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

PICO question 
In auction market calves at high risk of developing bovine respiratory disease (BRD), does delayed (14–30 days) vaccination with a modified live vaccine (MLV) for viral respiratory pathogens versus administration of MLV on arrival (within 24 hours of arrival) to the stocker operation, result in less calves with BRD morbidity diagnosed based on visual signs and rectal temperature >40°C, or less calves with BRD mortality? 
  
Clinical bottom line 
Category of research question 
Treatment 
The number and type of study designs reviewed 
Four papers were critically reviewed. All were randomised complete block designs 
Strength of evidence 
Moderate 
Outcomes reported 
In stocker calves, delaying administration of a MLV for respiratory viruses may result in numerically lower initial BRD morbidity rates, while giving at arrival may result in numerically lower BRD retreatments. One study shows statistically lower cases of BRD morbidity after the third antimicrobial treatment in cattle vaccinated on arrival with both a clostridial and MLV for respiratory viruses compared to cattle vaccinated on arrival with clostridial vaccine and delayed MLV for respiratory viruses. No conclusion about mortality can be drawn due to inconsistent numerical conclusions between studies 
Conclusion 
Due to conflicting evidence and a general lack of statistically significant differences in morbidity and mortality outcomes, a definite answer regarding the impact of delayed MLV respiratory vaccination in stocker calves cannot be made 
  
How to apply this evidence in practice 
The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. 
Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care. 
  


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.
Study design: Randomised complete block design with a 2x2 treatment factorial.
Outcome studied: Morbidity measured as: • First BRD treatment % (cattle exhibiting ≥2 clinical signs of BRD (ocular or nasal discharge, depressed appearance, gaunt or lacking normal fill, coughing, laboured breathing, or lack of appetite were pulled and rectal temperature taken, and antimicrobial treatment was administered if rectal temperature was ≥40°C) -subjective assessment; unblinded personnel. • Second, third, and fourth BRD treatment % (cattle with symptoms of BRD and a rectal temperature of ≥40°C at 72 hours after the previous treatment) -subjective assessment; unblinded personnel.

Main findings: (relevant to PICO question):
BRD-related morbidity did not differ statistically due to vaccine timing.

Limitations:
• No blinding of personnel.
• Pens had varying numbers of calves between blocks.
• The study reports that if any steers were identified as BRD cases >21 days following their previous treatment, they were restarted on the BRD treatment protocol as if they had never been diagnosed previously and considered a new incident case of BRD. However, it is unclear how new incidence of BRD after >21 days without clinical signs was managed statistically and if / where those animals are represented in the results. • Study did not evaluate mortality. • It is unclear whether calves were processed immediately upon arrival or after an overnight rest following arrival at the facility. • There appear to be two acceptable case definitions that could have qualified calves for first treatment for BRD. One being having a rectal temperature ≥40°C at processing, regardless of the presence of other symptoms, and the other having ≥2 clinical signs of BRD plus meeting temperature criteria as outlined above after day 0 processing. This makes interpreting BRD incidence and comparison between studies potentially complex. • This study did not describe any efforts to reduce potential cross-contamination between vaccinated and unvaccinated calves during treatment application, housing, subsequent sampling, and evaluation for and treatment of morbid animals.

Intervention details: Treatments:
• Initial vaccination on arrival processing (day 0) with a booster at day 14. • Delayed initial vaccination (day 14) with a booster at day 28. Vaccine: • Pentavalent modified live vaccine (MLV) for respiratory pathogens containing infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhoea virus (BVDV) types I and II, bovine respiratory syncytial virus (BRSV), and parainfluenza-3 virus (Pl3) in combination; (EXPRESS 5, subcutaneously; Boehringer-Ingelheim Vetmedica Inc). Metaphylaxis: • Calves received tilmicosin for metaphylaxis only if they had a rectal temperature of ≥40°C at arrival processing and were not included in subsequent morbidity outcomes. illness -depression, lethargy, rapid breathing, nasal or ocular discharge, slowness in going to feed bunk, and a gaunt or emaciated appearance-and with a rectal temperature ≥40°Csubjective assessment by blinded personnel. • Second and third morbidity (cattle were re-evaluated 72 hours after first or second treatment and were eligible for retreatment if they had a rectal temperature ≥40°C at that time) -objective assessment by blinded personnel. • Percentage of death loss over 56 day study.

Limitations:
• Animals per pen varies almost two-fold.
• Unclear whether reported death loss is BRD-specific or overall mortality. • Case definition is vague as there is no description of how many clinical signs were required for first treatment and it is unclear whether any clinical signs (other than a rectal temperature above their cut-off) were required in order to be eligible for second or third treatment. • Numerical differences are difficult to interpret in a meaningful manner and are not necessarily broadly applicable or repeatable. • Confidence intervals for estimates were not provided. • Cattle were received on day -1 and ear tags were placed and weights were obtained prior to arrival processing on day 0. • This study did not describe any efforts to reduce potential cross-contamination between vaccinated and unvaccinated calves during treatment application, housing, subsequent sampling, and evaluation for and treatment of morbid animals.
• A RESP vaccine booster was given 14 days after initial dose in all treatment groups. Metaphylaxis: • All calves received tilmicosin metaphylaxis on arrival with a 48 hour post-treatment interval where they were not eligible for bovine respiratory disease (BRD) treatment.
Study design: Randomised complete block design with a 2x2 treatment factorial.
Outcome studied: • BRD morbidity rate (cattle with two or more visual signs of BRD with rectal temperature ≥40°C) -subjective assessment, unblinded personnel. • Second BRD treatment (cattle with rectal temperature ≥40°C at 48 hours after initial treatment -objective assessment, unblinded personnel. • Third BRD treatment (cattle with rectal temperature ≥40°C at 72 hours after second treatment -objective assessment, unblinded personnel. • Percentage of chronic animals (displayed BRD symptoms after third antibiotic treatment) -subjective assessment; unblinded personnel. • Percentage of dead (not BRD-specific) in 56-day study.

Main findings: (relevant to PICO question):
• No statistical differences between delayed versus arrival vaccine administration in percentage of dead calves (RESP pvalue: 0.7). • BRD morbidity rates were not statistically different but were numerically less in calves with delayed administration of the MLV (65.1%) versus those vaccinated on arrival (73.4%; no standard error of the mean (SEM) reported for RESP contrast; RESP p-value: 0.23). • Percentage of chronic animals (cattle that displayed signs of BRD after the third antibiotic treatment) was greatest statistically in cattle administered clostridial vaccine on arrival and delayed respiratory vaccine (ACDR: 11.4%) compared to those receiving clostridial vaccine and respiratory vaccine on arrival (ACAR: 1.5%; p=0.04), and numerically higher than those receiving a delayed clostridial vaccine with either arrival (DCAR: 6.3%; P = 0.26) or delayed respiratory vaccine (DCDR: 3.2%; P = 0.08 Limitations: • No blinding of evaluators for subjective outcomes.
• Unclear whether reported death loss is BRD-specific or overall mortality. • Numerical differences are difficult to interpret in a meaningful manner and are not necessarily broadly applicable or repeatable. • Overall means in delayed vs arrival RESP were not provided for all outcomes. There were no SEMs available for main effects. Confidence intervals for estimates were not provided. • Cattle appear to have been processed the same day they arrived at the facility. • This study indicated that fenceline contact between vaccinated and non-vaccinated calves was possible. It did not describe efforts to reduce potential cross-contamination between vaccinated and unvaccinated calves during treatment application, subsequent sampling, and evaluation for and treatment of morbid animals.

Study design:
Randomised complete block design.
Outcome studied: • Percentage of cattle diagnosed with BRD at least once (cattle observed with ≥2 visual signs of BRD (depression, lethargy, rapid breathing, nasal or ocular discharge, and lack of appetite) and a rectal temperature ≥40°C were considered morbid and were treated) -subjective • Numerical differences are difficult to interpret in a meaningful manner and are not necessarily broadly applicable or repeatable. • Confidence intervals for estimates were not provided. • Cattle appear to have been processed the same day they arrived at the facility. • This study did not describe efforts to reduce potential crosscontamination between vaccinated and unvaccinated calves during treatment application, housing, subsequent sampling, and evaluation for and treatment of morbid animals.

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 ( ; 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 ( 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 ( 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 ( 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.