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Serologic response to Mannheimia haemolytica in calves concurrently inoculated with inactivated or modified-live preparations of M haemolytica and viral combination vaccines containing modified-live bovine herpesvirus type 1

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  • 1 Pfizer Animal Health, Pfizer Incorporated, 685 3rd Ave, New York, NY 10017
  • | 2 Pfizer Animal Health, Pfizer Incorporated, 685 3rd Ave, New York, NY 10017
  • | 3 Pfizer Animal Health, Pfizer Incorporated, 685 3rd Ave, New York, NY 10017
  • | 4 Horton Feedlot and Research Center, 5100 E County Rd 70, Wellington, CO 80549
  • | 5 Department of Animal Sciences, College of Agriculture, Food Systems, and Natural Resources, North Dakota State University, Fargo, ND 58108.
  • | 6 Pfizer Animal Health, Pfizer Incorporated, 685 3rd Ave, New York, NY 10017
  • | 7 Pfizer Animal Health, Pfizer Incorporated, 685 3rd Ave, New York, NY 10017

Abstract

Objective—To assess the serologic response of calves to inactivated and modified-live (ML) Mannheimia haemolytica (MH) preparations given alone and concurrently with combination viral vaccines containing ML bovine herpesvirus type 1 (BHV-1).

Animals—642 calves seronegative for BHV-1.

Procedures—In experiment 1, 192 calves received 1 of 3 MH preparations alone or concurrently received 1 of 3 MH preparations and 1 of 4 combination viral vaccines. In experiment 2, 450 calves received 1 of 4 MH preparations alone or concurrently received 1 of 4 MH preparations and 1 of 5 combination viral vaccines. Pretreatment and posttreatment blood samples were processed to obtain serum, which was analyzed to detect concentrations of antibodies against MH leukotoxin and BHV-1.

Results—In experiment 1, antibody titers against MH leukotoxin in calves receiving MH and ML virus vaccine appeared decreased, albeit nonsignificantly, compared with titers for calves receiving MH preparations alone. In experiment 2, all groups (except for 1) concurrently receiving an MH preparation and viral vaccine had a significant decrease in antibodies against MH leukotoxin. In both experiments, there was a significant decrease in the number of calves responding to MH leukotoxin when ML viral vaccine was coadministered.

Conclusions and Clinical Relevance—Coadministration of ML BHV-1 and MH preparations interfered with the serologic response to MH leukotoxin in calves seronegative for BHV-1. Serologic response to MH leukotoxin may be substantially improved in seronegative calves when MH vaccination is delayed until after calves have received a dose of ML BHV-1 vaccine.

Abstract

Objective—To assess the serologic response of calves to inactivated and modified-live (ML) Mannheimia haemolytica (MH) preparations given alone and concurrently with combination viral vaccines containing ML bovine herpesvirus type 1 (BHV-1).

Animals—642 calves seronegative for BHV-1.

Procedures—In experiment 1, 192 calves received 1 of 3 MH preparations alone or concurrently received 1 of 3 MH preparations and 1 of 4 combination viral vaccines. In experiment 2, 450 calves received 1 of 4 MH preparations alone or concurrently received 1 of 4 MH preparations and 1 of 5 combination viral vaccines. Pretreatment and posttreatment blood samples were processed to obtain serum, which was analyzed to detect concentrations of antibodies against MH leukotoxin and BHV-1.

Results—In experiment 1, antibody titers against MH leukotoxin in calves receiving MH and ML virus vaccine appeared decreased, albeit nonsignificantly, compared with titers for calves receiving MH preparations alone. In experiment 2, all groups (except for 1) concurrently receiving an MH preparation and viral vaccine had a significant decrease in antibodies against MH leukotoxin. In both experiments, there was a significant decrease in the number of calves responding to MH leukotoxin when ML viral vaccine was coadministered.

Conclusions and Clinical Relevance—Coadministration of ML BHV-1 and MH preparations interfered with the serologic response to MH leukotoxin in calves seronegative for BHV-1. Serologic response to MH leukotoxin may be substantially improved in seronegative calves when MH vaccination is delayed until after calves have received a dose of ML BHV-1 vaccine.

Bovine respiratory disease remains a major cause of death of beef cattle in feedlots, a major cause of production loss, and an economic threat to every segment of the beef production industry. Losses from BRD have persisted for decades despite the advent of potent and highly effective antimicrobial agents and advancements in the production and use of efficacious biologics. Factors contributing to BRD-associated losses in postweaning beef calves include long-distance transportation, commingling and crowding of cattle from multiple sources, poor ventilation, weather fluctuations, exposure to infectious pathogens from commingled cattle, adaptation to an increased amount of concentrates in diets fed in feedlots, and a focus on genetics for increased growth and more rapid attainment of finishing weight, which may have antagonistic effects on genetic factors that contribute to immunity. Consideration must also be given to the ongoing industry practice of vaccinating calves on a convenience basis aligned with other processing events (eg, branding and weaning) at a feedlot. Until recently, little attention has been given to the immunologic interactions in young calves when ML vaccines are administered concurrently with ML and inactivated bacterial preparations. A matter worthy of investigation is whether ML vaccines interfere with the protective capacity of MH vaccination when the viral and bacterial preparations are administered concurrently.

The terms dominant antigen, antigen interference, and immunodominance have been used interchangeably to describe a unique phenomenon of the immune system.1 Immunodominance, the designation most widely accepted in human immunology, is defined as the process by which immune expression, or recognition, of 1 epitope or antigen influences recognition of a second distinct epitope or antigen.2 More succinctly, immunodominance characterizes the immune system's selective response to one epitope or antigen at the expense of a response to another. This prioritization of epitope selection by the immune system has been widely studied, with many studies focusing on immunodominance in response to the multitude of epitopes within a specific antigen (virus or bacterium). For any virus or bacterium, only 0.2% of the possible epitopes elicit any measurable immune response.3 These highly immunogenic epitopes are termed immunodominant epitopes, and they can block immune responses to other epitopes, which are termed subdominant epitopes. These same concepts have been extended to interactions that might occur when different vaccine antigens are administered concurrently.4,5 In human medicine, the FDA requires vaccine manufacturers to investigate possible interactions that could occur between concurrently administered antigens. Although immunodominance is not a new concept, little research has been conducted on the subject of veterinary immunology.

One of the first studies6 conducted to determine the potential for interference between vaccine antigens in cattle was published in 1992. Investigators in that study6 found that vaccination of feedlot calves with ML BHV-1 blocked the calves' serologic response to inoculation with an experimental MH vaccine. The same phenomenon was later identified in a vaccine field trial conducted by investigators at Kansas State University.7 Results of these studies raise concerns about the interpretation of field trials in which attenuated BHV-1 and MH preparations were coadministered and call into question herd health programs in which seronegative calves are vaccinated. Despite these data, several MLV-MH combination vaccines are currently licensed with no restriction on their use, even though product literature8 from one of the vaccine manufacturers acknowledges interaction between the vaccine's antigens. It appears that calves not receiving MLV (infectious bovine rhinotracheitis) have a greater antibody response to MH whole cell and leukotoxoid, although insufficient numbers of calves in the groups did not allow detection of significant differences. One study9 revealed no interaction between vaccines when the BHV-1 component of a combination MH–BHV-1 vaccine was inactivated.

In each of these aforementioned studies, investigators compared the serologic responses to MH preparations when administered to cattle concurrently with attenuated BHV-1, and no MH challenge exposure was performed. However, it is accepted that antibodies against MH are protective and ELISA antibody titers, particularly against MH leukotoxin, correlate with protection against MH challenge exposure.10–15 Therefore, the purpose of the 2 experiments reported here was to determine whether there were interactions between combination viral vaccines containing ML BHV-1 and MH preparations when concurrently administered under field use conditions to beef and dairy calves of 2 age groups.

Materials and Methods

Experiment 1—Thirty days before the initiation of the experiment, approximately 250 crossbred beef calves (2 to 8 weeks old) at the North Dakota State University Central Grasslands Research and Extension Center in Streeter, ND, were evaluated to detect neutralizing antibodies against BHV-1, bovine viral diahrrea, and MH whole cell and leukotoxin. All dams of these calves had previously received the same vaccinations. The experiment was conducted in accordance with the guidelines of the North Dakota State Univerisity Animal Care and Use Committee.

A total of 192 calves were admitted to the study; blocked on the basis of ELISA antibody titer against BH V-1, age, and sex; and randomly assigned to 1 of 7 treatment groups. Forty-two calves with BHV-1 ELISA titers ≥ 1:16 were assigned to treatment group 1. The remaining 150 calves with BHV-1 SN titers ≤ 1:8 were assigned to treatment groups 2 through 7 (25 calves/group) via a list generated by use of statistical software.a Calves were allowed to remain with their dams, and cow-calf pairs were managed as a group for the duration of the experiment.

On day 0, calves were inoculated with an MH product alone or in combination with an ML viral vaccine. Calves in treatment groups 1 and 2 were inoculated with a vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and with a USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant; calves in treatment group 3 were inoculated with the same MH bacterin-toxoidc with an oil-in-water adjuvant as for treatment groups 1 and 2; calves in treatment group 4 were inoculated with a productd that contained ML BHV-1, PI3, BRSV, 1 strain of ML BVDV, and a USDA-licensed MH bacterin-toxoide with an oil-in-water adjuvant; calves in treatment group 5 were inoculated with the same USDA-licensed MH bacterin-toxoide with an oil-in-water adjuvant as used for group 4; calves in treatment group 6 were inoculated with a product that contained ML BHV-1, PI3, BRSV, 2 strains of ML BVDV, and avirulent streptomycin-dependent MH and PM; and calves in treatment group 7 were inoculated with an avirulent streptomycin-dependent MH and PM product.g Three serials of each product were used.

A blood sample (10 mL) was collected from each calf on days 0, 14, and 28. The sample on day 0 was collected before the calves were inoculated. All blood samples were processed on the day of collection. Serum was harvested by personnel at the North Dakota State University Veterinary Diagnostic Laboratory and stored frozen at −20°C for subsequent analysis. After completion of the experiment, BHV-1 serologic evaluation was performed at the North Dakota State University Veterinary Diagnostic Laboratory, and bovine viral diahrrea and MH serologic evaluation was performed at laboratories at Oklahoma State University.

Experiment 2—Thirty days before the initiation of the experiment, approximately 500 calves (6 to 8 months old) at 2 locations (Arambel Pyrenees Dairy, Hyrum, Utah, and Andrus Ranch, Soda Springs, Idaho) were evaluated to detect antibody titers against BHV-1 and MH whole cell and leukotoxin. All calves had individual ear tags for purposes of identification. The experiment was conducted in accordance with the guidelines of the Pfizer Animal Health Animal Care and Use Committee.

This experiment was designed to meet the statistical criteria required to evaluate serologic immune responses against MH whole cell and leukotoxin antigens when commercially available viral vaccines containing ML BHV-1 were coadministered with various MH preparations. Of the calves initially tested, 450 were selected for the study; blocked on the basis of age, sex, and BHV-1 SN titer; and assigned to treatment groups (50 calves/group). Within a block, calves were assigned to a treatment group by use of a random number generated by use of statistical software.a The study comprised 5 replicates with 90 BHV-1 seronegative (SN titer ≤ 1:4) calves in each replicate. Replicates 1, 2, and 3 consisted of dairy calves, and replicates 4 and 5 consisted of beef calves. Treatment groups within a replicate were commingled during the study but maintained separately from all other cattle at each location.

On day 0, calves were inoculated with an MH product alone or in combination with an ML viral vaccine. Calves in treatment group 1 were inoculated with a vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and with a USDA-licensed MH bacterintoxoidc with an oil-in-water adjuvant; calves in treatment group 2 were inoculated with a vaccineh containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV and with the same USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant used for calves in treatment group 1; calves in treatment group 3 were inoculated with the same MH bacterin-toxoidc with an oil-in-water adjuvant as for treatment groups 1 and 2; calves in treatment group 4 were inoculated with a productd containing ML BHV-1, PI3, BRSV, 1 strain of ML BVDV, and an MH bacterin-toxoid with an oil-in-water adjuvant; calves in treatment group 5 were inoculated with another USDA-licensed MH bacterin-toxoide with an oil-in-water adjuvant; calves in treatment group 6 were inoculated with a productf containing ML BHV-1, PI3, BRSV, 2 strains of ML BVDV, and avirulent streptomycin-dependent MH and PM; calves in treatment group 7 were inoculated with a productf containing avirulent streptomycin-dependent MH and PM; calves in treatment group 8 were inoculated with a producti containing ML BHV-1, PI3, BRSV, 2 strains of BVDV, and an MH toxoid with a saponin adjuvant; and calves in treatment group 9 were inoculated with an MH toxoidj with a saponin adjuvant. Thus, calves in treatment groups 1, 3, 4, 5, 6, and 7 were inoculated with the same products used for the corresponding treatment groups in experiment 1. Three serials of each product were used.

A blood sample (10 mL) was collected from each calf on days 0, 14, and 28. The sample on day 0 was collected before the calves were inoculated. All blood samples were stored on ice until processing. Serum was harvested and frozen at −20°C, and frozen sera were transported to the Oklahoma State University Veterinary Diagnostic Laboratory for analysis. All serum samples were stored frozen until completion of the study and were analyzed at 1 time. Analysis of antibody concentrations against MH leukotoxin was performed by personnel in the Department of Veterinary Pathobiology at Oklahoma State University using ELISAs as described elsewhere.16,17 Analysis of antibody concentrations against MH whole cells was also performed by personnel in the Department of Veterinary Pathobiology at Oklahoma State University as described elsewhere18; however, those results were not included in the present study. Serologic analysis for BHV-1 was performed by personnel at the Oklahoma Animal Disease Diagnostic Laboratory in Stillwater, Okla, using standard laboratory techniques.19

Data analysis—Serum antibody concentrations were analyzed with a linear mixed model with repeated measures that included the fixed effects of treatment, day of study, and the treatment × day of study interaction in addition to the random effects of replicate and batch within replicate. The antibody concentration against MH whole cell determined in samples obtained on day —30 was included as a covariate in the analysis of antibody concentrations against MH whole cell and leukotoxin. Least squares mean estimates of change in concentrations from day 0 to 28 were generated and tested by use of the appropriate estimate statements with statistical software.k Denominator df was calculated by use of the Kenward-Roger method. A significant (P ≤ 0.05) treatment or treatment × day of study interaction was required before conducting pairwise tests of treatment differences. Antibody titers for BHV-1 were geometrically transformed before analysis.

Results

Experiment 1—Independent administration of the MH bacterins (treatments 3 and 5) appeared to stimulate a positive antibody response (increase of ≥ 2 times the initial ELISA concentration) against MH leukotoxin in a higher percentage of calves than did concurrent administration of the bacterins and an MLV vaccine (treatments 1, 2, and 4; Table 1). Only treatment group 6 (a single MH-MLV combination product) had a greater percentage of calves with a positive antibody response against MH leukotoxin than did treatment group 7 (an MH-PM product). Compared with results for the other treatment groups, treatment groups 6 and 7 had considerably fewer calves with a serologic response against MH leukotoxin (6/25 [24%] and 5/25 [20%] for treatment groups 6 and 7, respectively).

Table 1—

Calves within each treatment group that had a positive antibody response (increase of ≥ 2 times the initial ELISA concentration) against MH leukotoxin following inoculation in experiment 1.

Treatment groupNo. of calves in treatment groupNo. (%) of calves with positive results
14221 (50)
22512 (48)
323*14 (61)
424*11 (46)
52518 (56)
6256 (24)
7255 (20)

Calves in treatment groups 1 and 2 were inoculated with a vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and with a USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant; calves in treatment group 3 were inoculated with the same USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant as for treatment groups 1 and 2; calves in treatment group 4 were inoculated with a productd containing ML BHV-1, PI3, BRSV, 1 strain of ML BVDV, and an MH bacterin-toxoid with an oil-in-water adjuvant; calves in treatment group 5 were inoculated with another USDA-licensed MH bacterin-toxoide with an oil-in-water adjuvant; calves in treatment group 6 were inoculated with a productf containing ML BHV-1, PI3, BRSV, 2 strains of ML BVDV and avirulent streptomycin-dependent MH and PM; and calves in treatment group 7 were inoculated with a productg containing avirulent streptomycin-dependent MH and PM.

Number of calves in these groups did not equal 25 because some calves were removed because of loss of identification tags or death.

A risk assessment of calves within each treatment group that had a positive antibody response against MH leukotoxin was conducted (Table 2). Success or failure of seroconversion was defined by the number of calves in each treatment group that had a positive antibody response against MH leukotoxin. The CER was the percentage of calves within groups inoculated with an MH preparation alone that failed to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin, and the PER was the percentage of calves within groups inoculated concurrently with MH and a viral vaccine that failed to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin. Relative risk was a measurement of the increased likelihood that calves receiving the MH and MLV combinations concurrently would fail to have an increase of ≥ 2 times the initial ELISA concentration, compared with the likelihood for calves receiving MH preparations alone. Relative risk was calculated by dividing the PER by the CER and multiplying the quotient by 100. Absolute risk reduction was the numeric difference between the CER and PER. Relative risk increase was a measurement of the percentage increase in failure to have a positive response (ie, increase of ≥ 2 times the initial ELISA concentration) against MH leukotoxin in calves concurrently receiving MH and MLV vaccines, compared with results for calves receiving MH preparations alone. Relative risk increase was determined by dividing the absolute risk reduction by the CER. The number needed to harm was a measurement of the number of calves that could be inoculated concurrently with MH and MLV vaccines before 1 more calf in the group would fail to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin, compared with the same number of calves inoculated with an MH preparation alone. The smaller the number needed to harm, the more likely the effect attributable to the principal treatment (failure to serologically respond) would occur. The number needed to harm was determined by dividing 1 by the absolute risk reduction.

Table 2—

Risk assessment for the failure to induce a positive antibody response (increase of ≥ 2 times the initial ELISA concentration) against MH leukotoxin by inoculation with an MH preparation alone (MH alone) or inoculation with an MH preparation in combination with a viral vaccine (MH + viral) in experiment 1.

 MH aloneMH+ viral      
MH alone vs MH + viralFailureSuccessFailureSuccessCER (%)PER (%)RR (%)ARR (%)*RRI (%)*NNH*
3 vs 1914212139.1350.00127.78−10.87 (−35.90 to 14.16)−27.78 (−91.74 to 36.19)9 (3 to ∞)
3 vs 2914131239.1352.00132.89−12.87 (−40.82 to 15.08)−32.89 (−104.32 to 38.55)8 (2 to ∞)
5 vs 41114131144.0054.17123.11−10.17 (−38.02 to 17.69)−23.11 (−86.42 to 40.21)10 (3 to ∞)
7 vs 620519680.0076.0095.004.00 (−18.94 to 26.94)5.00 (−23.67 to 33.67)25 (4 to ∞)

Failure of response is the number of calves in an inoculation group that had an increase of < 2 times the initial ELISA concentration against MH leukotoxin, whereas success is the number of calves in an inoculation group that had an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin. The CER is the percentage of calves within a group inoculated with an MH preparation alone that failed to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin; CER is calculated as the number of failures divided by the sum of the number of failures and successes. The PER is the percentage of calves within a group inoculated concurrently with MH and a viral vaccine that failed to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin; PER is calculated as the number of failures divided by the sum of the number of failures and successes. Relative risk (RR) is a measurement of the increased likelihood that calves receiving the MH and MLV combinations concurrently would fail to have an increase of ≥ 2 times the initial ELISA concentration, compared with the likelihood for calves receiving MH preparations alone; RR is calculated by dividing PER by CER and multiplying the quotient by 100. Absolute risk reduction (ARR) is the numeric difference between the CER and PER. Relative risk increase (RRI) is a measurement of the percentage increase in failure to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin in calves concurrently receiving MH and MLV vaccines, compared with results for calves receiving MH preparations alone; RRI is calculated by dividing ARR by CER. Number needed to harm (NNH) is a measurement of the number of calves that could be inoculated concurrently with MH and MLV vaccines before 1 more calf in the group would fail to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin, compared with the same number of calves inoculated with an MH preparation alone.

Value in parentheses is 95% confidence interval.

The only comparison in which concurrent administration resulted in less failure than did administration of an MH product alone.

See Table 1 for remainder of key.

For the risk assessment, the relative risk that calves would fail to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin was increased by 1.23 to 1.33 times in groups that received MH and MLV vaccines concurrently (treatments 1, 2, and 4), compared with results for calves in groups that received MH preparations alone (treatments 3 and 5). The difference in the percentage of calves with a positive response was detected regardless of BHV-1 serologic status at the time of treatment (calves in treatment group 1 had a high titer against BHV-1, whereas calves in treatment group 2 had a low titer against BHV-1). Calves in treatment group 6 (a single MH-MLV product) were more likely to have a positive response than were calves that received the MH preparation alone (calves receiving the MH preparation alone were 1.05 times more likely to not have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin, compared with results for calves treated with the single MH-MLV product).

On day 28, magnitude of the antibody response against MH leukotoxin was decreased, albeit not significantly, for calves in treatment group 2, compared with the response for calves in treatment group 3 (0.265 vs 0.380 ng/mL, respectively), and for calves in treatment group 6, compared with the response for calves in treatment group 7 (0.192 vs 0.220 ng/mL, respectively).

On the basis of the results for experiment 1, it was determined that a second experiment be conducted with a larger number of calves to establish adequate statistical power for detecting significant differences among treatment groups. Because the immune system of the young calves enrolled in experiment 1 may not have reached maturity, the decision was made to conduct the second experiment with older (6- to 8-month-old) calves.

Experiment 2—Of the 450 calves, 10 were removed from the study (replicate 1: treatment group 1 [n = 1], treatment group 2 [2], treatment group 5 [1], and treatment group 9 [1]; replicate 2: treatment group 2 [1], treatment group 4 [1], treatment group 7 [1], and treatment group 9 [1]; and replicate 5: treatment group 8 [1]). Calves were removed because of loss of identification tags, sale, or death. Deaths were not related to study procedures.

Administration of an MH bacterin alone (treatments 3, 5, and 9) and the ML MH-inactivated PM product (treatment 7) resulted in an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin in more calves, compared with results for concurrent administration of an MH preparation and an MLV vaccine (treatments 1, 2, 4, 6, and 8; Table 3).

Table 3—

Calves within each treatment group that had a positive antibody response (increase of ≥ 2 times the initial ELISA concentration) against MH leukotoxin following inoculation in experiment 2.

Treatment groupNo. of calves in treatment group*No. (%) of calves with positive results
14713 (28)
24612 (26)
35023 (46)
44914 (29)
54719 (40)
6483 (6)
7509 (18)
84910 (20)
94815 (31)

Calves in treatment group 1 were inoculated with a vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and with a USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant; calves in treatment group 2 were inoculated with vaccineh containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV and the same USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant used for calves in treatment group 1; calves in treatment group 3 were inoculated with the same USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant as used for treatment groups 1 and 2; calves in treatment group 4 were inoculated with a productd containing ML BHV-1, PI3, BRSV, 1 strain of ML BVDV, and an MH bacterin-toxoid with an oil-in-water adjuvant; calves in treatment group 5 were inoculated with another USDA-licensed MH bacterin-toxoide with an oil-in-water adjuvant; calves in treatment group 6 were inoculated with a productf containing ML BHV-1, PI3, BRSV, 2 strains of ML BVDV, and avirulent streptomycin-dependent MH and PM; calves in treatment group 7 were inoculated with a productg containing avirulent streptomycin-dependent MH and PM; calves in treatment group 8 were inoculated with a producti containing ML BHV-1, PI3, BRSV, 2 strains of BVDV, and an MH toxoid with a saponin adjuvant; and calves in treatment group 9 were inoculated with an MH toxoidj with a saponin adjuvant.

The number of calves in each group did not equal 50 because some calves were removed because of loss of identification tags, sale, or death.

The same analytic methods used in experiment 1 were applied in experiment 2 to assess the risk of failure for each treatment group to respond with an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin (Table 4). For this analysis, calves that received an MH preparation and MLV vaccine concurrently were from 1.15 to 1.37 times as likely to fail to have an increase of ≥ 2 times the initial ELISA concentration against MH leukotoxin as calves that received the MH preparations alone. The additional number of calves that would have such failure (ie, the absolute risk reduction) ranged from 11 to 20/100 calves in groups that received MH preparations and MLV vaccines concurrently. In other words, each time an MH preparation alone or a combination of an MH preparation and MLV vaccine would be administered to 11 to 20 calves, 1 additional calf in the group that received the MH-MLV combination would fail to seroconvert to the MH preparation, compared with results for calves in the group that received the MH preparation alone.

Table 4—

Risk assessment for the failure to induce a positive antibody response (increase of ≥ 2 times the initial ELISA concentration) against MH leukotoxin by inoculation with an MH product alone (MH alone) or inoculation with an MH product in combination with a viral vaccine (MH + viral) in experiment 2.

 MH aloneMH + viral      
MH alone vs MH+ viralFailureSuccessFailureSuccessCER (%)PER (%)RR (%)ARR (%)*RRI (%)*NNH*
3 vs 12723341354.0072.34133.96−18.34 (−37.17 to 0.49)−33.96 (−68.83 to 0.90)5 (3 to ∞)
3 vs 22723341254.0073.92136.88−19.91 (−38.67 to −1.15)−36.88 (−71.61 to −2.14)5 (3 to 87)
5 vs 42819351459.5771.43119.90−11.85 (−30.74 to 7.04)−19.90 (−51.61 to 11.81)8 (3 to ∞)
7 vs 641945382.0093.75114.33−11.75 (−24.41 to 0.91)−14.33 (−29.77 to 1.11)9 (4 to ∞)
9 vs 83315391068.7579.49115.77−10.84 (−28.14 to 6.46)−15.77 (−40.93 to 9.39)9 (4 to ∞)

See Tables 2 and 3 for key.

On day 0, there were no significant differences in prevaccination antibody concentrations against MH leukotoxin among any of the groups. Calves in treatment groups 3 and 5 had significantly higher antibody concentrations on days 14 and 28 than did calves in treatment groups 7 and 9 (Table 5). Significant decreases in antibody concentrations against MH leukotoxin were detected in calves receiving the same MH preparations coadministered with an MLV vaccine in treatment groups 1 (days 14 and 28) and 2 (day 14) and in calves in treatment groups 4 (day 28) and 6 (days 14 and 28; Table 6). At all other time points, all groups had a nonsignificant decrease in antibody concentration against MH leukotoxin when an MH preparation and an MLV combination vaccine were coadministered (Tables 7–11).

Table 5—

Least squares mean of the antibody concentration against MH leukotoxin for calves inoculated with a single product in experiment 2.

 Antibody concentration (ng/mL)Change in antibody concentration (ng/mL)
Treatment groupDay 0Day 14Day 28Day 0–14Day 0–28
30.661.101.010.440.35
50.571.041.020.470.45
70.650.75*†0.75*†0.100.10
90.610.79*†0.82*†0.180.21

Within a column, value differs significantly (P ≤ 0.05) from the value for treatment 3.

Within a column, value differs significantly (P ≤ 0.05) from the value for treatment 5.

See Table 3 for remainder of key.

Table 6—

Least squares mean of the antibody concentration against MH leukotoxin for calves inoculated with an MH preparation alone or with an MH preparation in combination with a viral vaccine in experiment 2.

 Antibody concentration (ng/mL)Change in antibody concentration (ng/mL)
Treatment groupDay 0Day 14Day 28Day 0–14Day 0–28
10.540.80*0.72*0.260.18
20.670.90*†0.86*0.230.19
40.620.88*†0.80*0.260.18
60.550.550.540.00−0.01
80.570.710.700.140.13

Within a column, value differs significantly (P ≤ 0.05) from the value for treatment 6.

Within a column, value differs significantly (P ≤ 0.05) from the value for treatment 8.

See Table 3 for remainder of key.

Table 7—

Least squares mean of the antibody concentration against MH leukotoxin for calves inoculated with a vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and with a USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant (treatment group 1) or inoculated with the USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant alone (treatment group 3) in experiment 2.

 Antibody concentration (ng/mL)Change in antibody concentration (ng/mL)
VariableDay 0Day 14Day 28Day 0–14Day 0–28
Treatment group 10.540.800.720.260.18
Treatment group 30.661.10*1.010.440.35
Difference between treatments 1 and 30.120.300.30NANA

Within a column, value differs significantly (*P = 0.002; P = 0.004) from the value for treatment group 1. NA= Not applicable.

Table 8—

Least squares mean of the antibody concentration against MH leukotoxin for calves inoculated with a vaccineh containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV and with a USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant (treatment group 2) or inoculated with the USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant alone (treatment group 3) in experiment 2.

 Antibody concentration (ng/mL)Change in antibody concentration (ng/mL)
VariableDay 0Day 14Day 28Day 0–14Day 0–28
Treatment group 20.670.900.860.230.19
Treatment group 30.661.10*1.010.440.35
Difference between treatments 2 and 30.010.200.16NANA

Within a column, value differs significantly (P = 0.041) from the value for treatment group 2.

NA= Not applicable.

Table 9—

Least squares mean of the antibody concentration against MH leukotoxin for calves inoculated with a productd containing ML BHV-1, PI3, BRSV, 1 strain of ML BVDV, and an MH bacterin-toxoid with an oil-in-water adjuvant (treatment group 4) or inoculated with a USDA-licensed MH bacterintoxoide with an oil-in-water adjuvant (treatment group 5) in experiment 2.

 Antibody concentration (ng/mL)Change in antibody concentration (ng/mL)
VariableDay 0Day 14Day 28Day 0–14Day 0–28
Treatment group 40.620.880.800.260.18
Treatment group 50.571.041.02*0.470.45
Difference between treatments 4 and 50.040.160.22NANA

Within a column, value differs significantly (P = 0.033) from the value for treatment group 4.

Table 10—

Least squares mean of the antibody concentration against MH leukotoxin for calves inoculated with a productf containing ML BHV-1, PI3, BRSV, 2 strains of ML BVDV and avirulent streptomycin-dependent MH and PM (treatment group 6) or inoculated with a productg containing avirulent streptomycin-dependent MH and PM (treatment group 7) in experiment 2.

 Antibody concentration (ng/mL)Change in antibody concentration (ng/mL)
VariableDay 0Day 14Day 28Day 0–14Day 0–28
Treatment group 60.550.550.540.00−0.01
Treatment group 70.650.75*0.750.100.10
Difference between treatment 6 and 70.100.200.21NANA

Within a column, value differs signficantly (*P = 0.040; P = 0.035) from the value for treatment group 6.

NA = Not applicable.

Table 11—

Least squares mean of the antibody concentration against MH leukotoxin for calves inoculated with a producti containing ML BHV-1, PI3, BRSV, 2 strains of BVDV, and an MH toxoid with a saponin adjuvant (treatment group 8) or inoculated with an MH toxoidj with a saponin adjuvant (treatment group 9) in experiment 2.

 Antibody concentration (ng/mL)Change in antibody concentration (ng/mL)
VariableDay 0Day 14Day 28Day 0–14Day 0–28
Treatment group 80.570.710.700.140.13
Treatment group 90.610.790.820.180.21
Difference between treatment 8 and 90.040.080.12NANA

NA= Not applicable.

The 450 calves enrolled in the study remained sero-negative (ELISA titer < 1:4) for antibodies against BHV-1 prior to vaccination on day 0 (Table 12). All calves inoculated with ML BHV-1 vaccines (treatment groups 1, 2, 4, 6, and 8) seroconverted by day 28, and calves inoculated with preparations of MH alone remained BHV-1 seronegative throughout the experiment. One notable exception was for the calves in treatment group 3, which seroconverted to BHV-1 (geometric mean antibody titer, 3.3) by the end of the experiment.

Table 12—

Geometric mean serum antibody titer against BHV-1 for calves inoculated with an MH preparation alone or inoculated with an MH preparation in combination with a viral vaccine in experiment 2.

Treatment groupDay 0Day 14Day 28
1≤ 1.003.04*†4.32
2≤ 1.002.663.47
3≤ 1.002.243.30
4≤ 1.002.564.31
5≤ 1.002.002.00
6≤ 1.002.77*†3.90
7≤ 1.002.002.13
8≤ 1.002.252.85
9≤ 1.002.002.00

Within a column, value differs significantly (P ≤ 0.05) from the value for treatment 4.

Within a column, value differs significantly (P ≤ 0.05) from the value for treatment 8.

See Table 3 for remainder of key.

Discussion

The number of cattle that are protected in a population affects the incidence of disease attributable to MH in a herd, and the serologic response to leukotoxin is related to clinical protection.10–15 However, the protective concentration or magnitude of that serologic response remains unknown.

The absolute risk reduction ranged from 11 to 20/100 calves in groups that received MH preparations and MLV vaccines concurrently. If veterinarians were to recommend protocols that included concurrent administration of MH preparations and MLV vaccines, they likely could expect 1 more calf/11 to 20 calves inoculated to be at an increased risk of developing BRD associated with MH than when the MH preparations and the MLV vaccines are administered at different times.

Inoculation with a vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV appeared to elicit the fastest antibody response to BHV-1 vaccination. On day 14, calves that received that viral vaccineb (treatment groups 1 and 2 in experiment 1 and treatment group 2 in experiment 2) had significantly higher antibody concentrations against BHV-1 than did calves that received a productd containing ML BHV-1, PI3, BRSV, 1 strain of ML BVDV, and an MH bacterin-toxoid with an oil-in-water adjuvant (treatment group 4 in both experiments) or calves inoculated with a producti containing ML BHV-1, PI3, BRSV, 2 strains of BVDV, and an MH toxoid with a saponin adjuvant (treatment group 8 in experiment 2). The antibody concentrations against BHV-1 in calves administered the vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and the vaccinec containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV in experiment 2 were not significantly (P = 0.062) different at 14 days after inoculation. Significant differences in antibody titers against BHV-1 were also detected between calves in treatment groups 2 and 6, treatment groups 2 and 8, and treatment groups 4 and 6. Throughout the 28-day study period, calves in treatment group 8 had the lowest postvaccination concentration of antibodies against BHV-1. On day 28, calves in treatment groups 1, 4, and 6 had significantly higher antibody concentrations against BHV-1 than did calves in treatment group 8. A comparison of the serologic responses of calves in groups coadministered MH preparations and vaccine containing ML BHV-1 (treatment groups 1, 2, 4, 6, and 8) revealed that each of the groups responded with an increase of ≥ 2 times the initial antibody concentration against BHV-1 (Table 12), whereas each of the same groups had a decrease in antibody concentration against MH leukotoxin (Table 6).

Of the 4 MH preparations evaluated in this study, only the MH bacterin-toxoidb with an oil-in-water adjuvant (treatments 1 and 2 in both experiments) and another USDA-licensed MH bacterin-toxoide with an oil-in-water adjuvant (treatment group 5 in both experiments) stimulated appreciable antibody concentrations against MH leukotoxin. An MH toxoidj with a saponin adjuvant stimulated lower postvaccination concentrations for treatment group 7 than for treatment groups 1,2, and 5, and a productg containing avirulent streptomycin-dependent MH and PM (treatment group 9) consistently induced the lowest antibody concentrations after vaccination. The antibody concentrations stimulated in treatment groups 7 and 9 were significantly lower than the antibody concentrations stimulated in treatment groups 3 and 5. Concentrations of antibodies against MH leukotoxin were lower in all treatment groups in which MH preparations were coadministered with an MLV vaccine, compared with the groups in which MH preparations were administered alone; however, a significant decrease in the antibody concentration against MH leukotoxin was detected only when a vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and a vaccineh containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV were coadministered with a USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant (treatment groups 1 and 2 in experiment 2). In calves seronegative to BHV-1 at the time of inoculation, the vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and the vaccineh containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV clearly interfered with the calves' ability to respond to the MH antigen in the USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant. The vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV induced the greatest and most rapid antibody response against BHV-1 on days 14 and 28. Because all calves were commingled and there were no changes in the antibody concentrations against BHV-1 in any other group inoculated with an MH preparation alone, the change in antibody concentration against BHV-1 in calves inoculated with the USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant likely was not attributable to natural exposure or inoculation. Similar interference between vaccine antigens has been reported for several other vaccines used in veterinary medicine.20,21,l

Immunodominance can occur via various mechanisms, including dominant epitope processing, which blocks antigen-presenting cells from processing sub-dominant epitopes3; dominant epitope T cells blocking expansion of subdominant T cells (CD4+ and CD8+)3; dominant epitope processing that uses and exhausts T-cell synaptic molecules or results in the release of defective synaptic molecules, thereby blocking attachment of subdominant T cells2; and shifting of CD4+ subsets toward antiviral or antibody formation.4,5

Immunologic studies in humans have revealed that immunodominance may not occur when different lymph node sites are used3; however, in the study reported here, we administered the vaccineb containing ML BHV-1, PI3, BRSV, and 2 strains of ML BVDV and the USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant (treatment groups 1 and 2 in experiment 1 and treatment group 1 in experiment 2) as well as the vaccineh containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV and the same USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant (treatment group 2 in experiment 2) on contralateral sides of each calf's neck, and the antibody concentrations against MH leukotoxin in the calves receiving the vaccineh containing temperature-sensitive ML BHV-1 and PI3 variants, ML BRSV, and 2 strains of inactivated BVDV and the USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant (treatment group 2 in experiment 2) were significantly lower than those in calves receiving the USDA-licensed MH bacterin-toxoidc with an oil-in-water adjuvant (treatment group 3 in both experiments).

It is important to clarify the difference between dominant antigen and antigen interference. In general, the dominant antigen theory describes a situation in which one or more antigens or epitopes on a microorganism have a more pronounced or important role than do other antigens on the same organism. In contrast, antigen interference is the phenomenon whereby antigens from different sources or classes (viral vs bacterial or cell-mediated immune responsive vs humoral responsive) competitively elicit different aspects of the acquired immune system. In some situations, the mechanisms may be similar for both.

On the basis of results of the study reported here, current recommendations for vaccinating calves likely should be changed to elicit improved protection against disease caused by MH. Whenever possible, MH preparations should be administered at the time of administration of a second dose of viral vaccine because antigen interactions appear to be reduced in cattle that have been previously vaccinated against BHV-1.22 In this regard, it should be recognized that the administration of ML BHV-1 vaccines in young calves takes on an increasingly important role because early vaccination may help circumvent antigen interactions that occur when ML BHV-1 and MH preparations are administered concurrently to cattle during preweaning and weaning vaccination programs. In herds subject to a high degree of challenge with infectious agents, multiple doses of MH vaccine may be required to protect cattle if the first dose of MH vaccine is administered concurrently with a viral vaccine. In all herds, it should be acknowledged that the serologic response of calves to MH antigen increases with immunologic maturity.23

Although much is known about immunodominance between epitopes in the same virus or bacterium, less information is available on the interaction between viral and bacterial antigens. In the experiments reported here, the magnitude of the serologic response to MH leukotoxin and the percentage of calves responding were significantly decreased when MH preparations were coadministered with a viral vaccine containing ML BHV-1. More research in this area of veterinary medicine is needed so that prudent vaccination programs can be designed on the basis of the most likely immunologic responses against vaccine antigens. Currently, knowledge of the potential for the occurrence of immunodominance can assist veterinarians in designing vaccination programs until additional studies are conducted to further clarify the issue.

ABBREVIATIONS

BHV-1

Bovine herpesvirus type 1

BRD

Bovine respiratory disease

BRSV

Bovine respiratory syncytial virus

BVDV

Bovine viral diarrhea virus

CER

Control event rate

MH

Mannheimia haemolytica

ML

Modified live

MLV

Modified-live virus

PER

Principal event rate

PI3

Parainfluenza type 3

PM

Pasteurella multocida

SN

Serum neutralizing

a.

SAS, version 9.1, SAS Institute Inc, Cary, NC.

b.

Bovi-Shield GOLD 5, Pfizer Animal Health, New York, NY.

c.

One Shot, Pfizer Animal Health, New York, NY.

d.

Express 5 PHM, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.

e.

Pulmo-Guard PHM-1, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.

f.

Vista Once SQ, Schering Animal Health, Boxmeer, The Netherlands.

g.

Once PMH SQ, Schering Animal Health, Boxmeer, The Netherlands.

h.

CattleMaster GOLD 5, Pfizer Animal Health, New York, NY.

i.

Pyramid 5 + Presponse SQ, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.

j.

Presponse SQ, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.

k.

PROC MIXED, SAS, version 9.1, SAS Institute Inc, Cary, NC.

l.

Darlington R. Comparison of clinical outcomes of dairy cows vaccinated with 7-way clostridial or Clostridium perfringens C and D vaccines, oral presentation. Western Large Dairy Herd Conf 1997.

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Contributor Notes

Supported by a grant from Pfizer Animal Health.

Address correspondence to Dr. Cortese (victor.cortese@pfizer.com).