Months following Vaccination. Am. Assoc. Bov. Pract. 2011, 45, 23–31.
  26. Salerno-Gonçalves, R.; Sztein, M.B. Cell-mediated immunity and the challenges for vaccine development. Trends Microbiol. 2006, 14, 536–542.
  27. West, K.; Petrie, L.; Haines, D.M.; Konoby, C.; Clark, E.G.; Martin, K.; A Ellis, J. The effect of formalin-inactivated vaccine on respiratory disease associated with bovine respiratory syncytial virus infection in calves. Vaccine 1999, 17, 809–820.
  28. Vangeel, I.; Antonis, A.F.; Fluess, M.; Riegler, L.; Peters, A.R.; Harmeyer, S.S. Efficacy of a modified live intranasal bovine respiratory syncytial virus vaccine in 3-week-old calves experimentally challenged with BRSV. Veter. J. 2007, 174, 627–635.
  29. Xue, W.; Ellis, J.; Mattick, D.; Smith, L.; Brady, R.; Trigo, E. Immunogenicity of a modified-live virus vaccine against bovine viral diarrhea virus types 1 and 2, infectious bovine rhinotracheitis virus, bovine parainfluenza-3 virus, and bovine respiratory syncytial virus when administered intranasally in young calves. Vaccine 2010, 28, 3784–3792.
  30. Chamorro, M.F.; Palomares, R.A. Bovine Respiratory Disease Vaccination Against Viral Pathogens: Modified-Live Versus Inactivated Antigen Vaccines, Intranasal Versus Parenteral, What Is the Evidence? Veter. Clin. Food Anim. 2020, 36, 461–472.
  31. Kerkhofs, P.; Tignon, M.; Petry, H.; Mawhinney, I.; Sustronck, B. Immune responses to bovine respiratory syncytial virus (BRSV) following use of an inactivated BRSV-PI3-Mannheimia haemolytica vaccine and a modified live BRSV–BVDV vaccine. Veter. J. 2004, 167, 208–210.
  32. Knudson, C.J.; Hartwig, S.M.; Meyerholz, D.; Varga, S.M. RSV Vaccine-Enhanced Disease Is Orchestrated by the Combined Actions of Distinct CD4 T Cell Subsets. PLoS Pathog. 2015, 11, e1004757.
  33. Woolums, A.R.; Singer, R.S.; Boyle, G.A.; Gershwin, L.J. Interferon gamma production during bovine respiratory syncytial virus (BRSV) infection is diminished in calves vaccinated with formalin-inactivated BRSV. Vaccine 1999, 17, 1293–1297.
  34. Demasius, W.; Weikard, R.; Hadlich, F.; Müller, K.E.; Kühn, C. Monitoring the immune response to vaccination with an inactivated vaccine associated to bovine neonatal pancytopenia by deep sequencing transcriptome analysis in cattle. Veter. Res. 2013, 44, 93.
  35. Ellis, J.A.; Gow, S.P.; Mahan, S.; Leyh, R. Duration of immunity to experimental infection with bovine respiratory syncytial virus following intranasal vaccination of young passively immune calves. J. Am. Veter. Med Assoc. 2013, 243, 1602–1608.
  36. Patel, J.R.; Didlick, S.A. Evaluation of efficacy of an inactivated vaccine against bovine respiratory syncytial virus in calves with maternal antibodies. Am. J. Veter. Res. 2004, 65, 417–421.
  37. Kim, H.W.; Canchola, J.G.; Brandt, C.D.; Pyles, G.; Chanock, R.M.; Jensen, K.; Parrott, R.H. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 1968, 89, 422–434, ISSN: 00029262.
  38. Antonis, A.F.G.; Schrijver, R.S.; Daus, F.; Steverink, P.J.G.M.; Stockhofe, N.; Hensen, E.J.; Langedijk, J.P.M.; van der Most, R.G. Vaccine-Induced Immunopathology during Bovine Respiratory Syncytial Virus Infection: Exploring the Parameters of Pathogenesis. J. Virol. 2003, 77, 12067–12073.
  39. Gershwin, L.J.; Schelegle, E.S.; Gunther, R.A.; Anderson, M.L.; Woolums, A.R.; Larochelle, D.R.; Boyle, G.A.; Friebertshauser, K.E.; Singer, R.S. A bovine model of vaccine enhanced respiratory syncytial virus pathophysiology. Vaccine 1998, 16, 1225–1236.
  40. Kalina, W.V.; Woolums, A.R.; Gershwin, L.J. Formalin-inactivated bovine RSV vaccine influences antibody levels in bronchoalveolar lavage fluid and disease outcome in experimentally infected calves. Vaccine 2005, 23, 4625–4630.
  41. Delgado, M.F.; Coviello, S.; Monsalvo, A.C.; A Melendi, G.; Hernandez, J.Z.; Batalle, J.P.; Diaz, L.; Trento, A.; Chang, H.-Y.; Mitzner, W.; et al. Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease. Nat. Med. 2009, 15, 34–41.
  42. Williams, P.D.; Paixão, G. On-farm storage of livestock vaccines may be a risk to vaccine efficacy: A study of the performance of on-farm refrigerators to maintain the correct storage temperature. BMC Veter. Res. 2018, 14, 1–7.
  43. Saylor, K.; Gillam, F.; Lohneis, T.; Zhang, C. Designs of Antigen Structure and Composition for Improved Protein-Based Vaccine Efficacy. Front. Immunol. 2020, 11, 283.
  44. Ren, Q.; Xiong, H.; Li, Y.; Xu, R.; Zhu, C. Evaluation of an outside-the-Cold-Chain Vaccine Delivery Strategy in Remote Regions of Western China. Public Health Rep. 2009, 124, 745–750.
  45. Glenn, G.M.; Smith, G.; Fries, L.; Raghunandan, R.; Lu, H.; Zhou, B.; Thomas, D.N.; Hickman, S.P.; Kpamegan, E.; Boddapati, S.; et al. Safety and immunogenicity of a Sf9 insect cell-derived respiratory syncytial virus fusion protein nanoparticle vaccine. Vaccine 2013, 31, 524–532.
  46. Atuhaire, D.K.; Lieberman, D.; Marcotty, T.; Musoke, A.J.; Madan, D. An alternative cold chain for storing and transporting East Coast fever vaccine. Veter. Parasitol. 2020, 288, 109304.
  47. Gomez, M.; McCollum, J.; Wang, H.; Bachchhav, S.; Tetreau, I.; Gerhardt, A.; Press, C.; Kramer, R.M.; Fox, C.B.; Vehring, R. Evaluation of the stability of a spray-dried tuberculosis vaccine candidate designed for dry powder respiratory delivery. Vaccine 2021, 39, 5025–5036.
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 79
Revisions: 2 times (View History)
Update Time: 17 Dec 2021
Table of Contents


    Are you sure to Delete?

    Video Upload Options

    Do you have a full video?
    If you have any further questions, please contact Encyclopedia Editorial Office.
    Lemon, J.L. Limitations of Currently Available Bovine Respiratory Disease Vaccines. Encyclopedia. Available online: (accessed on 03 October 2022).
    Lemon JL. Limitations of Currently Available Bovine Respiratory Disease Vaccines. Encyclopedia. Available at: Accessed October 03, 2022.
    Lemon, Joanne Laura. "Limitations of Currently Available Bovine Respiratory Disease Vaccines," Encyclopedia, (accessed October 03, 2022).
    Lemon, J.L. (2021, December 16). Limitations of Currently Available Bovine Respiratory Disease Vaccines. In Encyclopedia.
    Lemon, Joanne Laura. ''Limitations of Currently Available Bovine Respiratory Disease Vaccines.'' Encyclopedia. Web. 16 December, 2021.