Five field trials on the efficacy of a bovine respiratory syncytial virus vaccine

Five field trials evaluated whether immunization of beef cattle prior to weaning, at weaning, or immediately upon arrival at the feedlot with a commercial bovine respiratory syncytial virus (BRSV) vaccine would reduce subsequent treatment for respiratory disease.

Bovine respiratory syncytial virus vaccination was associated with a significant (p<0.05) reduction in treatment rate in one of three groups of calves immunized prior to weaning (−12%) and in calves immunized upon arrival at the feedlot (−4%).

There was no significant (p>0.05) effect of the BRSV vaccine on treatment rate in calves immunized at weaning, in calves immunized upon arrival at the Saskatoon bull test station, or in yearlings immunized upon arrival at the feedlot.

Although the trend in these field trials was to a sparing effect of the BRSV vaccine, the small reduction in treatment rate may not justify the cost of the vaccination program.

     

Efficacy of a modified live intranasal bovine respiratory syncytial virus vaccine in 3-week-old calves experimentally challenged with BRSV

Two experimental bovine respiratory syncytial virus (BRSV) challenge studies were undertaken to evaluate the efficacy of a single intranasal dose of a bivalent modified live vaccine containing BRSV in 3-week-old calves. In the first study, vaccine efficacy was evaluated in colostrum deprived (maternal antibody negative) calves 5, 10 and 21 days after vaccination. Nasal shedding of BRSV was significantly reduced in vaccinated calves challenged 10 or 21 days after vaccination. Virus excretion titres were also reduced in vaccinates challenged 5 days after vaccination but reduction in duration of shedding and total amount of virus shed were not statistically significant. Clinical disease after challenge in this study was mild. In the second study, vaccine efficacy was assessed in calves with maternal antibodies against BRSV by challenge 66 days post-vaccination. Vaccination significantly reduced nasal shedding after challenge and the severity of clinical disease was also reduced.     

Establishment of an attenuated strain of bovine respiratory syncytial virus for live virus vaccine

To develop a live virus vaccine for the prevention of bovine respiratory syncytial (BRS) virus infection in calves, an attempt was made to produce an attenuated virus. The RS-52 strain of BRS virus, isolated from the nasal secretions of a naturally infected calf, was subjected to serial passages in adult hamster lung established (HAL) cells at 30 degrees C and the attenuated rs-52 strain as a live virus vaccine was established. The rs-52 strain multiplied better at 30 degrees C than at 34 or 37 degrees C in HAL cells. The differences in the highest virus titers of this strain between the culture temperature of 30 degrees C and that of 34 or 37 degrees C were more than 2.25 log TCID50. Colostrum-deprived newborn calves and 2 approximately 4 months old calves inoculated with the rs-52 strain manifested no abnormal clinical sings at all. However, all inoculated calves produced serum neutralization antibody. When the colostrum-deprived newborn calves immunized with the rs-52 strain were challenged with the virulent NMK7 strain of BRS virus, they exhibited no pyrexia or other abnormal clinical signs at all. An attempt was made to recover the virus from nasal secretions of these calves, but in vain. On the other hand, a nonimmunized control colostrum-deprived newborn calf developed slight fever, mild cough, and slight serous nasal discharge after challenge exposure. The virus was recovered from nasal secretions of this calf. From these results, it was considered that the rs-52 strain could be used as an attenuated live virus vaccine for prevention of BRS virus infection.     

Efficacy of an inactivated respiratory syncytial virus vaccine in calves.

OBJECTIVE: To determine whether an inactivated bovine respiratory syncytial virus (BRSV) vaccine would protect calves from infection with virulent BRSV. DESIGN: Randomized controlled trial. ANIMALS: 27 nine-week-old calves seronegative for BRSV exposure. PROCEDURE: Group-1 calves (n = 9) were not vaccinated. Group-2 calves (n = 9) were vaccinated on days 0 and 21 with an inactivated BRSV vaccine containing a minimum immunizing dose of antigen. Group-3 calves (n = 9) were vaccinated on days 0 and 21 with an inactivated BRSV vaccine containing an amount of antigen similar to that in a commercial vaccine. All calves were challenged with virulent BRSV on day 42. Clinical signs and immune responses were monitored for 8 days after challenge. Calves were euthanatized on day 50, and lungs were examined for lesions. RESULTS: Vaccination elicited increases in BRSV-specific IgG and virus neutralizing antibody titers and in production of interferon-gamma. Virus neutralizing antibody titers were consistently less than IgG titers. Challenge with BRSV resulted in severe respiratory tract disease and extensive pulmonary lesions in control calves, whereas vaccinated calves had less severe signs of clinical disease and less extensive pulmonary lesions. The percentage of vaccinated calves that shed virus in nasal secretions was significantly lower than the percentage of control calves that did, and peak viral titer was lower for vaccinated than for control calves. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the inactivated BRSV vaccine provided clinical protection from experimental infection with virulent virus and decreased the severity of pulmonary lesions. Efficacy was similar to that reported for modified-live BRSV vaccines.     

Efficacy of a saponin-adjuvanted inactivated respiratory syncytial virus vaccine in calves

The objective of this study was to determine whether a commercially available, saponin-adjuvanted, inactivated bovine respiratory syncytial virus (BRSV) vaccine would protect calves from experimental infection with virulent BRSV. This was a randomized controlled trial comprising 14, 8- to 9-week-old calves seronegative for BRSV Group 1 calves (n = 8) were not vaccinated and group 2 calves (n = 6) were vaccinated on days 0 and 19 with an inactivated BRSV vaccine. All calves were challenged with virulent BRSV on day 46. Clinical signs, arterial PO2, and immune responses were monitored after challenge. Calves were euthanatized on day 54 (8 d after challenge) and lungs were examined for lesions. Vaccination elicited increases in BRSV-specific immunoglobulin (Ig) G and virus neutralizing antibody titers. Challenge with BRSV resulted in severe respiratory tract disease and extensive pulmonary lesions in control calves, but no signs of clinical disease and minimal or no pulmonary lesions in vaccinated calves. Arterial blood oxygen values on day 53 (7 d after challenge) in control calves were significantly lower than those in vaccinated calves, which remained within normal limits. Control calves shed BRSV for several days after challenge, whereas BRSV was not detected on deep nasal swabs from vaccinated calves. In summary, the results indicated that this inactivated BRSV vaccine provided clinical protection from experimental infection with virulent virus 27 d after vaccination and significantly decreased the prevalence and severity of pulmonary lesions. Efficacy was similar to that reported for other commercial inactivated and modified-live BRSV vaccines.     

Clenbuterol hydrochloride in calves with a natural bovine respiratory syncytial virus infection

The effect of clenbuterol hydrochloride on the course of disease in calves with a natural bovine respiratory syncytial virus infection was examined. Six calves (three to nine months of age) originating from four herds with respiratory tract disease and serological evidence of a bovine respiratory syncytial virus infection were used in this study. The calves were injected intravenously with clenbuterol hydrochloride. The effect of clenbuterol on the course of disease was measured using the PO2 in blood taken from an indwelling canula inserted in the caudal auricular artery and by clinical signs. Clenbuterol did not improve clinical signs. After clenbuterol administration arterial PO2 values decreased significantly in five out of six patients. Six to eight hours after medication the mean arterial PO2 values were higher than initial values. The moderate positive effect of clenbuterol after six to eight hours may be caused by enhancing ciliary activity and by the secretolytic activity of clenbuterol.     

Effects of bovine respiratory syncytial virus on airway function in neonatal calves

Respiratory syncytial virus (RSV) infection causes severe lower respiratory tract disease in infants and calves. Neonatal respiratory tract infection in children often produces persistent changes in lung function. The specific objective of this study was to determine whether neonatal calves have transient or persistent alterations in pulmonary function and airway reactivity following RSV infection. Six 2- to 3-day-old Holstein bull calves were inoculated with 10 ml of bovine respiratory syncytial virus (BRSV) inoculum (10(2.7) to 10(3.8) cell culture infective doses/ml) intranasally and 10 ml of BRSV inoculum (10(4.8) to 10(5.9) cell culture infective doses/ml) intratracheally for 4 consecutive days, and 5 other calves were sham-inoculated. Prior to inoculation (day 0) and on days 4, 14, and 30 after the last inoculation, body weight (kg), dynamic compliance (Cdyn), pulmonary resistance (RL), and 2 indices of airway reactivity (effective dose [ED] 65Cdyn and ED200RL) were measured. Control calves gained weight progressively throughout the study, whereas RSV-inoculated calves failed to gain weight for 14 days, but equaled control calf weight by 30 days after inoculation. The Cdyn of control calves increased significantly by 30 days, but did not in the RSV-infected calves. Pulmonary resistance was increased significantly at 4, 14, and 30 days, but was unaffected by sham inoculation. The ED65Cdyn and ED200RL indicated an age-dependent increase in reactivity to histamine and an increase in responsiveness in the infected group beginning at 14 days and persisting until the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization and identification of a bovine respiratory syncytial virus isolated from young calves.

Two identical viruses designated 371 and 375 were recovered from nasal secretions of 2 of 7 calves in a beef cow-calf herd in which calves (45 to 105 days of age) had signs of acute respiratory tract disease. The cytopathic, morphologic and physico-chemical characteristics of the isolates were those of bovine respiratory syncytial virus. Although a humoral antibody response to bovine respiratory syncytial virus was not observed, it was concluded that this virus probably had a part in the respiratory tract disease in these calves.     

T-cell populations responsive to bovine respiratory syncytial virus in seronegative calves

Calves lacking detectable serum antibodies against bovine respiratory syncytial virus (BRSV) were screened for virus-specific T-cell memory. Peripheral blood mononuclear cells were cultured in vitro with live BRSV and analyzed by dual-color flow cytometry for surface expression of CD25 on CD4(+), CD8(+), and gammadeltaT-cells. Significant recall responses were detected in some of the seronegative calves. Modified live BRSV vaccine was administered to these and to a group of non-responding calves. Following vaccination, virus-specific IgG, virus neutralizing antibody, and T-cell recall responses were all elevated more rapidly in the group with BRSV-sensitive T-cells than in the T-cell-negative group, which suggested that calves in the first group were previously exposed to BRSV. This demonstrates that exposure to BRSV can induce T and B cell memory in young calves without causing seroconversion. The calves were presumably exposed to BRSV while they had maternal antibody, which inhibited the calves from developing an antibody response.     

Experimental bovine respiratory syncytial virus infection in conventional calves: ultrastructural respiratory lesions

The morphogenesis and repair of airway and alveolar injury induced by bovine respiratory syncytial virus (BRSV) was studied ultrastructurally in conventional calves to characterize pulmonary cell types susceptible to viral infection and cytopathologic changes associated with infection. Viral nucleocapsids and budding virions were present in tracheal and bronchial ciliated and nonciliated epithelial cells and mucous cells 3, 5, and 7 days after inoculation and in bronchiolar ciliated and nonciliated epithelial cells 5 days after inoculation. Mild interstitial pneumonia was observed 5 days after inoculation and was characterized by swelling of type 1 and type 2 alveolar epithelial cells, interstitial edema, and infiltration by lymphocytes and macrophages. Viral assembly and release in tracheal and bronchial epithelial cells was associated with loss of cilia from ciliated cells, formation of syncytial epithelial cells, swelling of mitochondria and endoplasmic reticulum, and cell necrosis. Neutrophils, lymphocytes, and macrophages were present in close association with the viral-infected and damaged epithelial cells. There was intercurrent hyperplasia of basal epithelial cells that, in association with other epithelial lesions, resulted in the loss of normal ciliated epithelium in these airways 5 and 7 days after inoculation. Regeneration of airway epithelium was largely completed by 10 days after inoculation, except in 1 of 4 calves that had failure of epithelial repair and that developed secondary bacterial pneumonia. Pulmonary ultrastructure in BRSV-inoculated calves 30 days after inoculation was indistinguishable from that in controls. The results demonstrated that BRSV can induce reversible alterations in airway epithelium, which may cause depression of mucociliary clearance and thereby enhance susceptibility to bacterial infection.     

Flunixin meglumine in calves with natural bovine respiratory syncytial virus infection

Twenty-three calves (three to eight months of age) with serological evidence of bovine respiratory syncytial virus infection were used in this study. The calves originated from four herds with respiratory tract disease. In a double blind trial the calves were injected intravenously with either flunixin meglumine (2 mg/kg body weight) or with a placebo. The effect on the course of disease was measured using the PO2 in capillary blood samples from the ears of the calves and by the effect on body temperature and respiratory rate. Mean body temperature fell significantly in the flunixin meglumine treated group. Statistically significant differences were not found between the treated and control group during the seven-day examination period.     

Protection against bovine respiratory syncytial virus challenge following a single dose of vaccine in young calves with maternal antibody

Twenty-one young calves with maternally derived antibody to bovine respiratory syncytial virus (BRSV) were divided into three groups of seven, each group balanced for BRSV antibody titre. The calves had no evidence of previous exposure to BRSV. The calves in one group were given a single dose of a monovalent modified live BRSV vaccine; the calves in the second group were given a single dose of an inactivated combined BRSV, parainfluenza virus type 3, Mannheimia haemolytica vaccine and the calves in the third group were left as unvaccinated controls. Three weeks after the single doses of vaccine, all the calves were challenged with BRSV. The clinical signs of disease were mild, and virus excretion was limited to two calves in the group given the inactivated vaccine, compared with six in the negative controls (P = 0.05) and five in the group given the live vaccine. The mean virus excretion titres after the challenge were not significantly different between the groups. There was little seroconversion before the challenge, but six of the seven calves in the group given the inactivated vaccine showed significant seroconversion within two weeks after the challenge, compared with only one calf in each of the other two groups (P = 0.015).     

Evaluation of efficacy of an inactivated vaccine against bovine respiratory syncytial virus in calves with maternal antibodies

OBJECTIVE: To assess short- and long-term efficacy of an inactivated bovine respiratory syncytial virus (BRSV) vaccine administered i.m. to calves with maternally derived antibodies. ANIMALS: 28 two-week-old calves with neutralizing, maternally derived antibodies against BRSV. PROCEDURE: For evaluation of short-term efficacy, 6 calves were vaccinated i.m. at 2 and 6 weeks of age and challenged intranasally and intratracheally along with a matched group of 4 unvaccinated control calves at 10 weeks of age. For evaluation of long-term efficacy, 2 groups of 6 calves each were vaccinated i.m. at 2, 6, and 18 weeks of age or 14 and 18 weeks of age; these calves were challenged intranasally and intratracheally along with 6 matched unvaccinated control calves at 43 weeks of age. Serum virus neutralizing antibody titer, clinical reactions, and virus shedding in nasal mucus and lung washings were assessed. RESULTS: None of the vaccination regimens resulted in a significant increase in serum virus neutralizing antibody titer. As judged by virus shedding in nasal mucus and lung washings, vaccinated calves were protected against challenge, compared with unvaccinated control groups. Clinical signs attributable to challenge were coughing (short-term efficacy study) and tachypnea and dyspnea (long-term efficacy study). The severity and incidence of disease were significantly lower in the vaccinated groups, compared with that in the unvaccinated groups. CONCLUSIONS AND CLINICAL RELEVANCE: Through vaccination, it is possible to protect vulnerable calves with maternal antibodies against BRSV infection and reduce respiratory tract disease.     

Clinical and pathological observations on spontaneous bovine respiratory syncytial virus infections in calves

A clinical, pathological and microbiological study was made of acute spontaneous bovine respiratory syncytial virus infection in calves. Characteristic features were atelectatic areas, which had an exudative and, or, necrotising bronchiolitis with syncytial giant cells in the epithelial lining and in the lumina of these bronchioles. Restricted to these areas both bronchiolar and alveolar immunofluorescence for bovine respiratory syncytial virus were seen. Complications were severe interstitial oedema, interstitial emphysema and a catarrhal or fibrinous pneumonia due to secondary bacterial invasion.     

Human and bovine respiratory syncytial virus vaccine research and development

Human (HRSV) and bovine (BRSV) respiratory syncytial viruses (RSV) are two closely related viruses, which are the most important causative agents of respiratory tract infections of young children and calves, respectively. BRSV vaccines have been available for nearly 2 decades. They probably have reduced the prevalence of RSV infection but their efficacy needs improvement. In contrast, despite decades of research, there is no currently licensed vaccine for the prevention of HRSV disease. Development of a HRSV vaccine for infants has been hindered by the lack of a relevant animal model that develops disease, the need to immunize immunologically immature young infants, the difficulty for live vaccines to find the right balance between attenuation and immunogenicity, and the risk of vaccine-associated disease. During the past 15 years, intensive research into a HRSV vaccine has yielded vaccine candidates, which have been evaluated in animal models and, for some of them, in clinical trials in humans. Recent formulations have focused on subunit vaccines with specific CD4+ Th-1 immune response-activating adjuvants and on genetically engineered live attenuated vaccines. It is likely that different HRSV vaccines and/or combinations of vaccines used sequentially will be needed for the various populations at risk. This review discusses the recent advances in RSV vaccine development.     

Effects of a single intranasal dose of modified-live bovine respiratory syncytial virus vaccine on resistance to subsequent viral challenge in calves

OBJECTIVE: To determine whether a single intranasal dose of modified-live bovine respiratory syncytial virus (BRSV) vaccine protects calves from BRSV challenge and characterize cell-mediated immune response in calves following BRSV challenge. ANIMALS: 13 conventionally reared 4- to 6-week-old Holstein calves. PROCEDURES: Calves received intranasal vaccination with modified live BRSV vaccine (VC-group calves; n = 4) or mock vaccine (MC-group calves; 6) 1 month before BRSV challenge; unvaccinated control-group calves (n = 3) underwent mock challenge. Serum virus neutralizing (VN) antibodies were measured on days -30, -14, 0, and 7 relative to BRSV challenge nasal swab specimens were collected for virus isolation on days 0 to 7. At necropsy examination on day 7, tissue specimens were collected for measurement of BRSV-specific interferon gamma (IFN-gamma) production. Tissue distribution of CD3+ T and BLA.36+ B cells was evaluated by use of immunohistochemistry. RESULTS: The MC-group calves had significantly higher rectal temperatures, respiratory rates, and clinical scores on days 5 to 7 after BRSV challenge than VC-group calves. No difference was seen between distributions of BRSV in lung tissue of VC- and MC-group calves. Production of BRSV-specific IFN-gamma was increased in tissue specimens from VC-group calves, compared with MC- and control-group calves. Virus-specific IFN-gamma production was highest in the mediastinal lymph node of VC-group calves. Increased numbers of T cells were found in expanded bronchial-associated lymphoid tissue and airway epithelium of VC-group calves. CONCLUSIONS AND CLINICAL RELEVANCE: An intranasal dose of modified-live BRSV vaccine can protect calves against virulent BRSV challenge 1 month later.     

Efficacy of an intranasal modified live bovine respiratory syncytial virus and temperature-sensitive parainfluenza type 3 virus vaccine in 3-week-old calves experimentally challenged with PI3V

Two experimental parainfluenza type 3 virus (PI3V) challenge studies were undertaken to evaluate the efficacy of a single intranasal dose of an attenuated live vaccine containing modified live bovine respiratory syncytial virus (BRSV) and temperature-sensitive PI3V in 3-week-old calves. In the first study, vaccine efficacy was evaluated in colostrum deprived calves. Nasal shedding of PI3V was highly significantly reduced in vaccinated calves challenged 10 days or 21 days after vaccination. In the second study, vaccine efficacy was assessed in calves with maternal antibodies against PI3V by challenge 66 days post-vaccination. Vaccination also significantly reduced PI3V excretion after challenge in this study. In both studies, clinical signs after challenge were very mild and were not different between vaccinated and control calves.     

Pulmonary lesions induced by 3-methylindole and bovine respiratory syncytial virus in calves

Our objectives were to describe the ultrastructural morphogenesis of pulmonary lesions induced by 3-methylindole in 30- to 45-day-old Holstein calves and to determine whether toxic exposure to 3-methylindole exacerbates pulmonary lesions induced by bovine respiratory syncytial virus. Administration of 3-methylindole (0.25 g/kg) to calves resulted in interstitial edema and ultrastructural swelling of type-I alveolar epithelial cells and nonciliated bronchiolar epithelial cells as early as 4 to 6 hours after intraruminal administration. More severe alveolar edema containing protein was associated with swelling of capillary endothelial cells at 2 days after administration. Proliferation of type-II alveolar epithelial cells was first observed at 2 days after 3-methylindole administration, and marked hyperplasia of type-II epithelial cells and nonciliated bronchiolar epithelial cells was evident by 4 days after administration. Pulmonary cytochrome P-450 monooxygenase concentrations decreased significantly (P less than 0.001) by 12 hours after administration and did not increase significantly again by 8 days after administration. Calves were inoculated with bovine respiratory syncytial virus 3 days after administration of 3-methylindole, and pulmonary lesions were assessed 5 days after viral inoculation. Viral replication was demonstrated by fluorescence microscopy for viral antigen or by transmission electron microscopy in ciliated and nonciliated airway epithelial cells. Viral antigen was identified infrequently in alveolar macrophages and in type-II alveolar epithelial cells. 3-Methylindole exposure in calves did not result in more widespread distribution of viral antigen in alveolar tissue of respiratory syncytial virus-inoculated calves or in significant enhancement of viral pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)