Introduction
Administration of IN or parenteral MLV vaccines to young beef calves is the main strategy to reduce the development of bovine respiratory disease.1–4 However, antibody production following vaccination remains inconsistent when maternal antibodies are present.2,5–7 Additionally, a meta-analysis8 revealed that administration of an MLV vaccine against BRSV does not significantly decrease the risk of bovine respiratory disease– associated illness and death in calves; in the United States, BRSV morbidity and mortality rates are as high as 80% and 20%, respectively.9–12
Most BRSV vaccination protocols indicate that calves should be vaccinated between 3 and 30 days old. However, the presence of maternal antibodies in nasal secretions and serum of calves in this age range may interfere with priming of the humoral and cellular immune systems.2,4,13 Experimental studies2,5 revealed that calves that have maternal antibodies and receive an MLV BRSV vaccine at an early age have a short duration of immunity against BRSV. However, BRSV vaccination prior to complete intestinal absorption of maternal antibodies, which is possible when calves are vaccinated within 24 hours of birth, may improve priming of the local and systemic humoral and cellular immune systems.
The objective of the study presented here was to evaluate the effect of 3 vaccination protocols that called for BRSV vaccine administration to beef calves within 24 hours of birth and at 2 months of age on the concentrations of anti-BRSV antibodies in the calves’ nasal secretions and serum at 2 and 6 months of age. Antibody concentrations in nasal secretions but not in serum were hypothesized to differ between the 3 protocols.
Materials and Methods
Animals and experimental design
Sixty newborn beef calves from the Kansas State University Purebred Beef Unit (heifers, n = 31; bulls, 29) representing 3 breeds (Angus, n = 36; Simmental, 14; and Hereford, 10) with a mean birth body weight of 33 kg (range, 16 to 49 kg) were enrolled in the study between January 21 and March 31, 2018. Calves were born to first-calf heifers in individual stalls and remained indoors for 24 hours after birth before being placed in a single pasture. One month prior to breeding, all dams were vaccinated with 1 dose of an MLV that included antigens for BHV type 1; bovine viral diarrhea virus types 1 and 2; parainfluenza virus type 3; BRSV; Campylobacter fetus; Leptospira interrogans serovars Canicola, Icterohemorrhagiae, and Pomona; Leptospira kirschneri serovar Grip-potyphosa; and Leptospira borgpetersenii serovar Hardjo.a Calves were allowed to nurse colostrum from their dams after birth without assistance. This study was approved by the Kansas State University Institutional Animal Care and Use Committee (PRN No. 4039).
The calves were randomly assigned on the day of their birth by on-farm personnel with use of a random number generatorb to 1 of the following 3 vaccine groups:
IN-SC: One dose (2 mL) of an IN (right nares) MLV BRSV vaccinec within 24 hours of birth and 1 dose (2 mL) of a parenteral (SC; right side of neck) MLV BRSV vaccined at 2 months of age.
SC-IN: One dose (2 mL) of parenteral (SC; right side of neck) MLV BRSV vaccined within 24 hours of birth and 1 dose (2 mL) of an IN (right nares) MLV BRSV vaccinec at 2 months of age.
NO-IN: No vaccine within 24 hours of birth and 1 dose (2 mL) of an IN (right nares) MLV BRSV vaccinec at 2 months of age.
Nasal secretion and blood samples were collected within 24 hours of birth and at 2 and 6 months of age for the detection of anti-BRSV IgA in nasal secretions and BRSV neutralizing antibodies in serum. Nasal secretion samples were collected by use of a cotton plug attached to an approximately 5-cm piece of nonabsorbable suture.e Each cotton plug was soaked in sterile saline (0.9% NaCl) solution before being inserted in the left nares for 3 to 6 minutes. After removal from the nares, swabs were placed in 35-mL syringes and secretions were expressed through the syringe tip into sterile tubes. Then, nasal secretions in 0.5-mL aliquots were pipetted into cryogenic vials.f Nasal secretions and serum samples were stored at –80 °C until analysis. All calves received 5 mL of an inactivated vaccineh with antigens for Clostridium chauvoei, Clostridium septicum, Clostridium haemolyticum, Clostridium novyi, Clostridium sordellii, and Clostridium perfringens type C and D toxoid, SC, at the left side of the neck at 2 and 6 months of age.
Determination of anti-BRSV IgA in nasal secretions
Particles of BRSV were inactivated with 2μM binary ethyleneimine, neutralized with sodium thiosul-fate, and diluted 1:800 in carbonate bicarbonate buffer (pH, 9.5). The resulting solution was used to coat the microwells of 96-well plates; plates were then incubated overnight at 4 °C. Next, plates were washed 3 times with PBS containing 0.05% polysorbate 20.i
After the vials of nasal secretion solution were thawed, they were vortexed again and the solution was diluted 1:100 in polysorbate 20. From this initial dilution, serial 2-fold dilutions were prepared to 1:800 and each dilution was analyzed in triplicate (ie, each diluted solution was added to 3 wells). If the coefficient of variation among the 3 values was > 20%, the outlier value was dropped and the mean value of the 2 remaining samples was used in the calculation of the antibody titer. Each sample with an optical density value that was too high to be measured accurately was tested again at a higher dilution, and each sample with an optical density value that was too low to be measured accurately was tested again at a lower dilution, with the lowest dilution set at 1:25. In addition to the samples, each plate had 4 microwells each of the following: positive control, which was nasal secretion diluted 1:100 in polysorbate 20 that yielded a mean optical density between 0.3 and 0.8; negative control, which was low-IgG fetal bovine serumj diluted 1:100 in polysorbate 20; and blank, which was polysorbate 20 alone. Horseradish peroxidase–conjugated rabbit anti-bovine IgAk diluted 1:500 in an ELISA wash buffer (PBS plus 0.05% polysorbate 20) and ABTS substrate solution (2,2’-azino-bis[3-ethylbenzothiazoline-6-sulphonic acid])j were added to each well, and plates were read by a plate reader set at a wavelength of 405 nm. Wells positive for anti-BRSV IgA yielded a green end product when the bound peroxidase-conjugated rabbit anti-bovine IgA reacted with the ABTS substrate. Immunoglobulin A titers were reported as the inverse of last dilution that was ≥ 2 times the mean optical density value of the negative control. The final IgA titers were log10 transformed for statistical analysis.
Determination of BRSV neutralizing antibodies in serum
A virus neutralization assay for the detection of serum anti-BRSV antibodies was performed as described14,15 at the Veterinary Diagnostic Laboratory at Kansas State University. Serum samples were thawed and heat inactivated in a water bath at 56 °C for 30 minutes before being diluted from 1:10 to 1:1,000 in 96-microwell flat-bottom plates with 500 μL of 100 TCID50 BRSV suspended in minimum essential medium. Following incubation at 37 °C in 5% CO2 for 1 hour, cultures were inoculated with minimum essential medium that included 7% bovine serum and an antibiotic-antimycotic solution containing streptomycin, penicillin, and amphotericin B. The plates were then incubated for up to 2 weeks and microscopically evaluated daily for the absence of cytopathic effect. Antibody titers were then reported as the inverse of the lowest dilution of serum required to inhibit a cytopathic effect and were log2 transformed for statistical analysis.
Statistical analysis
The 2 dependent variables were anti-BRSV IgA titers (log10 transformed) from nasal secretions and BRSV neutralizing antibody titers from serum (log2 transformed). Log transformation of the titers was necessary because the titers were not normally distributed. Independent variables of interest included treatment group and sampling time. A priori, the independent variables breed and sex were considered possible confounders of the association between treatment group and antibody titers.
For both dependent variables, linear mixed-effect models were fitted by use of a Gaussian distribution, an identity link, and a restricted pseudolikeli-hood estimation. A bivariable analysis was performed to evaluate the effect of each independent variable on each dependent variable. The significance of the independent variable in the bivariable analysis was assessed by use of a Wald test with a χ2 distribution.
The variables breed and sex were evaluated for confounding by including each variable in a bivariable model that included the variable pertaining to treatment group and by comparing the magnitude of its coefficient of variation from the bivariable models, as well as by determining their significance. If the coefficient of variation changed by > 30% or a change in the P value was observed, the variable was considered a confounder and was included in the final model. The final (multivariable) model included the main effects of treatment, sampling time, and 2-way interaction term treatment and sampling time.
A Toeplitz covariance structure was fitted to account for repeated measures. Model assumptions of homoscedasticity and normality were visually assessed by use of residual plots and Cook-Weisberg and Shapiro-Wilk tests. Titers of IgA were log transformed (log2, log10, and natural log), and the reported log-transformed results were selected on the basis of Akaike information criteria and Bayesian information criteria values. Model-adjusted means, 95% CIs, and P values were also reported. The Tukey-Kramer correction was used to adjust the P value for multiple pairwise comparisons. Analyses were performed with commercially available software.l Values of P < 0.05 were considered significant.
Results
Sixty calves were initially enrolled, 59 calves remained in the study at 2 months, and 34 calves remained at 6 months. The calf that did not remain in the study at 2 months was removed because of severe lameness. The number of calves that remained at 6 months was less as a result of the inability to identify enrolled calves because of loss of their identification numbers (n = 20) and as a result of calves being leased to a producer (5). Other conditions and death of calves were not observed during the study period.
Nasal anti-BRSV IgA titers did not significantly (P = 0.09) differ between heifer and bull calves. Angus calves had significantly (P < 0.01) higher nasal anti-BRSV IgA titers than Simmental and Hereford calves (Table 1). The effect of treatment on nasal IgA titers was significantly (P = 0.01) dependent on sampling time (Table 2). For all treatment groups, mean nasal anti-BRSV IgA titers were lower within 24 hours of birth, compared with titers at 2 and 6 months of age. Within each time of sampling, mean nasal anti-BRSV IgA titers did not significantly differ among treatment groups. Breed did not act as a confounder of the association between each treatment and nasal anti-BRSV IgA titers.
Model-adjusted mean (95% CI) of anti-BRSV IgA titers (log10 transformed) for nasal secretions collected from 34 beef calves that were randomly assigned to 1 of 3 vaccination groups (IN-SC, SC-IN, or NO-IN) and included as the dependent variable to determine the effect of various independent variables in bivariable linear mixed-effect models.
| Independent variable | Mean* (95% CI) | P value† |
|---|---|---|
| Vaccination group | 0.26 | |
| IN-SC | 17.98 (15.08–21.45) | |
| SC-IN | 17.86 (15.08–21.15) | |
| NO-IN | 21.52 (17.91–25.86) | |
| Sampling time | < 0.01 | |
| Within 24 h of birth | 1.00 (0.80–1.22) | |
| 2 mo of age | 166.42 (135.33–204.69) | |
| 6 mo of age | 194.94 (151.84–250.26) | |
| Breed | < 0.01 | |
| Angus | 23.12 (20.60–25.94) | |
| Hereford | 19.52 (15.03–25.35) | |
| Simmental | 15.85 (13.15–19.10) | |
| Sex | 0.09 | |
| Female | 17.53 (15.30–20.08) | |
| Male | 20.85 (17.97–24.18) |
Mean anti-BRSV IgA titer of 1.00 within 24 hours of birth may have affected mean anti-BRSV IgA titers observed by treatment, breed, and sex.
Values of P < 0.05 were considered significant.
NO = No vaccine.
Model-adjusted mean (95% CI) of anti-BRSV IgA titers (log10 transformed) for nasal secretions collected from 34 beef calves that were randomly assigned to 1 of 3 vaccination groups (IN-SC, SC-IN, or NO-IN) and included as the dependent variable to determine the effect of various independent variables in a multivariable linear mixed-effects model. P values for select pairwise comparisons for anti-BRSV IgA titers between vaccination groups within each sampling time are also reported.
| Independent variable | Mean* (95% CI) | P value† |
|---|---|---|
| Vaccination group | 0.89 | |
| IN-SC | 32.55 (27.14–37.14) | |
| SC-IN | 32.95 (27.48–39.50) | |
| NO-IN | 31.07 (26.01–37.13) | |
| Sampling time | < 0.01 | |
| Within 24 h of birth | 1.00 (0.81–1.22) | |
| 2 mo of age | 170.61 (139.19–209.12) | |
| 6 mo of age | 196.61 (154.03–250.90) | |
| Treatment × sampling time | 0.01 | |
| IN-SC | ||
| Within 24 h of birth | 1.00 (0.70–1.43) | |
| 2 mo of age | 192.84 (134.90–275.68) | |
| 6 mo of age | 178.84 (116.79–273.91) | |
| SC-IN | ||
| Within 24 h of birth | 1.00 (0.69–1.44) | |
| 2 mo of age | 224.49 (155.49–324.12) | |
| 6 mo of age | 159.33 (105.00–241.82) | |
| NO-IN | ||
| Within 24 h of birth | 1.00 (0.69–1.40) | |
| 2 mo of age | 114.71 (82.30–159.88) | |
| 6 mo of age | 266.62 (174.42–407.47) | |
| Select pairwise comparisons‡ between vaccination group within each sampling time | ||
| Pairwise comparison | P value§ | |
| Within 24 h of birth | ||
| IN-SC vs SC-IN | > 0.99 | |
| IN-SC vs NO-SC | > 0.99 | |
| SC-IN vs NO-SC | > 0.99 | |
| 2 mo of age | ||
| IN-SC vs SC-IN | 0.99 | |
| IN-SC vs NO-IN | 0.47 | |
| SC-IN vs NO-IN | 0.17 | |
| 6 mo of age | ||
| IN-SC vs SC-IN | > 0.99 | |
| IN-SC vs NO-IN | 0.92 | |
| SC-IN vs NO-IN | 0.73 | |
Mean anti-BRSV IgA titer of 1.00 within 24 hours of birth for all groups may have affected mean anti-BRSV IgA titers by treatment.
Values of P < 0.05 were considered significant.
Other comparisons performed that yielded significant (P < 0.05) results were IN-SC within 24 hours of birth versus IN-SC at 2 months of age or versus at 6 months of age; IN-SC within 24 hours of birth versus SC-IN at 2 months of age or versus at 6 months of age; IN-SC within 24 hours of birth versus NO-IN at 2 months of age or versus at 6 months of age; IN-SC at 2 months of age versus SC-IN within 24 hours of birth or versus NO-IN within 24 hours of birth; IN-SC at 6 months of age versus SC-IN within 24 hours of birth; SC-IN within 24 hours of birth versus SC-IN at 2 months of age or versus at 6 months of age; SC-IN within 24 hours of birth versus NO-IN at 2 months of age or versus at 6 months of age; SC-IN at 2 months of age versus NO-IN within 24 hours of birth; SC-IN at 6 months of age versus NO-IN within 24 hours birth; and NO-IN within 24 hours of birth versus at 2 months of age or versus at 6 months of age.
P value adjusted with the Tukey-Kramer correction for multiple comparisons.
NO = No vaccine.
In the unconditional analyses, treatment, sampling time, breed, or sex was not significantly associated with serum BRSV neutralizing antibody titers (Table 3). Because of this, a multivariable model was not built.
Model-adjusted mean (95% CI) of BRSV neutralization antibody titers (log2 transformed) for serum samples collected from 34 beef calves that were randomly assigned to 1 of 3 vaccination groups (IN-SC, SC-IN, or NO-IN) and included as the dependent variable to determine the effect of various independent variables in bivariable linear mixed-effects models.
| Independent variable | Mean (95% CI) | P value* |
|---|---|---|
| Vaccination group | 0.72 | |
| IN-SC | 2.94 (2.29–3.58) | |
| SC-IN | 3.31 (2.66–3.96) | |
| NO-IN | 3.11 (2.47–3.74) | |
| Sampling time | 0.62 | |
| Within 24 h of birth | 2.99 (2.42–3.57) | |
| 2 mo of age | 3.32 (2.76–3.88) | |
| 6 mo of age | 3.09 (2.38–3.81) | |
| Breed | 0.17 | |
| Angus | 2.97 (2.50–3.43) | |
| Hereford | 3.91 (2.99–4.83) | |
| Simmental | 2.97 (2.22–3.71) | |
| Sex | 0.65 | |
| Female | 3.03 (2.52–3.55) | |
| Male | 3.20 (2.67–3.73) |
Values of P < 0.05 were considered significant.
NO = No vaccine.
Discussion
Current vaccination strategies associated with BRSV have not consistently reduced clinical signs of respiratory disease in young calves.2,8 The presence of colostrum-derived anti-BRSV IgG and IgA in the serum and mucosa of the upper respiratory tract could block vaccinal antigens and prevent successful immunization of young calves against BRSV. Variable concentrations of serum and nasal anti-BRSV IgG and IgA have been reported in young calves after colostrum intake6,16; however, only the presence of anti-BRSV and anti-BHV type 1 IgA in the mucosa of the upper respiratory tract has been associated with protection of calves against BRSV and BHV type 1 infections, repectively.5,7,13,17 Nasal anti-BRSV IgA and serum BRSV neutralizing antibody titers did not differ among the treatment groups, and serum neutralizing antibody titers were low. These findings suggested that vaccination of calves with an IN or SC MLV BRSV vaccine within 24 hours of birth did not result in greater locally or systemically induced BRSV humoral immunity at 2 months of age, compared with no vaccination of calves within 24 hours of birth. Possibly, absorption of maternal antibodies and subsequent translocation to the mucosa of the upper respiratory tract occurred rapidly after ingestion of colostrum. The highest apparent efficiency of absorption of immunoglobulins from colostrum in calves occurs within 6 hours of birth.18,19 Rapid absorption and translocation of anti-BRSV antibodies could have prevented adequate priming of local and systemic immunity by vaccination within 24 hours of age. Similar to the findings of the present study, results from previous studies6,7 indicate that serum neutralizing antibody titers are low following BRSV vaccination in young calves that had maternal antibodies.6,7 One of these studies6 does not indicate any differences in nasal or serum anti-BRSV antibody titers in calves that received a BRSV vaccine at birth and 2 months of age, compared with calves that received 1 dose of an SC MLV vaccine at 2 months of age. Rapid decay (35 days) of vaccine-induced IgA against BHV type 1 and bovine viral diarrhea virus type 2 in the nasal secretions is reported20 in seropositive neonatal Holstein calves that received 1 dose of an IN MLV vaccine between 3 and 8 days of age. Peak nasal anti-BRSV IgA titers in response to IN or SC vaccination (IN-SC and SC-IN treatment groups) within 24 hours of birth may have occurred earlier than 2 months of age, and the lack of testing at < 2 months of age may have prevented detection of peak titers in the present study.
Titers of anti-BRSV IgA noted in the NO-IN calves at 2 months of age may have been the result of trans-location of maternal antibodies following consumption and intestinal absorption of colostrum; however, compared with other immunoglobulins, IgA produced locally in a mammary gland is typically at the lowest concentration in colostrum and decays more rapidly.20,21 These findings suggest that detection of anti-BRSV IgA in the nasal secretions of 2-month-old calves that were not administered an IN or SC vaccine within 24 hours of birth (NO-IN treatment group) may have been the result of other factors. Exposure and subsequent immune response of these calves to BRSV antigens shed by calves that received an IN vaccine may have also explained the comparable anti-BRSV IgA concentrations detected in the nasal secretions of 2-month-old calves in all treatment groups; all calves were on the same pasture after birth, so exposure to BRSV antigen shed by calves that received an IN BRSV vaccine was possible. Antigens of BRSV in the nasal secretions of calves are detected up to 28 days following IN administration of an MLV vaccine.22 Exposure to field strains of BRSV circulating within the study herd may have also explained the presence of anti-BRSV IgA titers at 2 months of age in the NO-IN calves. Results from 1 study23 suggest that changes in serum anti-BRSV antibody titers and seroconversion of unvaccinated dairy cows may correspond to exposure to BRSV shed by subclinically infected cows or calves.
The concentrations of anti-BRSV nasal IgA detected at 2 months of age in calves that received an IN or SC vaccine within 24 hours of birth may have been the result of vaccine priming or transfer of maternal anti-BRSV antibodies. Unfortunately, the effect of passive transfer of anti-BRSV antibodies on local humoral responses is uncertain in the calves of the present study because their passive transfer status was unknown. Titers of nasal anti-BRSV IgA at 6 months of age for the NO-IN calves may have been the result of previous priming of local immunity. Lower concentrations of nasal anti-BRSV IgA in the NO-IN calves at 2 months of age may have allowed for greater replication of vaccinal virus and induction of local immune responses reflected by higher concentrations of nasal anti-BRSV IgA at 6 months of age. In contrast, higher concentrations of nasal anti-BRSV IgA in the IN-SC and SC-IN calves at 2 months of age may have reduced the immunologic effect of the second dose of vaccine (SC or IN) and resulted in lower concentrations of nasal anti-BRSV IgA at 6 months of age in these calves. Interestingly, Angus calves had higher concentrations of nasal anti-BRSV IgA titers, compared with Hereford and Simmental calves. Because more Angus calves were enrolled in the present study (Angus, n = 36; Simmental, 14; and Hereford, 10) and breeds were not equally distributed among treatment groups, a greater proportion of Angus calves received the IN vaccine and responded with production of nasal anti-BRSV IgA, compared with the proportion of calves of the other breeds.
One limitation of the study was the design, which did not include a group of calves that received no vaccine within 24 hours of birth and at 2 months of age (ie, negative control group); rather, all calves received at least 1 dose of an MLV BRSV vaccine, on the basis of the farm's vaccine protocol. Exclusion of such a group prevented evaluation of the decay of local and systemic anti-BRSV maternal antibodies. Given that the effect of breed on nasal anti-BRSV IgA titers was significant, unequal distribution of breeds among the treatment groups may have contributed to the lack of identification of a difference, if a difference was present, among treatment groups. Moreover, the farm underwent a management change during the time of the present study, so care of calves was discontinuous and calf records may have been inaccurate. The loss of calves between 2 and 6 months may have been attributed to this; several calves had ear tags that were missing, so to which treatment group they belonged could not be ascertained. This loss of calves by 6 months of age likely decreased the study power to detect a difference. Also, all calves were on the same pasture after vaccination, thereby allowing exposure to vaccinal BRSV antigen; colostrum quality and passive transfer status were not determined within 48 hours of birth; and nasal secretion and serum samples were not evaluated for anti-BRSV antibodies before 2 months of age. Therefore, other factors in addition to the vaccine protocol may have affected the lack of detection of any significant differences in the local and systemic humoral immune responses in the calves of the present study.
Acknowledgments
Funded in part by a research grant from the Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University.
The authors declare that there were no conflict of interest. Presented in abstract form at the American College of Veterinary Internal Medicine Forum, Phoenix, June 2019.
Footnotes
Bovi-Shield Gold FP5 VL5, Zoetis, Parsippany, NJ.
Excel, Microsoft Corp, Redmond, Wash.
Inforce 3, Zoetis, Parsippany, NJ.
Express, Boehringer Ingelheim, Duluth, Ga.
Braunamid White, Aesculap AG, Tuttlingen, Germany.
Nalgene Cryoware, Thermo Fisher Scientific, Rochester, NY.
Pluronic F-127, Sigma-Aldrich, St Louis, Mo.
Ultrabac 8, Zoetis, Parsippany, NJ.
Tween 20, Sigma-Aldrich, St Louis, Mo.
Sigma-Aldrich, St Louis, Mo.
Rabbit anti-bovine IgA, Bio-Rad, Hercules, Calif.
SAS, version 9.4, SAS Institute Inc, Cary, NC.
Abbreviations
| BHV | Bovine herpesvirus |
| BRSV | Bovine respiratory syncytial virus |
| IgA | Immunoglobulin A |
| IN | Intranasal |
| MLV | Modified-live virus |
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