Producers and veterinarians may select among multiple commercially available vaccines against virus antigens to administer to cattle with the goal to decrease the risk and severity of BRDC. The choice of the combination of virus antigens used is routinely influenced by the type and age of cattle, transportation history, previous experience with calves from the same origin, and other factors.1,2 A survey of 23 beef cattle veterinarians representing 11,295,000 cattle on feed in the United States and Canada revealed that when planning feedlot arrival vaccination programs for cattle considered at high risk for BRDC, 100% of the practitioners recommended vaccinating against BHV-1 and BVDV type 1 and 2, 65% recommended vaccinating against BRSV, and 61% recommended vaccinating against PI3.1 For cohorts of cattle considered to have low risk of clinical BRDC (ie, those having few factors associated with BRDC risk), 100% of practitioners recommended vaccination against BHV-1, 96% recommended vaccinating against BVDV type 1 and 2, and 52% recommended vaccinating against BRSV and PI3.1 In the most recent US National Animal Health Monitoring Survey results, 95.1% of cattle in feedlots with > 1,000 head were vaccinated against BVDV, 93.2% were vaccinated against BHV-1 with an injectable product, 61.4% were vaccinated against BRSV, and 55.1% of cattle were vaccinated against PI3.3 Many cattle in the United States receive vaccinations on arrival at a feedlot, but the recommendations and percentage vaccinated vary by specific virus antigen in the vaccination program.
Ideally, producers and veterinarians could make vaccination decisions on the basis of data obtained from randomized controlled trials with their own cattle populations and management situations. These data enable evidence-based decision making to determine the optimum efficacy and cost-efficiency of available products for specific management situations. For many cattle-rearing operations and consulting veterinarians, it may not be practical to perform clinical trials, and they must rely on published literature to determine the direction and magnitude of product efficacy when making vaccination program decisions.4
Various methods exist to test the effectiveness of a vaccination program. To assess the ability of virus vaccines to aid in the control of BRDC, randomized controlled trials in appropriate populations with adequate blinding of investigators provide the highest degree of evidence and external validity to determine vaccine efficacy when clinically relevant outcome measures such as risk of morbidity and death are evaluated. Randomized controlled blinded trials in commercial feedlots provide good internal validity because of their ability to control for common sources of bias and confounding. Such studies should also have a high degree of external validity for other feedlot populations because the host, environment, and pathogen triads are expected to be similar among typical feedlot production settings. In contrast, although experimental challenge studies allow investigators to use a smaller number of cattle and many sources of bias and confounding can be controlled, the amount and timing of pathogen exposure is not natural, host and environment may differ from those of typical production systems, and external validity is sacrificed. Challenge studies can provide important information about the potential for a vaccine to perform under field conditions, but demonstration of vaccine efficacy in a challenge study is not sufficient to assure protection from disease in a clinical setting. Results of studies with other designs, such as randomized controlled trials or challenge studies that use animals other than the cattle of interest (eg, use of young dairy calves to investigate BRDC vaccination as prophylaxis for use in feedlot calves) are difficult to interpret for evidence of efficacy because the host, environment, and pathogen triads differ in numerous ways among groups and settings.
Vaccines against viral pathogens can contain MLV or inactivated virus antigens. Modified-live virus vaccines are reported to stimulate cell-mediated and humoral immune responses by activating T lymphocytes to be prepared for the natural pathogen exposure.5 Inactivated antigen vaccines primarily stimulate the humoral response to produce B cells and antibodies against the antigen presented. Inactivated antigen vaccines require a booster to produce an adequate anamnestic immune response, whereas most MLV antigens provide adequate immune system stimulation with a single administration.6
The objective of the study reported here was to perform a systematic review of the available peer-reviewed published literature and a meta-analysis of appropriate studies to evaluate whether beef or dairy calves or cattle vaccinated with commercially available vaccines containing BHV-1, BVDV, BRSV, or PI3 viral antigens had lower risk ratios for being identified as clinically ill or dead due to BRDC, compared with nonvaccinated control cattle or controls without vaccination against the specific viral antigen in question. A similar analysis has been performed to evaluate the efficacy of vaccination against Mannheimia haemolytica, Pasteurella multocida, and Histophilus somnus for prevention or mitigation of BRDC in feedlot cattle.7 The goal of the meta-analysis was to provide information to cattle producers and veterinarians about the efficacy of vaccination against common viral pathogens associated with BRDC.
Materials and Methods
A literature search was performed to identify studies that reported the effectiveness of commercially available products for BHV-1, BVDV, BRSV, and PI3 vaccination in cattle. The search protocol was not registered but was agreed to by all authors prior to initiation of the search. Eligibility criteria considerations for studies to be included in the review included study type, study animal population, type of intervention, and outcomes reported.
Types of studies and animals—Studies reported in peer-reviewed journals in the English language were reviewed. Non–English language reports were not translated owing to resource limitations and the assumption that non–English language reports were less likely to be relevant to US cattle production management systems. For the initial phase of the systematic review, only studies that included a nonvaccinated control group (including cattle that were sham vaccinated or received no vaccination) were evaluated. A second phase of the systematic review evaluated studies that lacked negative control groups, but compared vaccine treatments that differed in the virus components included. Allocation of study animals or groups (eg, pens of cattle) to treatment must have been random or have used another appropriate allocation scheme that limited the potential for selection bias and confounding, or if allocation was not described, the treatment groups had to be assessed as appearing balanced and likely appropriately allocated. The report was required to include an indication that investigators were blinded to treatment allocation for subjective measures including morbidity. Studies that did not meet all the inclusion criteria were excluded. Studies were also excluded when treatment group assignment was confounded by pen allocation.
Types of intervention—Studies of commercially available vaccines against viruses associated with BRDC were included in the review. The review was limited to reports for commercially available vaccines to provide practicing veterinarians with information that can be applied to the care of client-owned cattle. For a study to be included, the virus investigated had to be identified and whether an MLV vaccine or an inactivated type of virus antigen was used had to be reported.
Types of outcome measures—Studies were included only if clinically relevant outcomes of interest, including morbidity and mortality risk or data from which risk ratios could be calculated, were reported. Proxy outcomes for the potential protective effect of vaccination such as titer response were not included in any of the analyses. Only studies that had a clinically meaningful case definition for morbidity associated with BRDC addressing such clinical signs and indices as respiratory rate, character, or both; indications of anorexia or depression; and body temperature above the reference limits were included. If blinding of evaluators was not mentioned in the study materials and methods, morbidity data were not used because of substantial risk of observer bias, but mortality data were included in the analysis because death, as an objective outcome, was less likely to be influenced by such bias. Reported morbidity risk and mortality risk attributed specifically to BRDC were extracted from each study if provided; otherwise, undifferentiated morbidity risk and mortality risk were used in the meta-analysis.
Literature search—The literature search was performed by use of PubMed (all available years), CAB (all available years), and Agricola (all available years) electronic databases to identify reports published in English. The initial literature search was performed July 1, 2013, and the search was repeated on November 6, 2013, to include additional publications. The terms used in the search were viral OR virus, bovine OR cattle OR calves, vaccin*, and respirator* OR BRD*. A combined search with the terms (viral OR virus) AND (bovine OR cattle OR calves) AND vaccin* AND (respirator* OR BRD*) was also performed. After studies were evaluated for eligibility and selected to be included in the review, a manual search of the reference lists was performed to find any possibly relevant and valid studies omitted from the electronic search results.
The titles and, if necessary, the abstracts from the electronic database search outcomes were assessed for eligibility independently by 2 investigators (MET and RLL), with disagreements resolved by consensus of all 3 investigators. We used a data collection sheet that had been developed and refined for an earlier systematic review. One individual (MET) extracted pertinent descriptive and outcome information from each trial directly comparing a vaccine treatment against a control treatment7 within each study, and others (RLL and BJW) checked the extracted data. Studies or trials were separated into natural exposure and experimental virus challenge categories and further grouped by type of virus investigated and whether MLV or inactivated types of vaccines were evaluated.
Statistical analysis—A meta-analysis was performed of the eligible trials with a summary Mantel-Haenszel risk ratio and 95% CI reported and a Forest plot created in a software program to graphically display the relative strength of results.a We assessed heterogeneity among studies or trials by use of the Cochran Q statistic, with P ≤ 0.10 and I2 statistic > 50% indicating potentially important sources of heterogeneity that would prompt evaluation of possible variability in results being explained by differences in cattle, interventions, or outcome case definitions. To be conservative, a random-effects model was used.8 Summary measures were considered to be significantly different between treatments if the 95% CI did not include 1.
In some studies, multiple trials used the same control animals. For those studies, the same control animals were used more than once in the meta-analysis. The decision was made to include each comparison as a separate data point in the meta-analysis, even though the trial was performed at the same time, to increase the number of trials included in the analysis. For study categories in which variability in the number of days that animals were monitored after challenge raised concerns, the investigators of the present study made a subjective determination that all eligible studies followed calves for at least a reasonable amount of time to detect disease onset.
Results
The number of articles identified with each search term and all search terms combined were listed for each database (Table 1). After evaluation of article titles and abstracts followed by complete review of manuscripts potentially eligible for study inclusion, 30 studies5,9–37 comprising 88 trials were included in the analysis. One additional study38 was included after a manual search of references cited in included articles. Approximately 890 studies were excluded from the initial screening review of title or abstracts from the CAB combined literature search response because the studies included only evaluation of bacterial BRDC pathogens, were review articles, included only pathogen challenge with no vaccine treatment groups, or involved species other than cattle. An additional 72 studies from the CAB combined literature search were excluded after full-text review because only titer response was reported or authors of the present study were unable to determine morbidity or mortality risk from the published results.
Numbers of records identified by a structured literature search of 3 databases for possible use in a systematic review and meta-analysis of effectiveness of commercially available vaccines against BHV-1, BVDV, BRSV, and PI3 for mitigation of the effects of BRDC in cattle.
| Search terms | CAB | PubMed | Agricola |
|---|---|---|---|
| Viral OR virus | 768,570 | 910,506 | 103,755 |
| Bovine OR cattle OR calves | 392,103 | 365,259 | 170,656 |
| Vaccin | 114,325 | 267,302 | 29,082 |
| Respirator OR BRD | 95,267 | 453,283 | 19,051 |
| Combined search terms | 992 | 569 | 190 |
Asterisks shown were included in search terms (representing a wildcard operator to enable retrieval of records with any character after the given string).
Natural exposure field studies—Only 2 natural exposure field studies9,10 comprising 5 trials evaluated the effectiveness of commercially available virus vaccines in beef calves by comparing the risk of BRDC morbidity in vaccinated calves with the risk for nonvaccinated control calves; however, viral antigens included in the vaccines differed among trials (Table 2). Analysis revealed a significantly lower morbidity risk for vaccinates, compared with controls, in 2 of the 5 trials, with no significant difference between groups in the remaining 3 trials (Figure 1). The summary risk ratio for these 5 trials was 0.44 with a 95% CI of 0.26 to 0.74, indicating a significantly lower morbidity risk for vaccinated beef calves, compared with that for nonvaccinated control calves. Mortality risk was reported for only 4 of the trials, and in each of these, there was no significant difference in mortality risk between vaccinates and controls; however, the summarized risk ratio for these 4 trials was 0.19, with a 95% CI of 0.06 to 0.67, indicating a significantly lower mortality risk for vaccinates, compared with controls.
Forest plots of morbidity (A) and mortality (B) risk ratios from natural exposure trials that evaluated commercially available vaccines against BHV-1, BVDV, BRSV, and PI3 for protection against BRDC in beef calves. Plots were generated in a meta-analysis of data from individual trials within studies reported in the published literature. Events represent the total number of calves identified as having morbidity (A) or death (B) associated with BRDC. Weight represents the stratum weight calculated as the inverse of the estimate variance. The control group comprised nonvaccinated calves. M–H = Mantel-Haenszel risk ratio. Lowercase letters (a, b, c) indicate different trials (ie, subgroups) within the same study.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated use of commercially available BHV-1, BVDV, BRSV, and PI3 vaccines for protection against BRDC with a natural exposure model in beef calves.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 9 | Stilwell et al, 2008 | Systematic (every other animal) allocation of weanling-aged calves to 2 treatment groups (nonvaccinated or vaccinated [IM, at weaning and 15 to 28 d later]); calves were followed for 40 d after weaning. | Inactivated BHV-1 and BVDV, MLV BRSV and PI3. |
| 10 | Makoschey et al, 2008 | Randomized controlled design in which calves on cow-calf farms were assigned to 3 treatment groups: 40% in each of 2 vaccination groups and 20% in a nonvaccinated group. Calves were initially vaccinated (route unspecified) at 2–6 wk of age, revaccinated 4 wk later, and followed for 120 d after vaccination. Both studies provided morbidity and mortality risk data. | One vaccine included inactivated BRSV and PI3 with iron-regulated proteins from Mannheimia haemolytica with a double-adjuvant system; the other included MLV BRSV and PI3 with inactivated BVDV. |
Three studies10–12 evaluated the effectiveness of commercial vaccine administration by comparison of BRDC morbidity risk in dairy calves that were or were not vaccinated (Table 3). Analysis revealed a significantly lower morbidity risk for vaccinates, compared with controls, in 1 of 9 trials, with no significant difference between groups in the remaining 8 trials (Figure 2). The summary risk ratio for these trials was 0.90 with a 95% CI of 0.72 to 1.13, indicating no significant difference in BRDC morbidity risk between vaccinates and controls. The summarized risk ratio for 5 trials for which mortality data were reported was 1.17, with a 95% CI of 0.73 to 1.89, also indicating no significant difference in mortality risk between vaccinated and control dairy calves.
Forest plots of morbidity (A) and mortality (B) risk ratios from natural exposure trials that evaluated commercially available vaccines against BHV-1, BVDV, BRSV, and PI3 for protection against BRDC in dairy calves. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated use of commercially available BHV-1, BVDV, BRSV, and PI3 vaccines for protection against BRDC with a natural exposure model in dairy calves.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 10 | Makoschey et al, 2008* | Randomized controlled design in which healthy dairy calves 2 wk to 4 mo of age were allocated to 2 vaccination groups or a nonvaccinated control group. Vaccines were administered (route unspecified) at the beginning of each month and then repeated 4 wk later. Calves were monitored for 2 mo after the second vaccination. | One vaccine included MLV BHV-1 and inactivated BRSV and PI3 with iron-regulated proteins from M haemolytica with a double-adjuvant system; the other included MLV BRSV and PI3 and inactivated BVDV. |
| 11 | Windeyer et al, 2012* | Randomized controlled block design allocation of commercial dairy calves to 4 groups (nonvaccinated or vaccinated IM at 2 wk of age, 5 wk of age, or both). Calves were monitored through 3 mo of age. | MLV BHV-1, BRSV, BVDV, and PI3. |
| 12 | Howard et al, 1987† | Unknown allocation of 3- to 13-wk-old Holstein-cross calves to 3 treatment groups (nonvaccinated or vaccinated with 1 of 2 vaccines [3 times, SC, at 3-wk intervals]). Calves were monitored through slaughter at approximately 18 mo of age. | One vaccine included inactivated BRSV, PI3, Mycoplasma bovis, and Mycoplasma dispar; the other consisted of inactivated BRSV. |
Evaluated morbidity and mortality risk.
Evaluated morbidity risk.
Experimental virus challenge studies—Studies on the effectiveness of MLV BHV-1 vaccine, inactivated BHV-1 vaccine, MLV BVDV vaccine, inactivated BVDV vaccine, MLV BRSV vaccine, inactivated BRSV vaccine, and MLV PI3 vaccine in experimental challenge models were evaluated.
MLV BHV-1 vaccine
Four studies13–16 comprising 10 trials evaluated use of MLV BHV-1 vaccine for protection of beef or dairy calves against experimental infection with BHV-1 and signs attributable to BRDC (Table 4). Analysis revealed a significantly lower morbidity risk for vaccinates, compared with controls, in 1 of the 10 trials, with no significant difference between groups in the remaining 9 trials (Figure 3). The summarized risk ratio for these 10 trials was 0.61, with a 95% CI of 0.43 to 0.86, indicating a significantly lower morbidity risk for vaccinates than for control calves. No mortality data were reported for these trials.
Forest plot of morbidity risk ratios from trials that evaluated use of commercially available MLV vaccines against BHV-1 in beef or dairy calves for protection against BRDC with an experimental virus challenge model. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated commercially available MLV vaccines for protection against BHV-1 infection in beef or dairy calves with an experimental virus challenge model.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 13 | Ellis et al, 2009 | Randomized controlled trial: 4- to 6-mo-old crossbred beef calves were allocated to treatment groups blocked by body weight. Calves were assigned to control vaccinated (MLV combination vaccine without a BHV-1 component) or vaccinated (MLV combination vaccine with BHV-1 antigen) groups. In replicate 1, calves were vaccinated (route unspecified) 8 d after weaning and underwent aerosol exposure to BHV-1 (delivered by nebulization in a sealed stock container) 30 d after vaccination. In replicate 2, calves were vaccinated 59 d after weaning and had aerosol exposure to BHV-1 ninety-seven d after vaccination. Calves were monitored for 10 d after challenge. | MLV BHV-1, BRSV, PI3, and BVDV type 1 and type 2 or MLV PI3, BRSV, and BVDV type 1 and type 2. |
| 14 | Ellis et al, 2005 | Randomized controlled trial of 4- to 6-mo-old crossbred beef calves allocated to 6 treatment groups: nonvaccinated or vaccinated (route unspecified) at 42 and 20 d prior to challenge (exposure to BHV-1 delivered by nebulization in a sealed stock container), 146 and 126 d prior to challenge, 117 and 96 d prior to challenge, 86 and 65 d prior to challenge, or 126 d prior to challenge. Calves were monitored for 14 d after challenge. | MLV BHV-1, BVDV, and PI3, and inactivated BRSV. |
| 15 | Fairbanks et al, 2004 | Random allocation of 6- to 8-mo-old beef calves (blocked by body weight) to 4 treatment groups: nonvaccinated or vaccinated (once, SC) 4, 3, or 2 d prior to challenge. Challenge aerosol exposure was achieved by administering Cooper strain BHV-1 virus on the nares and placing a rebreathing bag over the muzzle to induce disease. Calves were monitored for 14 d after challenge. | MLV BHV-1, BVDV type 1 and 2, BRSV, and PI3. |
| 16 | Xue et al, 2010 | Unknown allocation of 3- to 8-d old BVDV, BHV-1, and PI3 serum neutralizing antibody–free dairy calves to 2 treatment groups (vaccinated IN or nonvaccinated). Calves were challenged IN with aerosolized Cooper strain BHV-1 4 wk after a single IN vaccination and were monitored for 14 d after challenge. | MLV BVDV types 1 and 2, BHV-1, BRSV, and PI3 with avirulent M haemolytica and Pasteurella multocida. |
All 4 studies evaluated morbidity risk.
IN = Intranasally.
Inactivated BHV-1 vaccine
Two studies17,18 comprising 2 trials evaluated the effectiveness of inactivated BHV-1 vaccine for protection of beef or dairy calves against BHV-1 infection and signs attributable to BRDC in an experimental challenge model (Table 5). Analysis revealed a significantly lower morbidity risk for vaccinates, compared with controls, in 1 of the 2 trials, with no significant difference between groups in the remaining trial. The summarized risk ratio for morbidity risk in the 2 trials was 0.54, with a 95% CI of 0.30 to 0.98, indicating a significantly lower morbidity risk for vaccinates than for control calves (Figure 4). No mortality data were reported for these trials.
Forest plot of morbidity risk ratios from trials that evaluated use of commercially available inactivated vaccines against BHV-1 in beef or dairy calves for protection against BRDC with an experimental virus challenge model. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated commercially available inactivated vaccines for protection against BHV-1 infection in beef or dairy calves with an experimental virus challenge model.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 17 | Salt et al, 2007 | Unknown allocation of 5- to 9-mo-old beef or dairy calves seronegative for anti–BHV-1 antibodies to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, approx 3 wk apart]). Calves were challenged IN with BHV-1 five wk after the second treatment and monitored for 21 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960, and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
| 18 | Peters et al, 2004 | Randomized controlled trial of 5- to 6-mo-old beef and dairy calves blocked by serum anti–BHV-1 antibody titer and equally allocated to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 3 wk apart]). Calves were challenged IN with BHV-1 seven mo after the second treatment and monitored for 21 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960 and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
Both studies evaluated morbidity risk data.
IN = Intranasally.
MLV BVDV vaccine
Seven studies16,19–23,38 comprising 11 trials evaluated the effectiveness of an MLV BVDV vaccine against experimental infection with BVDV and signs attributable to BRDC in beef or dairy calves (Table 6). Analysis revealed a significantly lower morbidity risk for vaccinates, compared with controls, in 6 of the 11 trials, with no significant difference between groups in the remaining 5 trials (Figure 5). The summarized risk ratio for these 11 trials was 0.28, with a 95% CI of 0.17 to 0.45, indicating a significantly lower morbidity risk for vaccinates than for control calves. Two studies23,38 comprising 4 trials provided mortality data for vaccinated and nonvaccinated calves following experimental BVDV challenge. A significantly lower mortality risk was found for vaccinates in 1 of the 4 trials. The summarized risk ratio for these 4 trials was 0.26, with a 95% CI of 0.12 to 0.56, indicating a significantly lower mortality risk for vaccinates than for control calves.
Forest plots of morbidity (A) and mortality (B) risk ratios from trials that evaluated use of commercially available MLV vaccines against BVDV in beef or dairy calves for protection against BRDC with an experimental virus challenge model. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated commercially available MLV vaccines for protection against BVDV infection in beef or dairy calves with an experimental virus challenge model.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 19 | Xue et al, 2011* | Unknown allocation of nonpregnant, BVDV serum neutralizing antibody–free beef heifers to 2 treatment groups (nonvaccinated or vaccinated [once, SC]). Calves were vaccinated; challenged IN with aerosolized virulent BVDV-1b strain New York-1 or BVDV-1b strain T1186a at 21, 28, 180, or 183 d after vaccination; and monitored for 14 d after challenge. | MLV BVDV-1a and BVDV-2, BHV-1, PI3, and BRSV. |
| 20 | Kelling et al, 2005* | Unknown allocation of 5- to 7-mo-old BVDV serum neutralizing antibody–free crossbred beef calves to 2 treatment groups (nonvaccinated or vaccinated [once, SC]). Calves were challenged IN with aerosolized BVDV-1b strain New York-1 twenty-one d after vaccination and monitored for 9 d after challenge. | MLV noncytopathic BVDV type 1, BHV-1, PI3, and BRSV. |
| 21 | Kelling et al, 2007* | Unknown allocation of 5- to 7-mo-old crossbred beef calves to 2 treatment groups (nonvaccinated or vaccinated [once, SC]). Calves were challenged IN with aerosolized BVDV type 2 strain 890 twenty-one d after vaccination and monitored for 9 d after challenge. | MLV noncytopathic BVDV type 1, BHV-1, PI3, and BRSV. |
| 22 | Brock, 2007† | Random allocation of persistent BVDV infection–free bull calves at 8 to 9 mo of age to 4 treatment groups: nonvaccinated or vaccinated (once, SC) 7, 5, or 3 d prior to challenge. Calves were challenged IN with aerosolized BVDV noncytopathic type 2 strain 1373 and monitored for 14 d after challenge. | MLV BVDV type 1a and 2a, BHV-1, PI3, and BRSV. |
| 23 | Palomares et al, 2012* | Randomized controlled trial of 7- to 9-mo-old beef calves stratified by sex and assigned to 4 treatment groups: nonvaccinated or vaccinated (once, IM) 7, 5, or 3 d prior to challenge. Calves were challenged IN with aerosolized BVDV noncytopathic type 1b strain New York-1 and monitored for 14 d after challenge. | MLV BVDV type 1 and 2, BHV-1, BRSV, and PI3. |
| 24 | Stevens et al, 2011† | Random allocation of 3-d-old, persistent BVDV infection–free Holstein bull calves that had not suckled their dams to 2 treatment groups (nonvaccinated or vaccinated [once, SC]). Calves were challenged IN with aerosolized BVDV type 2a strain 1373 seven mo after vaccination and monitored for 21 d after challenge. | MLV BVDV type 1a and 2a, BHV-1, BRSV, and PI3. |
| 16 | Xue et al, 2010* | Unknown allocation of 3- to 8-d-old BVDV, BHV-1, and PI3 serum neutralizing antibody–free dairy calves to 2 treatment groups (vaccinated or nonvaccinated controls). Calves were vaccinated (once, IN) and challenged IN 21 d after vaccination with aerosolized virulent BVDV-1b strain New York-1 or BVDV type 2 strain 1373. Calves were monitored for 14 d after challenge. | MLV BVDV types 1 and 2, BHV-1, BRSV, and PI3 with avirulent M haemolytica and P multocida. |
Evaluated morbidity risk.
Evaluated mortality risk.
IN = Intranasally.
Inactivated BVDV vaccine
Two studies17,18 comprising 2 trials evaluated the effectiveness of inactivated BVDV vaccine against infection with BVDV and signs attributable to BRDC in beef or dairy calves following experimental challenge with the virus (Table 7). Analysis revealed no significant difference in morbidity risk for vaccinates, compared with controls, in both trials (Figure 6). The summarized risk ratio for these 2 trials was 0.66, with a 95% CI of 0.35 to 1.26, also indicating no significant difference in morbidity risk between vaccinates and control calves. One study24 comprising 2 trials evaluated mortality risk for calves that did or did not receive inactivated BVDV vaccine prior to BVDV challenge; both trials found a lower mortality risk for vaccinates. The summarized risk ratio for these 2 trials was 0.12, with a 95% CI of 0.02 to 0.79, indicating a significantly lower mortality risk for vaccinates than for control calves.
Forest plots of morbidity (A) and mortality (B) risk ratios from trials that evaluated use of commercially available inactivated vaccines against BVDV in beef or dairy calves for protection against BRDC with an experimental virus challenge model. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated commercially available inactivated vaccines for protection against BVDV infection in beef or dairy calves with an experimental virus challenge model.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 17 | Salt et al, 2007* | Random allocation of 2- to 5-mo-old beef or dairy calves seronegative for anti-BVDV antibodies to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 3 wk apart]). Calves were challenged IN with BVDV strain 11249 three wk after the second vaccination and monitored for 14 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960, and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
| 18 | Peters et al, 2004* | Randomized controlled trial of 5- to 6-mo-old beef and dairy calves blocked by serum anti-BVDV antibody titer and equally allocated to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 3 wk apart]). Calves were challenged IN with BVDV strain 11249 seven mo after the second vaccination and monitored 21 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960, and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
| 25 | Cravens, 1991† | Random allocation of beef calves seronegative for antibodies against BHV-1, BVD, and BRSV to 3 treatment groups (nonvaccinated or vaccinated with 1 of 2 vaccines). Unknown blinding status. Calves were challenged IN with aerosolized BVDV strain New York-1 and monitored for 21 d after challenge. | One vaccine included chemically altered BHV-1 and PI3, MLV BRSV, inactivated BVDV, and 5 Leptospira serovars; the other included inactivated BHV-1, BVDV, BRSV, and PI3 and 5 Leptospira serovars. |
Evaluated morbidity risk.
Evaluated mortality risk.
IN = Intranasally.
MLV BRSV vaccine
Six studies5,17,18,26–28 comprising 7 trials evaluated the effectiveness of MLV BRSV vaccine for protection of beef or dairy calves against experimental BRSV infection and signs attributable to BRDC (Table 8). Analysis revealed a significantly lower morbidity risk for vaccinates, compared with controls, in 1 of the 7 trials, with no significant difference between groups in the remaining 6 trials (Figure 7). The summarized risk ratio for these 7 trials was 0.61, with a 95% CI of 0.36 to 1.06, indicating no significant difference in morbidity risk for vaccinated versus nonvaccinated calves. Results of the Cochran Q test (P = 0.02) and the I2 statistic (60%) both provided evidence for study heterogeneity, potentially limiting confidence in the pooled estimate. Four studies5,25,28,29 comprising 5 trials also provided mortality data for vaccinated and nonvaccinated control calves following BRSV challenge. Analysis revealed no significant mortality risk difference for vaccinates, compared with controls, in any of the trials. The summarized risk ratio for these 5 trials was 0.95, with a 95% CI of 0.54 to 1.68, indicating no significant difference in mortality risk between calves that did or did not receive the vaccine.
Forest plots of morbidity (A) and mortality (B) risk ratios from trials that evaluated use of commercially available MLV vaccines against BRSV in beef or dairy calves for protection against BRDC with an experimental virus challenge model. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated commercially available MLV vaccines for protection against BRSV infection in beef or dairy calves with an experimental virus challenge model.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 17 | Salt et al, 2007* | Random allocation of 2- to 4-mo-old beef or dairy calves to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 3 wk apart]). Calves were challenged IN and intratracheally with BRSV strain SNK 3 wk after the second vaccination and monitored for 14 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960, and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
| 18 | Peters et al, 2004* | Random allocation of 6-mo-old calves seronegative for anti-BRSV antibodies to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 3 wk apart]). Calves were challenged IN with BRSV strain 165 twelve mo after the second treatment and monitored for 40 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960, and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
| 26 | Ellis et al, 2010† | Unknown allocation of 3- to 8-d-old BRSV-seropositive and BRSV-seronegative dairy calves to 2 treatment groups (nonvaccinated or vaccinated [IN, once]). Calves were challenged (exposure to BRSV delivered by nebulization in a sealed stock container) 21 d or 4.5 mo after vaccination and monitored for 8 d after challenge. | MLV BRSV, BHV-1, BVDV type 1 and 2, and avirulent live culture of M haemolytica and P multocida. |
| 5 | West et al, 1999‡ | Random allocation of 2- to 4-mo-old dairy calves to 2 treatment groups (vaccinated [once, IM] or nonvaccinated). Calves were challenged with aerosolized BRSV via face mask 3 wk after vaccination and monitored for 8 d after challenge. | MLV BRSV, BHV-1, PI3, and BVDV. |
| 27 | West et al, 1999* | Random allocation of Holstein calves to 3 treatment groups (nonvaccinated, vaccinated with MLV BRSV [once, ID], or vaccinated with formalin-inactivated BRSV [once, ID]) at 4 to 5 mo of age. Only MLV vaccinated and nonvaccinated control calves were considered for this portion of the analysis. Treatment was repeated 3 wk after initial vaccination, and calves were challenged with aerosolized BRSV strain RB94 thirty-four d after the second treatment. Calves were monitored for 8 d after challenge. | MLV BRSV. |
| 28 | Ellis et al, 2007* | Unknown allocation of 6-wk-old dairy calves to 2 groups (nonvaccinated or vaccinated [IN, twice, 21 d apart]) in 1 trial. In a second trial, unknown treatment allocation was used to assign 9-wk-old dairy calves to 2 treatment groups (nonvaccinated and vaccinated [once, IN]). Calves were challenged 1 wk after vaccination (exposure to BRSV delivered by nebulization in a sealed stock container) and monitored for 8 d after challenge. | One vaccine included MLV BRSV (first trial); the other included MLV BRSV, PI3, BHV-1, and BVDV, (second trial). |
| 29 | Vangeel et al, 2007‡ | Random allocation of 3-wk-old dairy calves blocked by serum anti-BRSV antibody titers to 2 treatment groups (vaccinated [once, IN] or nonvaccinated). Calves were challenged IN with BRSV field strain Odijk delivered via airjet nebulizer 66 d after vaccination. Calves were monitored for 14 d after challenge. | MLV BRSV and PI3. |
| 30 | Woolums et al, 2004† | Paired allocation of 4- to 6-wk-old Holstein calves to 2 treatment groups (nonvaccinated or vaccinated). Calves were challenged with aerosolized BRSV through use of a mask and nebulizer 30 d after vaccination. Calves were monitored for 7 d after challenge. | MLV BRSV. |
Evaluated morbidity risk.
Evaluated mortality risk.
Evaluated morbidity and mortality risk.
IN = Intranasally.
Inactivated BRSV vaccine
One study26 comprising 1 trial evaluated the effectiveness of inactivated BRSV vaccine against experimental BRSV infection and signs attributable to BRDC in dairy calves (Table 9). In that study,26 all calves in the vaccinated and nonvaccinated control groups developed disease; thus, there was no difference in morbidity risk between groups. Two studies30,31 comprising 3 trials provided mortality data for calves that did or did not receive inactivated BRSV vaccine in experimental challenge models. Analysis revealed no significant mortality risk difference for vaccinates, compared with controls, for any of the trials (Figure 8). However, the summarized risk ratio for these 3 trials was 0.26, with a 95% CI of 0.09 to 0.77, indicating a significantly lower mortality risk for vaccinates than for control calves.
Forest plot of mortality risk ratios from trials that evaluated use of commercially available inactivated vaccines against BRSV in dairy calves for protection against BRDC with an experimental virus challenge model. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated commercially available inactivated vaccines for protection against BRSV infection in dairy calves with an experimental virus challenge model.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 27 | West et al, 1999* | Random allocation of Holstein calves to 3 treatment groups (nonvaccinated or vaccinated [once, ID] with an MLV BRSV or formalin-inactivated BRSV component) at 4 to 5 mo of age. Only calves that received formalin-inactivated vaccine and nonvaccinated controls were considered for this portion of the analysis. Treatment was repeated 3 wk after initial vaccination, and calves were challenged with aerosolized BRSV strain RB94 thirty-four d after the second treatment. Calves were monitored for 8 d after challenge. | Formalin-inactivated BRSV. |
| 31 | Ellis et al, 2001† | Randomized allocation of 9-wk-old dairy calves seronegative for anti-BRSV antibodies to 3 treatment groups (vaccinated with adjuvanted vaccine containing a minimum immunizing dose of BRSV antigen [twice, IM, 21 d apart], vaccinated with adjuvanted vaccine containing a greater dose of BRSV antigen [same interval], or nonvaccinated). Calves were challenged with aerosolized BRSV through use of a nebulizer and face mask 21 d after the second treatment and monitored for 8 d after challenge. | Inactivated BRSV. |
| 32 | Ellis et al, 2005† | Randomized allocation of 9-wk-old BRSV-seronegative dairy calves to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 20 d apart]). Calves were challenged with aerosolized BRSV delivered by nebulization in a sealed room 26 d after the second vaccine administration and monitored for 8 d after challenge. | Inactivated BRSV, BHV-1, BVDV type 1, and PI3. |
Evaluated morbidity risk.
Evaluated mortality risk.
MLV PI3 vaccine
Four studies16–18,32 comprising 5 trials evaluated the effectiveness of MLV PI3 vaccine against PI3 infection and signs attributable to BRDC in beef or dairy calves in an experimental challenge model (Table 10). Analysis revealed a significantly lower morbidity risk for vaccinates, compared with controls, in 1 of the 5 trials, with no significant difference between groups in the remaining 4 trials (Figure 9). The summarized risk ratio for these trials was 0.66, with a 95% CI of 0.39 to 1.12, indicating no significant difference in morbidity risk between vaccinates and control calves. Results of the Cochran Q test (P = 0.006) and the I2 statistic (72%) both provided evidence for study heterogeneity that may limit confidence in the pooled estimate. No mortality data were reported for these trials.
Forest plot of morbidity risk ratios from trials that evaluated use of commercially available MLV vaccines against PI3 in beef or dairy calves for protection against BRDC with an experimental virus challenge model. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed studies that evaluated commercially available MLV vaccines for protection against PI3 infection in beef or dairy calves with an experimental virus challenge model.
| Reference No. | Reference | Study or trial description | Vaccine |
|---|---|---|---|
| 17 | Salt et al, 2007 | Random allocation of 3- to 4-mo-old beef or dairy calves to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 3 wk apart]). Calves were challenged IN and intratracheally with PI3 strain J121 six mo after the second treatment and monitored for 14 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960, and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
| 18 | Peters et al, 2004 | Random allocation of 7- to 9-wk-old dairy or beef-cross calves seronegative for antibodies against PI3 to 2 treatment groups (nonvaccinated or vaccinated [twice, IM, 3 wk apart]). Calves were challenged IN and intratracheally with PI3 strain J121 six mo after the second treatment and monitored for 14 d after challenge. | Inactivated BHV-1, BVDV type 1 cytopathic strain 5960, and BVDV type 1 noncytopathic strain 6309; MLV PI3 and BRSV. |
| 33 | Bryson et al, 1999 | Unknown allocation of colostrum deprived-dairy calves to 2 treatment groups (nonvaccinated or vaccinated [twice, IN]) in 1 trial. Calves were vaccinated at 1 wk of age and again at 5 wk or 2 mo of age. In a second trial, unknown treatment allocation was used to assign colostrum-fed dairy calves to 2 treatment groups (nonvaccinated or vaccinated [twice, IN]). Two wk after the second vaccine, calves were IN and intratracheally challenged with PI3. Calves were monitored 6 d after challenge. | MLV temperature sensitive–PI3. |
| 16 | Xue et al, 2010 | Random allocation of 3- to 8-d-old BVDV, BHV-1, and PI3 serum neutralizing antibody–free dairy calves to 2 treatment groups (nonvaccinated or vaccinated [once, IN]). Calves were challenged IN 28 d after vaccination with aerosolized lung wash from calves with PI3 virus. Calves were monitored for 14 d after challenge. | MLV BVDV types 1 and 2, BHV-1, BRSV, and PI3. |
All studies evaluated morbidity risk.
IN = Intranasally.
Field studies evaluating various vaccination programs—Field studies of vaccines with various combinations of MLV antigens were evaluated.
Vaccines with and without an MLV BRSV component
Two field studies33,34 comprising 7 trials compared BRDC-related morbidity and mortality risk data for beef calves that received commercially available vaccines with or without an MLV BRSV component (Table 11). Analysis revealed a significantly lower morbidity risk for vaccinates that received a BRSV vaccine component, compared with control calves that received vaccines without a BRSV component, in 1 of the 5 trials, with no significant difference between groups in the remaining 4 trials (Figure 10). The summarized risk ratio for these 5 trials was 0.85, with a 95% CI of 0.67 to 1.08, indicating no significant difference in morbidity risk between the 2 treatment groups. Three trials provided mortality data, and 1 of the 3 found a significantly lower mortality risk in calves that received a multivalent vaccine that included a BRSV component, compared with calves that received a multivalent vaccine without the BRSV component. The summarized risk ratio for these trials was 0.76, with a 95% CI of 0.20 to 2.88, indicating no significant difference in mortality risk between calves administered a vaccine that included a BRSV component and those vaccinated without the BRSV component.
Forest plots of morbidity (A) and mortality (B) risk ratios from natural exposure trials that evaluated use of commercially available vaccines that did or did not include a BRSV component for protection against BRDC in beef calves. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
Reviewed field studies that compared use of commercially available vaccines with or without an MLV BRSV component for protection against BRDC in beef calves.
| Reference No. | Reference | Study description | Vaccine |
|---|---|---|---|
| 34 | Van Donkersgoed et al, 1990 | Five trials were performed with cattle of different ages at first vaccine administration. Trial 1 included calves on a cow-calf ranch 3 wk prior to weaning; trial 2, bulls at a central bull test station; trial 3, weanling Charolais-crossbred stocker calves at a research station; trials 4 and 5, yearling-aged calves at 2 commercial feedlots. Cattle were systematically allocated to treatment (BRSV-containing vaccine) and control groups.* After vaccination, ranch calves were monitored for 135 d, cattle treated at the bull test station for 140 d, stocker calves for 99 d, and yearling calves until slaughter. | One vaccine contained MLV BRSV; the other included MLV BHV-1, PI3, and Haemophilus somnus with clostridial bacterins. |
| 35 | MacGregor and Wray, 2004 | A 2-y study of yearling-aged feedlot calves randomly allocated to 2 treatment groups (4-component or 3-component vaccination, once, route not specified) and blocked by sex. Calves were followed from arrival to closeout for a mean of 161 d. | One vaccine included MLV BRSV, BHV-1, BVDV, and PI3; the other vaccine included MLV BHV-1, BVDV, and PI3. |
Both studies evaluated morbidity and mortality risk.
Control animals were previously administered an MLV vaccine without the BRSV component.
5-way (MLV BHV-1, BVDV type 1 and 2, BRSV, and PI3) versus 3-way (MLV BHV-1 and BVDV type 1 and 2) vaccines
One study37 comprising 2 trials evaluated BRDC-related morbidity and mortality risks in beef calves that received 1 of 2 five-way (MLV BHV-1, BVDV type 1 and 2, BRSV, and PI3) vaccines, compared with the risks for cattle that received a 3-way (MLV BHV-1 and BVDV type 1 and 2) vaccine. Pens of feeder steers were blocked by truckload and then randomly allocated to treatment groups. Calves were vaccinated once, IM, ≤ 36 hours after arrival to a feedlot and monitored for 234 days until slaughter. Analysis revealed no significant morbidity risk difference for vaccinates, compared with controls, in both trials (Figure 11). The summarized risk ratio for these trials was 0.98, with a 95% CI of 0.87 to 1.10, indicating no significant difference in morbidity risk between treatment groups. Both trials compared mortality risks for calves vaccinated with 5-way and 3-way vaccines. Analysis revealed no significant mortality risk difference for vaccinates versus controls in both trials. The summarized risk ratio for these trials was 0.81, with a 95% CI of 0.60 to 1.10, indicating no significant difference in mortality risk between calves that received the 5-way vaccines and those that received a 3-way vaccine.
Forest plots of morbidity (A) and mortality (B) risk ratios from natural exposure trials that evaluated vaccination with a commercially available 5-way (MLV BHV-1, BVDV type 1 and 2, BRSV, and PI3) vaccine versus administration of a 3-way (MLV BHV-1 and BVDV type 1 and 2) control vaccine for protection against BRDC in beef calves. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 246, 1; 10.2460/javma.246.1.126
3-way (MLV BHV-1 and BVDV type 1 and 2) versus 4-way (MLV BHV-1, BVDV type 1, BRSV, and PI3) vaccines
One study35 comprising 1 trial compared BRDC-related morbidity and mortality risks for crossbred beef calves that received a 3-way (MLV BHV-1 and BVDV type 1 and 2 combination with an M haemolytica and P multocida bacterin-toxoid) vaccine with the risks for those that received a 4-way (MLV BHV-1, BVDV type 1, BRSV, and PI3 combination with M haemolytica bacterin-toxoid) vaccine. Calves were randomly allocated to treatment group, revaccinated 69 days after initial vaccine administration, and monitored until slaughter after approximately 224 days on feed. The morbidity risk ratio (for the 3-way vs 4-way vaccine groups) for this trial was 0.78, with a 95% CI of 0.69 to 0.89, indicating that calves vaccinated with the 3-way vaccine had a lower morbidity risk, compared with that of calves vaccinated with the 4-way vaccine. In addition, the mortality risk ratio was 0.56, with a 95% CI of 0.38 to 0.79, indicating that calves vaccinated with the 3-way vaccine had a lower mortality risk than did calves vaccinated with the 4-way vaccine.
Monovalent versus multivalent MLV vaccines
One study36 comprising 1 trial of 8- to 10-month-old crossbred beef steers and bull calves compared BRDC-related morbidity and mortality risks between calves that received a monovalent MLV BHV-1 vaccine and those that received a multivalent MLV BHV-1, BVDV, BRSV, and PI3 vaccine. Calves were randomly allocated to treatment groups and vaccinated (route not specified) twice, (on arrival at a feedlot and again 70 days later). Calves were followed to slaughter at approximately 200 days on feed. The morbidity risk ratio (for multivalent vs monovalent vaccine groups) was 0.77, with a 95% CI of 0.69 to 0.86, indicating a significantly lower morbidity risk in calves that received the multivalent vaccine, compared with that in calves that received the monovalent vaccine. The mortality risk ratio was 0.83, with a 95% CI of 0.56 to 1.23, indicating no significant difference in mortality risk between groups.
Discussion
Overall, the relative scarcity of peer-reviewed publications on natural exposure field studies evaluating the effectiveness of commercially available virus vaccines for protection against BRDC-related morbidity and death in feedlot cattle was surprising. This lack of strong supportive evidence was unexpected, considering the common use of vaccines against viral BRDC pathogens in US feedlots.1 Tripp et al39 provided a summary of published studies involving vaccines against viral components of BRDC, but no summarized meta-analysis was performed to evaluate the direction and overall magnitude of intervention effects. Because we were interested in clinical outcomes rather than proxy indications of efficacy, several studies that evaluated antibody titer responses of calves following vaccination were excluded from the present study. Several studies also had to be excluded because of the lack of blinding of evaluators to treatment group assignment or other study design flaws. Diagnosis of BRDC in the field setting is a subjective determination, and without blinding to treatment groups, investigators may naturally classify more animals in 1 group as affected with disease owing to conscious or subconscious observer bias. Although case definitions used to diagnose BRDC may have differed among studies, we used risk ratios to compare results between treatment groups for individual trials. Case definition should be the same within a given trial; therefore, the analysis should provide a valid result.
An estimated benefit of multivalent virus vaccine administration was found on the basis of randomized controlled field trials9,10 in commercial feedlot settings with natural disease exposure; morbidity and mortality risks were significantly lower in vaccinated beef calves than in nonvaccinated controls (Figure 1). However, we were unable to determine which components of the vaccines used were the important drivers for these outcomes. The fact that these 2 studies9,10 were the only identified field trials comparing results for feedlot cattle vaccinated against BRDC-associated viral antigens with those for nonvaccinated controls reflects the sparse amount of published literature in support of incorporating viral vaccines into BRDC prevention programs. Efficacy in field trials with natural exposure in study populations of interest under similar management conditions provides the highest level of support for use of a product. Inability in the present study to detect differences between treatment groups in trials that involved dairy calves, compared with the results for feedlot cattle, may be attributable to differences in age at the time calves of each type are vaccinated, the magnitude of disease challenge faced by each group, or the variety of vaccines evaluated; it may also be possible that the virus vaccines are not effective in mitigating the incidence of BRDC-related morbidity or death in dairy calves. Maternal antibodies have been shown to decrease the degree of response to vaccination,40 which may explain some of the difference in risk ratios between the dairy calf studies and the feedlot cattle studies.
Extrapolation of results from disease challenge studies to commercial field settings must be performed with caution. Challenge studies are an important means to assess the potential for vaccines to provide disease protection, but such studies have severe limitations if used to guide clinical decision making in commercial settings. Challenge studies allow more in-depth evaluation of mechanisms of action of protective immunity and provide more insight into pathophysiologic processes, compared with field studies that involve natural pathogen exposure, but challenge studies are not a substitute for proof of effectiveness in field settings.41 During initial evaluation for potential value in BRDC control, a vaccine should demonstrate efficacy in challenge studies where the timing of vaccination relative to exposure and the route and magnitude of challenge exposure are controlled. However, final evaluation of BRDC control effectiveness must be performed in field settings where the host, environment, and pathogens are not controlled as in the challenge studies.
Meta-analyses of trials evaluating effectiveness of commercially available MLV and inactivated vaccines for protection against BHV-1 infection in beef or dairy calves in experimental challenge models revealed a significantly lower risk of BRDC-related morbidity for vaccinates, compared with that for nonvaccinated control calves. Similarly, our analysis of trials involving beef or dairy calves experimentally challenged with BVDV exposure demonstrated significantly lower BRDC-related morbidity and mortality risks for calves that received MLV BVDV vaccine than for nonvaccinated controls; for calves that received inactivated BVDV vaccine prior to experimental challenge with the virus, mortality risk, but not morbidity risk, was lower than that for nonvaccinated control calves. However, analysis of trials evaluating MLV BRSV and PI3 vaccines in experimental challenge settings found no difference in BRDC-related morbidity and mortality risks between vaccinated and nonvaccinated calves. On the basis of these findings, current MLV BRSV and PI3 vaccines may not be effective for controlling BRDC.
The meta-analysis evaluating field studies of different vaccination programs provided some novel results. Although MacGregor and Wray34 reported a lower BRDC morbidity risk for calves that received a multivalent vaccine including a BRSV component, compared with the risk for calves that received a similar vaccine without a BRSV component, the risk ratios in the present study were not significantly different between treatment groups. The difference in results between the 2004 study34 and the present study is most likely attributable to the difference in statistical analysis performed. In this study, we compared risk ratios between treatment groups, whereas MacGregor and Wray34 evaluated the overall prevalence of BRDC in each treatment group. The meta-analysis found no evidence to support lower morbidity or mortality risks for calves that received the vaccine with a BRSV component, compared with those of calves that received the alternate treatment, which was in agreement with the results for meta-analysis of experimental challenge studies that evaluated the use of an MLV BRSV vaccine for protection against BRDC. Results of the comparison between 5-way (MLV BHV-1, BVDV type 1 and 2, BRSV, and PI3) and 3-way (MLV BHV-1 and BVDV type 1 and 2) vaccines for protection against BRDC were consistent with meta-analysis results for trials that investigated the effectiveness of multivalent vaccines that included either PI3 or BRSV, compared with multivalent vaccines without these antigens, in that morbidity and mortality risk ratios were not significantly different between treatment groups.37
Limitations of this systematic review and meta-analysis included the limitations of the studies included in the analysis and the relatively few published reports available. The fact that few randomized controlled studies evaluating effectiveness of vaccines against BRDC-associated viral pathogens have been published raises the possibility for publication bias if trials with neutral or unfavorable results have not been published. No unpublished data were used in the meta-analysis. Multiple trials in some studies used the same control animals for comparisons. In those studies, the same control animals were used more than once in the meta-analysis. Although not ideal, this was deemed an acceptable means to provide a thorough summary of the published literature. The decision was made to include each comparison as a separate data point in the meta-analysis, even though multiple trials were performed at the same time, to increase the number of trials included in the analysis. Some studies did not describe allocation schemes, the lack of which could serve as cause to remove them from the analysis. But the authors judged that if the study group characteristics were consistent with appropriate allocation and nothing in the materials and methods indicated evidence for improper allocation, the studies were to be included. There was considerable variability in the number of days that calves were monitored after challenge, especially in the BRSV trials. This may have impacted the investigators’ ability to detect BRSV-related disease in some trials; however, we believe all trials included a sufficiently long amount of monitoring time to detect disease given the challenge models used. When analyzing the summary statistic for trials evaluating MLV BRSV vaccination association with BRDC morbidity, the Cochran Q test (P = 0.02) and the I2 statistic (60%) both provided evidence for study heterogeneity, potentially limiting confidence in the pooled estimate. However, the pooled risk ratio estimate was interpreted as failing to provide evidence to reject the null hypothesis, and 6 of the 7 separate studies also failed to provide evidence to reject the null hypothesis of vaccine effect; therefore, we are comfortable presenting the pooled summary as a reasonable estimate based on the available information. Another limitation of the present study was inability to compare duration of morbidity in vaccinated and nonvaccinated control groups. Investigators of some studies13,16–18 reported a shorter duration of morbidity for vaccinated calves, compared with nonvaccinated control calves, in experimental virus challenge studies, which we did not attempt to quantify because the objective of the present study was to evaluate overall morbidity risk.
Although the available data support the use of vaccines directed against BRDC-associated viral pathogens, published natural exposure field studies with blinded evaluation of clinically important outcomes are sparse. In addition, extrapolation of results for BHV-1 and BVDV vaccine effectiveness studies involving experimental virus challenge in controlled settings to field settings is not wholly appropriate. Further research performed in field settings with natural exposure is needed to evaluate effectiveness of the available vaccines. These studies should assess clinically relevant outcomes with adequate blinding of evaluators to treatment allocations and appropriate study design to allow true determination of the magnitude and direction of vaccine efficacy as described by Perino and Hunsaker.41
Although evidence-based guidance for veterinarians making vaccination recommendations for control of BRDC in feedlot cattle is desirable, little published literature is available to provide strong evidence to guide decision making. Because of limited published evidence and the fact that vaccination programs may need to differ from one setting to another, current best recommendations concerning vaccination of feedlot cattle for protection against BRDC may have to include unpublished feedlot-specific or veterinarian-generated data to support situation-by-situation decisions. For future research focus, other methods to control BRDC, such as nutrition management, stress reduction, and type of cattle imported, may be as important as or even more important than vaccine selection.
ABBREVIATIONS
| BHV | Bovine herpesvirus |
| BRDC | Bovine respiratory disease complex |
| BRSV | Bovine respiratory syncytial virus |
| BVDV | Bovine viral diarrhea virus |
| CI | Confidence interval |
| MLV | Modified-live virus |
| PI3 | Parainfluenza type 3 |
RevMan, version 5.0. The Nordic Cochrane Centre, Copenhagen, Denmark.
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