Systemic and secretory antibody responses to sequential bovine respiratory syncytial virus infections in vaccinated and nonvaccinated calves

To investigate the influence of humoral immunity on the severity of disease caused by infection with bovine respiratory syncytial virus (BRSV), an experimentally induced infection study was performed on vaccinated and nonvaccinated calves. Fifteen weanling calves were allotted to 3 groups: 1 group of 6 calves was exposed to 2 live virus aerosols, 35 days apart; another group of 6 calves was vaccinated prior to the same aerosol exposures; and the remaining 3 calves served as controls. Clinical signs of infection were converted to a numerical score for evaluating disease severity. For 14 days after each virus exposure, BRSV-specific IgG and IgM concentrations in serum and BRSV-specific IgA concentration in nasopharyngeal exudate and lung lavage fluid were measured by ELISA. Serum BRSV-specific IgG and IgM and secretory BRSV-specific IgA concentrations did not correlate with disease sign expression. There was a strong correlation between viral isolation and disease scores. Vaccination prior to virus exposure appeared to have little or no effect on severity of the disease, but it did appear to affect disease persistence. Findings indicate that the immunoglobulins evaluated may be primarily protective in nature and do not contribute to disease severity.     

Effects of allergen challenge on plasma concentrations of prostaglandins, thromboxane B2, and histamine in calves infected with bovine respiratory syncytial virus.

To examine the influence of allergen-induced type-1 hypersensitivity on the pathogenesis of bovine respiratory syncytial virus (BRSV) infection, we sensitized calves by aerosol to Micropolyspora faeni (MF) and challenge exposed them during infection with BRSV. The development of MF-specific IgE serum concentrations was confirmed by ELISA. The dynamics of arachidonic acid metabolism and histamine release during a type-1 hypersensitivity reaction in the bovine lung were studied by quantitating the concentrations of prostaglandin (PG)E2, PGF2 alpha, PGI2 as 6-keto-PGF1 alpha, thromboxane (TX) A2 as TXB2, and histamine in plasma of BRSV-infected and/or MF-sensitized/challenge-exposed calves. Four treatment groups were established: (1) BRSV infection only, (2) aerosol sensitization to MF followed by BRSV infection and aerosol challenge exposure to MF, (3) MF aerosol sensitization and challenge exposure without BRSV infection, and (4) aerosol sensitization to MF followed by BRSV infection without MF challenge exposure. Significantly increased concentrations of PGI2 were associated with MF aerosol exposure, particularly when combined with BRSV infection in group 2. After MF challenge exposure, TXB2 concentrations were significantly greater in the virus and MF challenge-exposed group 2. Individual calf data for the change in MF-specific IgE concentration between the first and second MF challenge exposures and the change in PGE2 concentration 30 minutes after the second MF challenge exposure had a highly significant direct correlation. Histamine concentrations were significantly greater in calves infected with BRSV than in uninfected controls regardless of MF exposure. These data further substantiate the thesis that implicates type-1 hypersensitivity as a pathogenic mechanism in BRSV-related disease.     

Immune mechanisms of pathogenetic synergy in concurrent bovine pulmonary infection with Haemophilus somnus and bovine respiratory syncytial virus

Bovine respiratory syncytial virus (BRSV) and Haemophilus somnus are two bovine respiratory pathogens that cause disease singly or as part of a polymicrobial infection. BRSV infection is often associated with a predisposition towards production of a T helper type 2 (Th2) response and IgE production. In contrast, an IgG2 response to H. somnus has been shown to be most important for recovery. An experiment was performed to evaluate the hypothesis that infection with H. somnus on day 6 of experimental BRSV infection would result in disease enhancement and potentially an altered immune response when compared with single infection. Three groups of calves were either dually infected or singly infected with H. somnus or BRSV. Serum and bronchoalveolar lavage fluid (BALF) pathogen specific IgG1, IgG2, IgE, and IgA responses were evaluated by ELISA. TaqMan RT-PCR was used to examine cytokine gene expression by PBMC and BAL cells. Clinical signs were evaluated for 28 days after BRSV infection, followed by necropsy and histological examination of the lungs. In dually infected calves, disease was significantly more severe, H. somnus was isolated from the lungs at necropsy, and high IgE and IgG responses were detected to H. somnus antigens. Cytokine profiles on day 27 were elevated in dually infected calves, but did not reflect a skewed profile. These results contrasted with singly infected calves that were essentially normal by day 10 of infection and lacked both lung pathology and the presence of H. somnus in the lung at necropsy. The increase in IgE antibodies specific for antigens of H. somnus presents a possible mechanism for pathogenesis of the disease enhancement.     

Alternaria aerosol during a bovine respiratory syncytial virus infection alters the severity of subsequent re-infection and enhances IgE production

BACKGROUND: Previous studies with cattle and rodent models have shown that bovine and human RSV infections influence the immune response to inhaled allergen. In the present study, we extended these observations to examine the effect of fungal allergen Alternaria alternata aerosol exposure (prior to and during BRSV infection) on the immune response and clinical outcome of a secondary BRSV infection. METHODS: Calves were either Alternaria (Alt)/mock Alt (mAlt) and BRSV/mBRSV exposed. Exposures began on day -6 and continued every other day until day 6 post infection. A second set of aerosols/infection began on day 103 and continued as before. Clinical outcome during infections was measured in each group. IgG1, IgA, and IgE responses to Alternaria were measured in serum or bronchiolar alveolar lavage fluid (BALF). Cytokine responses, including IL-4, were also measured. RESULTS: Alternaria did not influence primary infection; however, the Alt/BRSV group had less disease than mAlt/BRSV group (median clinical score 8 vs 476.5; p相似文献   

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.     

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.     

Increased pulmonary secretion of tumor necrosis factor-alpha in calves experimentally infected with bovine respiratory syncytial virus

Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease among calves in the Danish cattle industry. An experimental BRSV infection model was used to study the pathogenesis of the disease in calves. Broncho alveolar lung lavage (BAL) was performed on 28 Jersey calves, of which 23 were experimentally infected with BRSV and five were given a mock inoculum. The presence of the cytokine tumor necrosis factor alpha (TNF-alpha) in the BAL fluids was detected and quantified by a capture ELISA. TNF-alpha was detected in 21 of the infected animals. The amount of TNF-alpha in the BAL fluid of calves killed post inoculation day (PID) 2 and 4 was at the same very low level as in the uninfected control animals. Large amounts of TNF-alpha were detected on PID 6, maximum levels of TNF-alpha were reached on PID 7, and smaller amounts of TNF-alpha were seen on PID 8. The high levels of TNF-alpha appeared on the days where severe lung lesions and clinical signs were obvious and the amounts of BRSV-antigen were at their greatest. Although Pasteurellaceae were isolated from some of the BRSV-infected calves, calves treated with antibiotics before and through the whole period of the infection, as well as BRSV-infected calves free of bacteria reached the same level of TNF-alpha as animals from which bacteria were isolated from the lungs. It is concluded that significant quantities of TNF-alpha are produced in the lungs of the calves on PID 6-7 of BRSV infection. The involvement of TNF-alpha in the pathogenesis of, as well as the anti-viral immune response against, BRSV infection is discussed.     

Prostaglandin and thromboxane concentrations in plasma and lung lavage fluids during sequential infection of vaccinated and nonvaccinated calves with bovine respiratory syncytial virus

The potential action of immunologic reactions and mediators released during the course of bovine respiratory syncytial virus infection in pathogenesis of the ensuing disease process was examined in an experimental infection study. Prostaglandin (PG) E2, PGF2 alpha 6-keto-PGF1 alpha, and thromboxane B2 (TxB2) concentrations were quantitated in plasma and lung lavage fluid by radioimmunoassay at 3- to 4-day intervals during a primary and secondary virus infection of vaccinated, nonvaccinated, and control (mock-infected) calves. A significant increase in the plasma PGE2 concentration for the nonvaccinated calves was noticed on day 3 after primary infection and on day 7 after secondary infection. The PGF2 alpha plasma concentrations increased significantly for the nonvaccinated groups on day 10 after primary infection. Plasma 6-keto-PGF1 alpha concentrations increased for nonvaccinated and vaccinated calves 3 days after the secondary infection. Plasma TxB2 concentrations during the primary exposure did not vary significantly. However, 14 days after the secondary exposure, both experimental groups had concentrations significantly greater than did the control group. Lung lavage fluid concentrations of TxB2 had peaks of activity 7 days after primary and secondary viral infections for the nonvaccinated group. Increases in plasma PG concentrations corresponded variably with disease expression, whereas plasma TxB2 concentrations did not have any correlation with disease expression. However, there was a significant correlation between TxB2 concentration in lung lavage fluid of the nonvaccinated group with disease expression 7 days after primary and secondary virus infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

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).     

Inhibition of priming for bovine respiratory syncytial virus-specific protective immune responses following parenteral vaccination of passively immune calves

The effect of maternal antibodies (MatAb) on immunological priming by neonatal parenteral vaccination for bovine respiratory syncytial virus (BRSV) was addressed for the first time in experimental infection in 34 Holstein calves. Both vaccinated and control calves developed moderate to severe respiratory disease characteristic of acute BRSV infection. There were no differences in clinical signs, BRSV shed, arterial oxygen concentrations, or mortality between vaccinated and control calves after BRSV challenge approximately 11 wk after vaccination. There were no anamnestic antibody or cytokine responses in the vaccinates after challenge. Lung lesions were extensive in both groups, and although there was a statistically significant (P = 0.05) difference between groups, this difference was considered not biologically significant. These data indicate that stimulation of protective immune responses was inhibited by maternal antibodies when a combination modified-live BRSV vaccine was administered parenterally to young passively immune calves. Alternate routes of administration or different vaccine formulations should be used to successfully immunize young calves with good passive antibody transfer.     

Antibody response of calves to immunoaffinity-purified bovine respiratory syncytial virus VP70 after vaccination and challenge exposure.

Immunoaffinity-purified bovine respiratory syncytial virus (BRSV) fusion (F) protein elicited anti-BRSV-specific antibody responses in BRSV-seronegative calves. After primary vaccination, all calves seroconverted to BRSV as determined by the virus neutralization (VN) test and developed anti-F protein antibodies detectable by protein immunoblot analyses. Subsequent vaccinations induced greater than twofold increase in VN titer in 3 of 9 (33%) calves, and 1 calf became VN-negative, but still had nonneutralizing antibody detectable by protein immunoblot analysis. This calf remained seronegative after challenge exposure. Two groups of calves were vaccinated IM with immunoaffinity-purified BRSV F protein. Each dose was 2 ml containing 20 micrograms of purified F protein. Freund's adjuvants were used for all vaccinations, with Freund's complete adjuvant used for the primary vaccination and Freund's incomplete adjuvant for subsequent vaccinations. The vaccine was administered to both groups at weeks 0 and 3; the first group received a third vaccination at weeks 21. Group-1 and -2 vaccinated calves and non-vaccinated contact controls were intranasally aerosol challenge-exposed with low cell culture-passage BRSV on weeks 22 and 9, respectively. Eight of 9 vaccinated calves did not develop a humoral anamnestic response following challenge exposure, as demonstrated by VN test and protein immunoblot analyses. Calf 14 from group 1 which had a 1:2 VN antibody titer prior to vaccination, was the only calf that developed an anamnestic response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response of calves to challenge exposure with virulent bovine respiratory syncytial virus following intranasal administration of vaccines formulated for parenteral administration

OBJECTIVE: To determine whether single-fraction and combination modified-live bovine respiratory syncytial virus (BRSV) vaccines commercially licensed for parenteral administration could stimulate protective immunity in calves after intranasal administration. DESIGN: Randomized controlled trial. ANIMALS: 39 calves. PROCEDURES: Calves were separated from dams at birth, fed colostrum with a minimal concentration of antibodies against BRSV, and maintained in isolation. In 2 preliminary experiments, 9-week-old calves received 1 (n = 3) or 2 (3) doses of a single-component, modified-live BRSV vaccine or no vaccine (8 control calves in each experiment), and were challenged with BRSV 21 days after vaccination. In a third experiment, 2-week-old calves received combination modified-live virus (MLV) vaccines with or without BRSV and calves were challenged with BRSV 8 days later. Calves were euthanized, and lung lesions were measured. Immune responses, including serum and nasal antibody and nasal interferon-alpha concentrations, were assessed. RESULTS: BRSV challenge induced signs of severe clinical respiratory tract disease, including death and pulmonary lesions in unvaccinated calves and in calves that received a combination viral vaccine without BRSV. Pulmonary lesions were significantly less severe in BRSV-challenged calves that received single or combination BRSV vaccines. The proportion of calves that shed virus and the peak virus titer was decreased, compared with control calves. Protection was associated with mucosal IgA antibody responses after challenge. CONCLUSIONS AND CLINICAL RELEVANCE: Single and combination BRSV vaccines administered intranasally provided clinical protection and sparing of pulmonary tissue similar to that detected in response to parenteral delivery of combination MLV and inactivated BRSV vaccines previously assessed in the same challenge model.     

A severe outbreak of respiratory tract disease associated with bovine respiratory syncytial virus probably enhanced by vaccination with modified live vaccine

A severe outbreak of respiratory tract disease associated with bovine respiratory syncytial virus (BRSV) on a large beef-fattening farm is described. The outbreak started two days after five- to seven-month-old calves were vaccinated with a modified live BRSV vaccine. The disease ran a very severe course among five- to seven-month-old vaccinated calves, but disease was absent in eight-month-old an older non-vaccinated calves. The presence of IgM antibodies in sera of non-vaccinated calves indicated that BRSV was spreading on the farm between two to 15 days before the day of vaccination. The data indicate that vaccination with modified live vaccine during the course of a natural infection may enhance the severity of disease. The possible pathogenesis of the disease is discussed.     

Evaluation of a quadrivalent inactivated vaccine for the protection of cattle against diseases due to common viral infections

Efficacy of an inactivated quadrivalent vaccine containing infectious bovine rhinotracheitis (IBR) virus, parainfluenza type 3 (PI3) virus, bovine virus diarrhoea virus (BVDV) and bovine respiratory syncytial virus (BRSV) was assessed in naive bovine calves to evaluate short-term (4-18 weeks) and long-term (24-38 weeks) protection following the basic intramuscular vaccination regime of 2 inoculations a month apart. Vaccination was staggered between the long-term and the short-term groups by about 5 months so that both groups, along with a matched group of 6 unvaccinated (control) calves, could be challenged at the same time. Sequential challenges at intervals of 3-8 weeks were done in the order: IBR virus (intranasally, IN), PI3 virus (IN and intratracheally, IT), pestiviruses (IN) and BRSV (IN and IT). The IBR virus challenge produced febrile rhinotracheitis (FRT) in control calves but both the severity and the duration of FRT was significantly reduced in both vaccinated groups. The amount and the duration of IBR virus shed by the vaccinated groups was significantly reduced compared to the control group. Although PI3 virus, pooled pestivirus and BRSV challenges did not result in a noteworthy disease, challenge virus shedding (amount and duration) from the upper (all 3 viruses) and the lower (BRSV) respiratory tracts was significantly reduced in vaccinated groups. After pestivirus challenge, sera and leukocytes from all control calves were infectious for 6-9 days whereas virus was recovered only from leukocytes in vaccinated calves and only for 1.6-2.7 days. Thus a standard course of the quadrivalent vaccine afforded a significant protection against IBR virus, PI3 virus, BVDV and BRSV for at least 6 months.     

A severe outbreak of respiratory tract disease associated with bovine respiratory syncytial virus probably enhanced by vaccination with modified live vaccine

Summary

A severe outbreak of respiratory tract disease associated with bovine respiratory syncytial virus (BRSV) on a large beef‐fattening farm is described. The outbreak started two days after five‐ to seven‐month‐old calves were vaccinated with a modified live BRSV vaccine. The disease ran a very severe course among five‐ to seven‐month‐old vaccinated calves, but disease was absent in eight‐month‐old an older non‐vaccinated calves. The presence of IgM antibodies in sera of non‐vaccinated calves indicated that BRSV was spreading on the farm between two to 15 days before the day of vaccination. The data indicate that vaccination with modified live vaccine during the course of a natural infection may enhance the severity of disease. The possible pathogenesis of the disease is discussed.     

Evaluation of severe disease induced by aerosol inoculation of calves with bovine respiratory syncytial virus

OBJECTIVE: To develop a model of bovine respiratory syncytial virus (BRSV) infection that induces severe disease similar to that seen in some cattle with naturally acquired BRSV infection. ANIMALS: 25 male Holstein calves, 8 to 16 weeks old. PROCEDURE: 17 calves were given a low-passage field isolate of BRSV by aerosolization; 8 control calves were given supernatant from noninfected cell culture. Disease was characterized by evaluating clinical signs, virus isolation and pulmonary function tests, and results of blood gas analysis, gross and histologic postmortem examination, and microbiologic testing. RESULTS: Cumulative incidence of cough, harsh lung sounds, adventitious sounds, and dyspnea and increases in rectal temperature and respiratory rate were significantly greater in infected calves. Three infected calves developed extreme respiratory distress and were euthanatized 7 days after inoculation. Virus was isolated from nasal swab specimens from all infected calves but not from mock infected calves. On day 7 after inoculation, mean PaO2 and PaCO2 were significantly lower, and pulmonary resistance was significantly higher, in infected calves. During necropsy, infected calves had varying degrees of necrotizing and proliferative bronchiolitis and alveolitis with syncytial formation. The 3 calves euthanatized on day 7 had emphysematous bullae in the caudal lung lobes; 1 had unilateral pneumothorax. CONCLUSION AND CLINICAL RELEVANCE: Severe disease similar to that seen in some cattle with naturally acquired BRSV infection can be induced in calves with a single aerosol exposure of a low-passage clinical isolate of BRSV. Our model will be useful for studying the pathogenesis of BRSV infection and for evaluating vaccines and therapeutics.     

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.