Delayed versus on arrival modified live viral vaccination in stocker cattle on bovine respiratory disease

a Knowledge Summary by

Ashlee Ambs MS ¹

Heather K. Moberly MSLS AHIP FHEA PgCert (Vet Ed) ²

Sarah Capik DVM PhD ^{1, 3*}

¹Texas A&M University College of Veterinary Medicine and Biomedical Sciences, 660 Raymond Stotzer Pkwy, College Station, TX 77843 USA
²202 Olsen Blvd, University Libraries, Texas A&M University, College Station, TX 77843–4462 USA
³Texas A&M AgriLife Research, 6500 W Amarillo Blvd, Amarillo, TX 79106 USA
^*Corresponding Author (sarah.capik@ag.tamu.edu)

Clinical scenario

Stocker cattle are young and lightweight calves (often somewhere in the range of 204–250 kg) purchased to utilise pasture for frame-growth before moving to a feedlot for the finishing phase of their production life. Since this is often also a situation where recently weaned calves are commingled, bovine respiratory disease (BRD) is a concern. Modified live vaccines (MLV) containing viral respiratory pathogens are commonly administered to calves on arrival to stocker operations as a way to manage BRD risk. Recently, vaccine protocols have been reexamined in the interest of reducing BRD morbidity and several research projects have explored changing the timing of vaccine administration. In particular, delaying MLV administration for viral respiratory pathogens may allow an adjustment period for calves before challenging their immune system with a live vaccine. Stocker operations and veterinarians should review the research evidence and consider the financial and production impact of any changes in MLV timing on their operations.

The evidence

There is no statistical evidence that delayed MLV administration for viral respiratory pathogens reduces BRD morbidity or mortality in stocker calves. While there is some evidence of numerical reductions in BRD morbidity, there is disagreement in the numerical differences in retreatment and mortality rates between arrival and delayed vaccinated calves between studies.

Summary of the evidence

Appraisal, application and reflection

Overall, we identified no statistical evidence that delayed modified live vaccination (MLV) for viral respiratory pathogens lowered bovine respiratory disease (BRD) morbidity or mortality rates. One study (Richeson et al., 2009) indicated statistically lower cases of BRD morbidity in chronic animals (displaying clinical signs of BRD after the third antimicrobial treatment) vaccinated on arrival with both a clostridial vaccine and MLV for respiratory viruses compared to cattle vaccinated on arrival with clostridial vaccine and delayed MLV for respiratory viruses. However, there were several interesting numerical differences in initial BRD morbidity favouring delayed vaccination in several of the studies that suggest perhaps additional, well-powered studies on this question are warranted. Mortality and retreatment numerical differences were inconsistent between studies. Additionally, there were numerous other differences between studies including BRD case definition, vaccines used, different treatment regimens employed, and other management differences that made comparing results between studies difficult.  Although we did not specifically limit our search geographically, all four studies that met our criteria and are discussed in this Knowledge Summary were performed in the United States.

Although, numerical differences cannot be used to support study conclusions they are important to report for discussion. Two studies showed numerical differences in retreatment and relapses (Richeson et al., 2009; and Richeson et al., 2015). In one study (Richeson et al., 2015) with blinded observers, all cattle that relapsed and required retreatment were counted once regardless of the number of times this occurred, while in the other (Richeson et al., 2009) which did not have blinded observers, retreatment rates were measured as a percentage treated with second or third antibiotic treatments and each retreatment was analysed individually. Including all the relapses in one analysis, as in Richeson et al. (2015), does not allow evaluation of multiple retreatments and limits our ability to compare this study to others that specifically separate evaluations of subsequent treatments. Given the potential impact that delayed vaccination could have on the resulting immune responses of the cattle, it would be beneficial to evaluate second and third treatment rates separately.

Limitations related to study design, such as lack of blinding or small sample sizes, increase the chances for biased results and the results, especially numerical differences, must be interpreted with caution. Bovine respiratory disease morbidity is inherently a subjective assessment of health, because identifying a potentially ill animal is largely accomplished via visual signs and sometimes followed by an objective measurement of temperature. Blinding of individuals that are evaluating subjective outcomes like BRD morbidity helps prevent unintentional biases that could impact those subjective outcomes in unpredictable ways. Two of the four papers evaluated (Poe et al., 2013; and Richeson et al.,2009), indicated that evaluators were not blinded when evaluating subjective outcomes. Three of the four papers evaluated had varying, or uneven, numbers of animals in pens or between blocks among treatments (Poe et al., 2013; Richeson et al., 2008; and Richeson et al., 2015). It remains uncertain whether the density of a pen influences the risk of BRD for the animals in it, potentially due to a decrease in available space and resources or due to stress from the commingling experience. Additionally, three of the studies (Poe et al. 2013; Richeson et al., 2009; and Richeson et al., 2015) had smaller sample sizes than the other (Richeson et al., 2008) which may have impacted their ability to detect smaller differences in morbidity.

Even though each study provided evidence for a very specific question, there are multiple differences between the four studies that must be considered when interpreting the results. A notable difference is that two studies (Richeson et al., 2008; and Richeson et al., 2009) evaluated one MLV for respiratory viruses (EXPRESS 5) while the other two studies (Poe et al., 2013; and Richeson et al., 2015) evaluated another MLV for respiratory viruses (BoviShield Gold® 5). These are only two of multiple MLV for respiratory viruses available on the market in the US and there are differences in the adjuvant used, different pathogen loads, different virus types and strains included, routes of administration, etc., between manufacturers and vaccines that could impact the results. Therefore, although the studies provide evidence for our question related to delayed versus on-arrival MLV use, the evidence each provides is not necessarily externally valid when considering all MLV for respiratory viruses. Another area of variability between studies is the difference in the definition of ‘arrival’. Two studies appear to have processed calves on the day they arrived (Richeson et al., 2009; and Richeson et al., 2015); one indicates they were processed the day after they arrived (Richeson et al., 2008), and one seems to indicate calves were processed after resting ‘overnight’ on grass and hay (Poe et al., 2013). Further potential variability exists regarding the amount of potential cross-contamination possible via direct or fomite contact between calves that were and were not vaccinated in each study during the period when they may have shed vaccine virus; mitigation strategies were not well-described. Treatment and prophylaxis regimens are an additional area of variability in these protocols and throughout different feeding operations; it is possible that the impact of delayed vaccination could vary between operations due to differences in these other important health management factors.

The two studies that used the EXPRESS 5 MLV (Richeson et al., 2008; and Richeson et al., 2009) gave prophylactic tilmicosin and treated for internal and external parasites on arrival to all cattle, and boostered the MLV 14 days after they were first administered. However, one study (Richeson et al., 2009) was also evaluating timing of clostridial vaccine while the other (Richeson et al., 2008) gave all calves a clostridial vaccine on arrival. For prophylaxis, one (Richeson et al., 2008) only administered tilmicosin if arrival rectal temperature was ≥40°C and those cattle were excluded from further morbidity assessment, while the other (Richeson et al., 2009) administered it to all cattle on arrival and all were able to be evaluated for morbidity the next day. There was not a statistical difference in the number of cattle in each treatment that were excluded in Richeson et al. (2008), which should have prevented a differential bias in morbidity outcomes between vaccine treatments. However, those cattle appear to have remained with their pen mates who did not receive prophylaxis, which may have differentially influenced the morbidity during the study in general and especially when compared to studies that provide metaphylaxis to all calves equally. These differences in arrival management between the two studies makes them difficult to compare. Additionally, in both studies, cattle were able to be evaluated for retreatment due to BRD morbidity after 72 hours, when they could be administered a different antibiotic. Each allowed up to three retreatments. However, each study used different antibiotics as their first, second, and third treatments (Richeson et al. [2008] used tilmicosin, enrofloxacin, and florfenicol, respectively; Richeson et al. [2009] used florfenicol, ceftiofur, and danofloxacin, respectively), which also makes comparison of retreatment rates between studies difficult.

The two studies that evaluated BoviShield Gold® 5 MLV (Poe et al. 2013; and Richeson et al., 2015) administered a clostridial vaccine and treated for internal and external parasites on arrival to all animals but differed in other parts of their protocols. For prophylaxis, Richeson et al. (2015) administered tilmicosin to all cattle on arrival and cattle were able to be evaluated for BRD morbidity after 24 hours. In Poe et al. (2013) cattle with a rectal temperature that was ≥40°C at processing received their first treatment of florfenicol at processing regardless of clinical signs. They were presumably then able to be reevaluated after 72 hours when they could receive the second antibiotic treatment in their protocol, though this was not explicitly described. However, cattle who were not treated at processing seemed to be eligible to be evaluated the next day to determine if initial BRD treatment should be administered. Additionally, it does not appear that treatment during processing was a criteria for randomising nor is it clear whether delayed or arrival vaccinated calves had similar incidences of calves treated at processing. The differential treatment of calves in this study complicates assessment of BRD incidence. In both papers, morbid cattle could be evaluated for retreatment due to BRD morbidity after 72 hours, when they could be administered a different antibiotic (Richeson et al. [2015] used florfenicol, enrofloxacin, tilmicosin, ceftiofur, then tulathromycin; Poe et al. [2013] used florfenicol, tilmicosin, enrofloxacin, then tulathromycin).However, one study (Poe et al., 2013) described that cattle going >21 days following treatment before exhibiting additional BRD symptoms, were considered a new case of BRD and their treatment regimen began again at florfenicol. Selection of an antibiotic protocol is often a producer or veterinarian preference based on known efficacy, availability, pharmacology, etc. Due to the different spectrums and modes of action associated with these drugs their use as metaphylaxis or treatment may impact BRD morbidity outcomes (O’Connor et al., 2019).

Case definition and criteria that make a calf eligible for BRD treatment or retreatment was also a notable difference between studies that complicated comparisons. Poe et al. (2013) actually used two different case definitions, one during processing where calves could receive treatment if they had a rectal temperature ≥40°C regardless of clinical signs, and then after day 0 when they had to have ≥2 clinical signs plus a rectal temperature of ≥40°C. Richeson et al. (2008) required an unspecified number of visual signs plus rectal temperature of ≥40°C for initial treatment while Richeson et al. (2009; and 2015) required ≥2 clinical signs plus a rectal temperature of ≥40°C to be eligible for initial treatment. Retreatment criteria also varied between studies with some requiring some form of clinical signs plus a temperature threshold to be met (Poe et al., 2013; and Richeson et al., 2015) while others evaluated only the rectal temperature of calves at predetermined intervals after initial or subsequent treatment (Richeson et al., 2008; and 2009). These different criteria, while externally valid, highlight one of the reasons why repeatability of BRD research is so difficult to realise and how variable identification and management of BRD cases can be within the literature.

All four studies evaluated male calves that were either procured already castrated or castrated on arrival. Although they all accounted for castration status in their analyses, three of the four studies (Poe et al., 2013; Richeson et al., 2008; and Richeson et al., 2015) used a California banding technique for castration while the other study (Richeson et al., 2009) used surgical castration. Cattle react differently to alternate castration methods and the variable inflammatory response plus the impact castration can have on clinical signs such as depression, decreased appetite, etc., could alter the impact of delayed vaccination in a commercial setting (Roberts et al., 2018). The lack of representation of heifers in the study populations also limits our ability to extrapolate these results to high risk heifer calves in stocker operations.

Mortality was evaluated in three studies (Richeson et al., 2008; Richeson et al., 2009; and Richeson et al., 2015) but none found a statistical difference between delayed versus on arrival vaccine administration treatment groups. In Richeson et al. (2009) there were inconsistent numerical differences due to the added variable of clostridial vaccine timing. The other two studies had opposing numerical differences, where one (Richeson et al., 2008) showed a higher percentage of death loss over the 56 day study in calves vaccinated on arrival and the other (Richeson et al., 2015) had a higher percentage of mortality associated with clinical BRD in delayed vaccination calves during the 42 day study. The latter study revealed an association with BRD and death loss while the former did not describe a cause for death. Therefore, it cannot be concluded that all deaths were related to BRD making comparison of the two studies more complicated. Since these studies disagreed numerically, it is important to recognise these differences as well as those previously mentioned, such as the use of prophylaxis in Richeson et al. (2015) which was not used in Richeson et al. (2008). Given the small percentages in death loss among the treatments in these studies, which ranged from 0.8–2.3%, it is also possible that they were underpowered to truly evaluate mortality.

Even with a similar goal for these studies and some with the same vaccines administered, there are many aspects of a protocol that can introduce variability and make it difficult to interpret outcomes. Producers and veterinarians should use the information provided in this summary to make vaccine protocol decisions considering the limitations listed above. Since the evidence differed among studies and no statistical difference between arrival versus delayed vaccine administration was identified, no answer can be given to the clinical question.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts on OVID platform: 1910–2021 Week 42 Search run with no limits or filters Limit results to English and 2000–current PubMed on NCBI Website: 1946–27 October 2021 Search run with no limits or filters Limit results to English and 2000–current
Search strategy:	CAB Abstracts: ((exp cattle/ or (calf or calves or steer or steers or heifer or heifers or bull or bulls or bovine or bovines or cattle or youngstock or young-stock or (young adj2 stock)).mp.) and (exp vaccines/ or vaccin*.mp. or exp immunization/ or immuni*.mp.) and (delay or delays or delayed or arrive or arrives or arrived or arrival or postarrival or "post arrival" or post-arrival).mp. and (pneumon*.mp. or (respiratory adj1 disease*).ti,ab. or "respiratory diseases".sh. or (respiratory adj2 disease*).ti,ab. or ((shipping or undifferentiated) adj1 fever).ti,ab. or (BRD or BRDC).ti,ab. or (bovine adj1 respiratory adj1 disease*).ti,ab. or (bovine adj1 respiratory adj1 disease* adj1 complex).ti,ab. or (summer adj1 pneumon*).ti,ab. or (enzootic adj1 pneumon*).ti,ab. or pleuropneumon*.mp. or bronchopneumon*.mp. or (respiratory adj1 tract adj1 disease*).mp.))   PubMed: (("pneumonia"[MeSH Terms] OR "pneumonia"[Title/Abstract] OR "pneumoniae"[Title/Abstract] OR "pneumonias"[Title/Abstract] OR "respiratory diseases"[All Fields] OR "respiratory disease"[Title/Abstract] OR "shipping fever"[Title/Abstract] OR "undifferentiated fever"[Title/Abstract] OR "BRD"[Title/Abstract] OR "BRDC"[Title/Abstract] OR "bovine respiratory disease"[Title/Abstract] OR "bovine respiratory disease complex"[All Fields] OR "summer pneumonia"[Title/Abstract] OR "enzootic pneumonia"[Title/Abstract] OR ("pleuropneumonia"[MeSH Terms] OR "pleuropneumonia"[Title/Abstract] OR "pleuropneumonias"[Title/Abstract] OR "pleuropneumoniae"[Title/Abstract]) OR ("bronchopneumonia"[MeSH Terms] OR "bronchopneumonia"[Title/Abstract] OR "bronchopneumonias"[Title/Abstract] OR "bronchopneumoniae"[Title/Abstract]) OR "respiratory tract disease"[Title/Abstract] OR "respiratory tract diseases"[All Fields]) AND ("calf"[Title/Abstract] OR "calves"[Title/Abstract] OR "steer"[Title/Abstract] OR "steers"[Title/Abstract] OR "heifer"[Title/Abstract] OR "heifers"[Title/Abstract] OR "bull"[Title/Abstract] OR "bulls"[Title/Abstract] OR "bovine"[Title/Abstract] OR "bovines"[Title/Abstract] OR "cattle"[Title/Abstract] OR "cattle"[MeSH Terms] OR "youngstock"[Title/Abstract] OR "young stock"[Title/Abstract] OR "young-stock"[Title/Abstract]) AND ("immunization"[MeSH Terms] OR "immunization"[Title/Abstract] OR "immunisation"[Title/Abstract] OR "immunizations"[Title/Abstract] OR "immunisations"[Title/Abstract] OR "immunize"[Title/Abstract] OR "immunise"[Title/Abstract] OR "immunized"[Title/Abstract] OR "immunised"[Title/Abstract] OR "vaccination"[MeSH Terms] OR "vaccine"[Title/Abstract] OR "vaccines"[Title/Abstract] OR "vaccination"[Title/Abstract] OR "vaccinating"[Title/Abstract] OR "vaccinated"[Title/Abstract]) AND ("delay"[Title/Abstract] OR "delayed"[Title/Abstract] OR "delays"[Title/Abstract] OR "post-arrival"[Title/Abstract] OR "post-arrival"[Title/Abstract] OR "postarrival"[Title/Abstract] OR "arrive"[Title/Abstract] OR "arrival"[Title/Abstract] OR "arrives"[Title/Abstract] OR "arrived"[Title/Abstract])
Dates searches performed:	27 Oct 2021

Exclusion / Inclusion Criteria
Exclusion:	Publication date prior to 2000, is a systematic review and / or meta-analysis, is conference proceedings, does not evaluate the bovine species, does not compare arrival versus delayed vaccine administration groups, does not evaluate the same vaccine given on arrival versus delayed administration, the delayed time was less than 14 days post-arrival, does not evaluate BRD morbidity, or calves not evaluated in a stocker operation.
Inclusion:	BRD morbidity assessment, respiratory vaccine used when evaluating vaccine timing, and comparison of effects of delayed modified live vaccine administration and administration of vaccine on arrival to the stocker operation.

Search Outcome
Database	Number of results	Excluded – Not a research trial	Excluded – Not an MLV respiratory vaccine study in calves	Excluded – Does not compare arrival versus delayed (14–30 days) administration of the same MLV vaccine	Excluded – Calves not evaluated or administered treatment at stocker operation	Total relevant papers
CAB Abstracts	94	17	35	35	3	4
PubMed	50	7	16	24	1	2
Total relevant papers when duplicates removed						4

• Ambs was advised and led by Dr. John Richeson (one of the authors or co-authors of all papers that are evaluated within this summary) to obtain her Master’s degree at West Texas A&M University from January 2016 to May 2017.
• Capik collaborates regularly with Dr. John Richeson (one of the authors or co-authors of all papers that are evaluated within this summary) and has collaborated with two of the co-authors on Richeson et al. 2009 (Kegley and Powell) and on co-author on Poe et al. 2013 (Kegley).
• Moberly serves on the CABI Publishing North American Library Advisory Board and the VetStream Academic Advisory Board.

1. O’Connor, A.M., Hu, D., Totton, S.C., Scott, N., Winder, C.B., Wang, B., Wang, C., Glanville, J., Wood, H., White, B., Larson, R., Waldner, C. & Sargeant, J.M. (2019). A systematic review and network meta-analysis of injectable antibiotic options for the control of bovine respiratory disease in the first 45 days post arrival at the feedlot. Animal Health Research Reviews. 20, 163–181. DOI: https://doi.org/10.1017/S1466252320000031
2. Poe, K.D., Beck, P.A., Richeson, J.T., Gadberry, M.S., Kegley, E.B., Hess, T.W. & Hubbell, D.S. (2013). Effects of respiratory vaccination timing and growth-promoting implant on health, performance, and immunity of high-risk, newly received stocker cattle. Applied Animal Science. 29(4), 413–419. DOI: https://doi.org/10.15232/S1080-7446(15)30254-0
3. Richeson, J.T., Beck, P.A., Gadberry, M.S., Gunter, S.A., Hess, T.W., Hubbell, D.S. & Jones, C. (2008). Effects of on-arrival versus delayed modified live virus vaccination on health, performance, and serum infectious bovine rhinotracheitis titers of newly received beef calves. Journal of Animal Science. 84(4), 999–1005. DOI: https://doi.org/10.2527/jas.2007-0593  
4. Richeson, J.T., Kegley, E.B., Gadberry, M.S., Beck, P.A., Powell, J.G. & Jones, C.A. (2009). Effects of on-arrival versus delayed clostridial or modified live respiratory vaccinations on health, performance, bovine viral diarrhea virus type I titers, and stress and immune measures of newly received beef calves. Journal of Animal Science. 87(7), 2409–2418. DOI: http://dx.doi.org/10.2527/jas.2008-1484
5. Richeson, J.T., Beck, P.A., Poe, K.D., Gadberry, M.S., Hess, T.W. & Hubbell, D.S. (2015). Effects of administration of a modified-live virus respiratory vaccine and timing of vaccination on health and performance of high-risk beef stocker calves. The Bovine Practitioner. 49(1), 37–42. DOI: https://doi.org/10.21423/bovine-vol49no1p37-42
6. Roberts, S.L., Powell, J.G., Hughes, H.D. & Richeson, J.T. (2018). Effect of castration method and analgesia on inflammation, behavior, growth performance, and carcass traits in feedlot cattle. Journal of Animal Science. 91(1), 66–75. DOI: https://doi.org/10.1093/jas/skx022