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Paper
Paper Field study of pneumonia in vaccinated cattle associated with incorrect vaccination and Pasteurella multocida infection W. M. Crawshaw, G. L. Caldow This field study used data on the vaccine courses against bovine respiratory disease sold by one pharmaceutical company in conjunction with pharmacovigilance data to explore reported suspected lack of expected efficacy and the reasons for this. The study ran from May 1, 2007, to April 30, 2010, and covered vaccines sold in Scotland and part of Northumberland. In total, 83 groups of cattle reported suspected lack of expected efficacy, representing 1.6 per cent of the 804,618 vaccine courses sold. It was possible to investigate 45 of these outbreaks in depth using a standard questionnaire and diagnostic protocol. Vaccine usage outwith the specific product characteristics (SPC) occurred in 47 per cent of cases (21/45). The proportion of vaccination courses used where a pathogen contained in the vaccine was detected in the diseased cattle and vaccine use was consistent with the SPC was estimated at 0.12 per cent of the courses sold. Pasteurella multocida was the most common pathogen detected and was found in 21 of the outbreaks. For outbreaks where a pathogen contained in the vaccine was detected, P. multocida was found at a significantly greater frequency (P=0.03) where vaccine use was compliant with the SPC (five of six outbreaks) compared with outbreaks where vaccine use had not been compliant with the SPC (one of seven outbreaks). The limitations of the study, including the diagnostic tests employed and definition of vaccination outwith the SPC, are discussed.
Vaccination as a control method for bovine respiratory disease (BRD) has been increasingly adopted in the UK, as indicated by the number of BRD vaccine courses sold by all manufacturers in 2012 compared with 2002, which showed an estimated increase of 36 per cent over this period (Pfizer Animal Health (2002, 2012); Market Report, Walton-on-the-Hill, personal communication). The evidence to support vaccination as an intervention is largely based on experimental challenge trials that have assessed immune response, clinical disease and pathogen shedding, often with encouraging results (e.g. Vangeel and others 2007). In contrast, there are few field studies investigating BRD vaccine efficacy. Field studies are difficult to conduct due to the potential for extensive confounding, variability in risk factors for BRD between farms, the multifactorial nature of BRD and inadequate methods for diagnosis (Taylor and others 2010). Furthermore, in the UK, the relatively small group sizes and numbers of replicates typically available limit statistical power. Two reviews of
field studies of vaccination against BRD concluded that evidence of efficacy is equivocal (Mosier and others 1989, Perino and Hunsaker 1997). This study sought to estimate the proportion of cattle vaccinated against BRD using any of the nine vaccines marketed by one pharmaceutical company that were in groups spontaneously reported with BRD; to investigate how the vaccines had been used compared with the directions in their specific product characteristics (SPC) and also to investigate which BRD pathogens were present in affected cattle using a standard laboratory diagnostic protocol. Studies of this type have not been previously reported but have value in quantifying the failure rate of BRD vaccines and offering potential explanations for failure of vaccination to prevent BRD that could be the subject of further research.
Materials and methods Veterinary Record (2015) W. M. Crawshaw, BVetMed DCHP DipECBHM MRCVS, Pfizer Animal Health (now Zoetis UK Ltd), Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS, UK MBM Veterinary Group, 21 Hill Street, Kilmarnock, Ayrshire KA3 1HF, UK (current address) G. L. Caldow, BVM&S MSc DipECBHM CertCHP MRCVS FRAgS,
doi: 10.1136/vr.102701 SAC Consulting Veterinary Services, Greycrook, Melrose, St.Boswells, Roxburghshire TD6 0EU, UK E-mail for correspondence: [email protected] Provenance: not commissioned; externally peer reviewed Accepted February 9, 2015
All veterinary practices in Scotland and one in north Northumberland were included in the study. The study period was May 1, 2007, to April 30, 2010. The denominator for the proportion of vaccinated cattle that were identified in groups with BRD was estimated from the number of courses of the nine vaccines (Table 1) produced by one pharmaceutical company (Pfizer Animal Health) sold to these practices during the study period using sales data from the company. For vaccines licensed for a two-dose primary course only, or in the case of vaccine 7 where a single- or two-dose primary course was licensed, the number of vaccination courses was calculated by dividing the number of doses sold by two. 10.1136/vr.102701 | Veterinary Record | 1 of 7
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Paper TABLE 1: For the nine vaccines included in the study, the antigens and the number of doses for primary and booster vaccination recommended in the specific product characteristics of each vaccine Vaccine
Vaccine trade name
Live antigen(s)
1 2 3
Rispoval 4 Rispoval 3 Rispoval Pasteurella
BRSV, PI3 BRSV, PI3
4 5 6 7 8
Rispoval IntraNasal RS+PI3 Imuresp RP Tracherine Rispoval IBR marker live Rispoval IBR marker inactivated Rispoval RS
BRSV, PI3 BoHV-1, PI3 BoHV-1 BoHV-1 (gE deleted)
9
Inactivated antigen(s)
Primary course doses
Booster doses
BoHV-1, BVD BVD Leukotoxoid and capsular antigens of MAHA
2 2 1
None licensed None licensed None licensed
1 1 1 1 or 2 2
None licensed None licensed None licensed 1 1
2
None licensed
BoHV-1 (gE deleted) BRSV
BoHV-1, bovine herpesvirus 1; BRSV, bovine respiratory syncytial virus; BVDV, bovine virus diarrhoea virus; gE, glycoprotein E; MAHA, Mannheimia haemolytica; PI3, parainfluenza virus type 3
For the single-dose vaccines, the number of vaccination courses was equal to the number of doses of vaccine sold. The numerator for estimating the proportion of vaccinated cattle that were identified in groups with BRD was the sum of the number of vaccine courses administered to both affected and unaffected cattle in each affected group. An affected group was vaccinated with any of the nine BRD vaccines and was also reported to the UK Suspected Adverse Reaction Surveillance Scheme (SARSS) due to suspected lack of expected efficacy either directly to the company or via the UK Veterinary Medicines Directorate. For all outbreaks, an attempt was made to collect basic epidemiological information specific to the affected group from the reporting veterinary surgeon by the company’s pharmacovigilance staff using a standardised data collection form. The information included dates of vaccination, age range of calves when vaccinated, batch number of vaccine used, expiry date of vaccine, concurrent treatments or vaccinations, date of onset of first case of BRD, number of cattle in the affected group and production class of cattle (e.g. suckled calves, dairy calves, finishing cattle). Consistent collection of more detailed information from a large number of veterinarians and farmers managing disease outbreaks under commercial farming conditions was not considered possible. Where the reporting veterinary surgeon was unable to supply accurate information on group size (n=13), the median group size of all the other groups of cattle that were included in the study and in the same production class was used for the calculations for this group. The collected data were used to calculate the proportion of courses administered to groups that were recognised to have experienced BRD. For outbreaks where the attending veterinary practitioner and farmer were willing to supply complete epidemiological information, collect the diagnostic samples and animals that met the sampling criteria were available, a standard laboratory investigation was performed according to the following protocol. In live cattle in the affected group, the attending veterinary practitioner collected bronchoalveolar lavage (BAL) samples from two to four recently affected ( pyrexic temperature ≥39.5°C and clear nasal and/or ocular discharge) untreated cattle. From the same cattle, a nasopharyngeal swab was submitted in virus transport medium. In some outbreaks where fatalities occurred in the affected group, one to three fresh carcases of recently affected cattle were submitted in addition to the above or as an alternative. All laboratory investigations were conducted at the eight veterinary laboratories of the Scottish Agricultural College Consulting: Veterinary Services (SACCVS). Standard culture methods following the standard operating procedures (SOPs) in place at SACCVS for the detection of bacteria and mycoplasmas were used in all BAL samples, and where the lung of any carcase showed gross lesions of pneumonia, the surface of the lesion was seared and sampled aseptically. Indirect fluorescent antibody tests (IFAT) for bovine respiratory syncytial virus (BRSV) and parainfluenza virus type 3 (PI3) were 2 of 7 | Veterinary Record | 10.1136/vr.102701
performed on lung impression smears and cellular deposits from BAL samples and for bovine herpesvirus 1 (BoHV-1) on nasopharyngeal swabs by standard procedures following the SOPs in place at SACCVS. As there were concerns over the specificity of the BoHV-1 conjugate, an aliquot from all samples that yielded a positive BoHV-1 IFAT result was sent to a reference laboratory for further testing by virus isolation, immunocytochemistry or PCR. The diagnostic criteria employed were detection of a recognised pathogenic bacteria or Mycoplasma species by culture, detection of BRSV or PI3 by IFAT and detection of BoHV-1 by virus isolation or PCR or immunocytochemistry in at least one animal in the group that met the case selection criteria. Outbreaks with a standard laboratory investigation were also studied to compare the practice of vaccine administration with the recommendations in the SPC for the vaccine(s) used. For the purpose of analysis where the BRD incident had started before the expected onset of immunity from the vaccine, as detailed in the SPC, this was classified as ‘vaccine use not compliant with the SPC’. For vaccine 4, changes to the SPC made in 2010 in connection with age at vaccination (reduced from 21 to 9 days) and concurrent vaccine use (changed from contraindicated to veterinary judgement on a case-by-case basis) were applied retrospectively to all cases included in the study. Therefore, for this study, concurrent use of another vaccine was assessed as compliant with the SPC. The reported production classes of cattle involved in the BRD outbreaks were recorded.
Statistical analysis For all outbreaks with standard laboratory investigation, the two-tail Fisher’s exact test was used to assess the effect of the class of cattle on compliance with the SPC; if the frequency of 'no diagnosis' was affected by whether the vaccine(s) had been used in compliance with the SPC, detection of multiple pathogens, detection of two pathogens, detection of three pathogens and isolation of different pathogens. For those outbreaks where a pathogen was diagnosed that was also contained in the vaccine, the effect of whether the vaccine(s) had been used in compliance with the SPC on the frequency isolation of different pathogens was examined. The cut-off for statistical significance was taken to be probability greater than or equal to 0.05.
Results The total number of courses of vaccine sold during the study period of May 1, 2007, to April 30, 2010, was 804,618, ranging from 221,460 for vaccine 1 to 10,790 for vaccine 8 (Table 2). Notifications under the UK SARSS for BRD in cattle vaccinated with any of nine bovine respiratory vaccines marketed by the pharmaceutical company during the study period totalled 91 cases of the case type suspected lack of expected efficacy. Eight cases were excluded from analysis because the BRD outbreak had started before any vaccine had been administered (n=2); only one dose of a primary course requiring two doses had been
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Paper TABLE 2: Total number of vaccine courses sold and total courses used in all the 83 BRD outbreaks studied, the 45 outbreaks investigated with a standard laboratory investigation (SLI) and the six outbreaks where a diagnosed pathogen was also contained in the vaccine and the vaccine was used according to specific product characteristics (SPC) Vaccine 1 2 3 4 5 6 7 8 9 Total
Total vaccine courses sold
Total courses used in 83 groups reported with BRD
Total courses used in 45 groups investigated with an SLI
Total courses used in six groups where pathogen diagnosed contained in vaccine and vaccine used according to the SPC
221,460 20,098 101,665 152,820 71,200 199,835 11,120 10,790 15,630 804,618
4531 (2.0) 1850 (9.2) 2229 (2.2) 1476 (1.0) 175 (0.2) 2378 (1.2) 0 (0.0) 50 (0.5) 170 (1.1) 12859 (1.6)
2570 (1.2) 1800 (9.0) 2170 (2.1) 1091 (0.7) 175 (0.2) 2005 (1.0) 0 (0.0) 0 (0.0) 170 (1.1) 9981 (1.2)
440 (0.20) 0 (0.00) 250 (0.25) 165 (0.11) 150 (0.21) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 940 (0.12)
Figures in parenthesis are the percentage of courses of this vaccine sold BRD, bovine respiratory disease
given (n=1); investigation revealed that the disease was not BRD but another diagnosis (n=3); there was no additional information (n=1); or the same outbreak had been reported twice (n=1). This left 83 cases used in the study. The distribution of these cases by month of onset of BRD is shown in Fig 1. October to February showed the highest number of reports, with a peak in November. In 82 of the 83 cases, one or more of the nine vaccines had been used exclusively as respiratory vaccines. The exception was one outbreak where a vaccine from a second company had been used in combination with one of the company’s nine vaccines in 117 cattle. The absence of denominator data precluded these courses from the second company being included in the analysis. Group size information was missing in 13 outbreaks (16 per cent). Group size ranged from 5 to 1700 cattle, with a median of 65 (inter-quartile range: 40–119). In 12 outbreaks comprising 1038 cattle, two vaccines had been used; and in two outbreaks comprising 1765 cattle, three vaccines had been used. It was calculated that the 8408 cattle in 83 groups reported with BRD had received 12,859 courses of one of the nine vaccines from the company (Table 3) and 117 courses of a vaccine from the second company. In the 83 BRD outbreaks, 12,859 courses had been used, representing 1.6 per cent of courses sold over the whole nine vaccine range (Table 2). No standard laboratory investigation was carried out in 38 (42 per cent) of the 83 BRD outbreaks, and in 23 of these the epidemiological information was incomplete. These 38 outbreaks were used only to estimate the proportion of vaccinated cattle that were identified in groups with BRD. The standard laboratory investigation was completed in 45 (58 per cent) of the 83 BRD outbreaks. However, in six outbreaks, culture for Mycoplasma bovis was not carried out (due to laboratory error) and group size information was missing from 35 30
one outbreak. In these outbreaks, 5726 cattle (68.1 per cent of all the cattle in 83 groups where BRD was reported) received 9981 courses of vaccine (Table 3). Group size ranged from 5 to 1700 cattle, with a median of 70 (inter-quartile range: 48–110). In six outbreaks comprising 685 cattle, two vaccines had been used; and in two outbreaks comprising 1765 cattle, three vaccines had been used. The majority of outbreaks investigated involved beef cattle, particularly suckled calves (calves from beef cow herds) and most commonly spring-born calves (48.9 per cent) (Table 4). An approximation of age ranges at BRD onset for the different classes of cattle reported is shown in Table 4. In 21 of the 45 outbreaks (47 per cent), at least one failure to use the vaccine in accordance with the SPC was identified and a total of 27 failures to follow the SPC occurred in these 21 outbreaks (Table 4). However, in eight of these, one failing was that the BRD incident had started before the expected onset of immunity. In three outbreaks, this was the only non-compliance, and if these are excluded, then the number of outbreaks with failure to use the vaccine in accordance with the SPC is 18/45 (40 per cent). The other most common reasons for use outwith the SPC were vaccination of cattle at too early an age (8/21) and unlicensed concurrent vaccine administration (6/21). There was no statistically significant difference for cattle class and SPC compliance. The type of samples collected and examined in the 45 outbreaks where the standard laboratory investigation was carried out is shown in Table 5. In total, 38 carcases, 78 BAL samples and 103 nasopharyngeal swabs were examined. The time of sampling in relation to the first detected case in the outbreak was available for 35 cases and ranged from 0 to 58 days. However, all
TABLE 3: Number of vaccine courses used and number of cattle in all the 83 BRD outbreaks studied, the 45 outbreaks with a standard laboratory investigation (SLI) and the six outbreaks where a diagnosed pathogen was also contained in the vaccine and the vaccine was used according to specific product characteristics (SPC)
25
Total in 45 groups with an SLI (%)
Total in six groups where pathogen diagnosed contained in vaccine and vaccine used according to the SPC (%)
12,859 (100)
9981 (77.6)
940 (7.3)
8408 (100)
5726 (68.1)
650 (7.7)
20 Total in 83 groups reported with BRD (%)
15 10 5 0 Jan
Feb Mar
Apr May Jun
Jul
Aug Sep
Oct
Nov Dec
FIG 1: Month of onset of respiratory disease reported for all the 83 outbreaks studied 2007–2010. The black part of each bar represents the 45 outbreaks with a standard laboratory investigation
Number of courses of vaccine used in reported outbreaks Number of cattle in reported outbreaks
BRD, bovine respiratory disease
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Paper TABLE 4: The number of bovine respiratory disease (BRD) outbreaks by whether one or more of the vaccination courses used was compliant with the specific product characteristics (SPC), reasons for non-compliance, class of cattle and approximate age range in the 45 outbreaks with a standard laboratory investigation
Class of cattle
Reason for non-compliance with the SPC
Approximate age range at time of BRD onset (days)
Vaccinated according to the SPC (%)
Not vaccinated according to the SPC (%)
Total (%)
Fisher’s exact test P value
38–180 187–480 94 55–82
5 (20.8) 1 (4.2) 0 (0.0) 0 (0.0)
1 (4.8) 5 (23.8) 1 (4.8) 3 (14.3)
6 (13.3) 6 (13.3) 1 (2.2) 3 (6.7)
0.19 0.08 0.47 0.09
2 1 3
3
183–270
15 (62.5)
7 (33.3)
22 (48.9)
0.08
1
2
150–245
1 (4.2)
2 (9.5)
3 (6.7)
0.59
1
2
105–300 38–480
2 (8.3) 24 (100.0)
4 (8.9) 45 (100.0)
1.00 NA
8
Dairy bred Finishing unit Heifer rearer Suckled calves: autumn born Suckled calves: spring born Suckled calves: summer born Undefined Total
2 (9.5) 21 (100.0)
A
B
C
D
E
F
4
1
1
1 1
8
2
2
2
6
1 2
A, pneumonia outbreak started before the expected onset of immunity stated in the SPC; B, pneumonia outbreak started after the duration of immunity stated in the SPC had elapsed; C, vaccination of one or more calves commenced at an earlier stage than stated in the SPC; D, the interval between vaccinations was different to that stated in the SPC; E, unlicensed concurrent vaccine administration. For vaccine 4, changes to the 2010 SPC applied retrospectively; F, the route of vaccine administration was different to that stated in the SPC; NA, not applicable
but five outbreaks were sampled 0–7 days after the first detected case. The diagnostic results are presented in Table 6, showing the number of diagnoses by pathogen and whether the vaccine had been used according to the SPC. No diagnosis was made in 10 outbreaks (22.2 per cent). Multiple pathogens were detected in 19 outbreaks (42.2 per cent), most commonly two pathogens, which were detected in 17 outbreaks (37.8 per cent). Bacterial pathogens were detected in 32 of 35 outbreaks where a diagnosis was made; in one outbreak only BoHV-1 was detected and in two only BRSV. The frequency of detection of the different bacterial pathogens did not differ significantly whether or not vaccination was compliant with the SPC. The commonest diagnosis was Pasteurella multocida (a pathogen not included in any of the vaccines used), which was present in 21 (46.7 per cent) outbreaks. Of the agents included in the vaccines, Mannheimia haemolytica was identified in nine outbreaks (20.0 per cent), BoHV-1 and BRSV were each identified in five outbreaks (11.1 per cent) and PI3 in two outbreaks (4.4 per cent). However, the vaccines against these specific pathogens had not been necessarily used in all of these outbreaks. The details of the six outbreaks where the diagnosis was a pathogen contained in one of the vaccines used and the vaccination had been carried out according to the SPC are shown in Tables 7 and 8. Of the pathogens contained in the vaccines, BoHV-1 and BRSV were the commonest diagnoses in this category (each 2/6 outbreaks). P. multocida was also confirmed in 5/6 cases always concurrent with one or more other pathogens. M. bovis was not detected in any of these six outbreaks. In total, the number of vaccinated cattle in the investigated BRD outbreaks where a pathogen contained in the vaccine was diagnosed as a cause of respiratory disease and the vaccine was used in accordance with the SPC varied from 0.0 per cent (vaccines 2, 6, 7, 8 TABLE 5: The sample types submitted and the number of cattle sampled in the 45 outbreaks with a standard laboratory investigation No. of cattle sampled Sample type Total Carcase only Carcase and BAL Carcase and NPS BAL and NPS Carcase and BAL and NPS
No. of outbreaks
Carcase
BAL
NPS
45 19 0 4 19 3
38 25 0 7 NA 6
78 NA 0 NA 69 9
103 NA NA 19 74 10
BAL, bronchoalveolar lavage; NA, not applicable; NPS, nasopharyngeal swab
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and 9) to 0.25 per cent (vaccine 3) and totalled 0.12 per cent (940 courses) over the whole nine vaccine range (Tables 2 and 7). The details of the seven outbreaks where the diagnosis was a pathogen contained in one of the vaccines used and the vaccination had not been carried out according to the SPC are shown in Tables 7 and 9. Of the pathogens contained in the vaccines, BoHV-1 and BRSV were diagnosed in three outbreaks each. M. bovis was confirmed in two outbreaks. P. multocida was detected in one outbreak concurrent with BoHV-1. The three commonest reasons for use outwith the SPC were pneumonia outbreak started before the expected onset of immunity, calves vaccinated at too early an age and unlicensed concurrent vaccine administration. P. multocida was present in 5/6 (83 per cent) outbreaks where the vaccine was used according to the SPC but in only 1/7 (14 per cent) outbreaks where the vaccine was not used according to the SPC (Table 7) and this difference was significant (P=0.03). No other significant difference in the frequency of isolation of different pathogens was identified. BoHV-1 was diagnosed in three outbreaks that were not included in the 45 with a standard laboratory investigation because they were investigated for BoHV-1 only. In two of these outbreaks, vaccines including BoHV-1 had been used (vaccines 1 and 6) but only vaccine 1 had been used in compliance with the SPC.
Discussion The number of vaccine courses used in groups of cattle reported with BRD represented 1.6 per cent of the total courses of vaccine sold during the study period. The suspected adverse reactions surveillance scheme is widely publicised to the UK veterinary profession and is used frequently, particularly for significant BRD outbreaks in cattle vaccinated against BRD. However, it is accepted that not all cases of BRD occurring in vaccinated cattle were reported, particularly where veterinarians were unwilling to report or for groups of cattle experiencing a low incidence of BRD or cases where clinical disease was mild. Farms where BRD did not occur in vaccinated cattle were not studied, and the general prevalence of respiratory disease in cattle in the UK has not been reported. Therefore, it is not possible to compare the prevalence of BRD in the vaccinated cattle included in the study with unvaccinated cattle. The methodology used to estimate the proportion of vaccinated cattle that were identified in groups with BRD may result in four potential sources of error. First, it could not be determined whether all the vaccine doses sold were actually administered during the study period. Secondly, there was potential error associated with reports of BRD in cattle
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Paper TABLE 6: The number of different diagnoses for the 45 BRD outbreaks with a standard laboratory investigation Total outbreak cases No diagnosis Outbreaks with multiple pathogens Outbreaks with two pathogens Outbreaks with three pathogens BoHV-1 PI3 BRSV Histophilus somni Mannheimia haemolytica Mycoplasma bovis Pasteurella multocida Trueperella pyogenes
Vaccination compliant with the SPC (%)
Vaccination not compliant with the SPC (%)
Total (%)
Fisher’s exact test P value
24 (100.0) 7 (29.2) 9 (37.5) 7 (29.2) 2 (8.3) 2 (8.3) 1 (4.2) 2 (8.3) 5 (20.8) 5 (20.8) 1 (4.2) 10 (41.7) 2 (8.3)
21 (100.0) 3 (14.3) 10 (47.6) 10 (47.6) 0 (0.0) 3 (14.3) 1 (4.8) 3 (14.3) 2 (9.5) 4 (19.0) 4 (19.0) 11 (52.4) 0 (0.0)
45 (100.0) 10 (22.2) 19 (42.2) 17 (37.8) 2 (4.4) 5 (11.1) 2 (4.4) 5 (11.1) 7 (15.6) 9 (20.0) 5 (11.1) 21 (46.7) 2 (4.4)
NA 0.30 0.56 0.23 0.49 0.65 1.00 0.65 0.42 1.00 0.17 0.56 0.49
The diagnoses are categorised by whether the vaccination courses used in that group of cattle were compliant with the specific product characteristics (SPC). There was more than one diagnosis in outbreaks with multiple pathogens BoHV-1, BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus; PI3, parainfluenza virus type 3
vaccinated using vaccine sold before the start of the study period and reports of BRD not being included for cattle administered courses near the end of the study period. To minimise the first two potential sources of error, the study period began on May 1, 2007, and ended on April, 30, 2010, because the majority of cattle in the population under study were born in the beef cow herd and could be reasonably expected to be outside during the grazing season where the BRD risk was low and vaccination rarely carried out. This ensured that both the time period when cattle were most likely to be vaccinated and to experience BRD during the period of cover from that vaccination were included. Thirdly, when calculating the number of courses sold from the number of doses sold it was not known what proportions of doses were used for two- or single-dose primary courses or for single-dose boosters. However, the error here is likely to be low as 782,708 of 804,618 (97.3 per cent) of the vaccine doses sold were either licensed only for a two-dose primary course with no option for a single-dose booster (vaccines 1, 2 and 9) or a singledose primary course (vaccines 3, 4, 5 and 6). This methodology may overestimate the incidence of BRD in vaccinated cattle by underestimating the number of cattle vaccinated with vaccines 7 and 9, which could both be boosted with a single dose at sixmonthly intervals and for the former a single-dose primary course is also an option. However, vaccines 7 and 8 showed a low proportion of courses sold (2.7 per cent) during the study period (Table 2), so this error is likely to be small. Fourthly, movement of vaccinated cattle in and out of the region was not known and could not be taken into account; however, the error here is likely to be small also as vaccination before movement
was unusual in the UK during the study period (W. M. Crawshaw and G. L. Caldow, unpublished observations). A high proportion of the total reported BRD outbreaks in vaccinated cattle included in the study were subjected to the standard laboratory investigation (45 of 83 outbreaks comprising 68.1 per cent of the cattle and 77.6 per cent of the total vaccine courses used). Outbreaks with a standard laboratory investigation reported in this study primarily involved beef cattle (36 of 45 outbreaks), and the findings should be extrapolated to dairy cattle with caution. Non-SPC-compliant vaccine use was a frequent finding, accounting for 47 per cent of outbreaks with a standard laboratory investigation. Where this was due to one or more calves initially being vaccinated at too young an age, it should be noted that it was not possible to quantify the proportion of the group that was too young and therefore any influence this may have had. Exclusion of outbreaks where the only non-compliance with the SPC was that BRD occurred before the expected onset of vaccine immunity reduces outbreaks with non-SPC-compliant vaccine use to 40 per cent. Occurrence of BRD before the expected onset of immunity following vaccination stated in the SPC was classified as non-compliance with the SPC because it is stated in most BRD vaccine SPCs that the timing of vaccine administration should allow the onset of immunity before the BRD risk period. Similarly to other non-compliances with SPC, vaccine efficacy could be compromised in these circumstances. Likewise, Meadows (2010) reported that the use of bovine virus diarrhoea virus vaccines outwith the SPC was also common in 71 farms in England, with 21 per cent of farmers using the wrong dose or route of
TABLE 7: The number of different diagnoses for 13 of the 45 BRD outbreaks with a standard laboratory investigation where at least one diagnosis was a pathogen contained in one of the vaccines used Number of outbreak cases No diagnosis Outbreaks with multiple pathogens Outbreaks with two pathogens Outbreaks with three pathogens BoHV-1 PI3 BRSV Histophilus somni Mannheimia haemolytica Mycoplasma bovis Pasteurella multocida Trueperella pyogenes
Vaccination compliant with the SPC (%)
Vaccination not compliant with the SPC (%)
Total (%)
Fisher’s exact test P value
6 (100.0) 0 (0.0) 5 (83.3) 3 (50.0) 2 (33.3) 2 (33.3) 1 (16.7) 2 (33.3) 0 (0.0) 2 (33.3) 0 (0.0) 5 (83.3) 1 (16.7)
7 (100.0) 0 (0.0) 4 (57.1) 4 (57.1) 0 (0.0) 3 (42.9) 0 (0.0) 3 (42.9) 0 (0.0) 2 (28.6) 2 (28.6) 1 (14.2) 0 (0.0)
13 (100.0) 0 (0.0) 9 (69.2) 7 (53.8) 2 (4.4) 5 (38.5) 1 (7.7) 5 (38.5) 0 (0.0) 4 (30.8) 2 (15.4) 6 (46.2) 1 (4.7)
NA NA 0.56 1.00 0.19 1.00 0.46 1.00 NA 1.00 0.46 0.03 0.46
The diagnoses are categorised by whether the vaccination courses used in that group of cattle were compliant with the specific product characteristics (SPC). There was more than one diagnosis in outbreaks with multiple pathogens BoHV-1, BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus; NA, not applicable; PI3, parainfluenza virus type 3 Bold typeface indicates significance.
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Paper TABLE 8: For 6 of the 45 BRD outbreaks with a standard laboratory investigation, where the diagnosis was a pathogen contained in one of the vaccines and vaccination was compliant with the specific product characteristics; the vaccine used, number and class of cattle in the group, doses of vaccine used and the diagnoses Vaccine
Number in group
1 and 3
250
1 and 4 4
40 60
Class of cattle
Number of vaccines used
Total courses used
Suckled calves: summer born Dairy bred Dairy bred
2
500
2 1
80 60
Diagnosis 1
Diagnosis 2
Mannheimia haemolytica BRSV PI3
Pasteurella multocida
5
150
Suckled calves: undefined
1
150
BoHV-1
1
85
Suckled calves: spring born
1
85
BoHV-1
1
65
Suckled calves: spring born
1
65
BRSV
Total
650
Pasteurella multocida Pasteurella multocida Pasteurella multocida Pasteurella multocida
Diagnosis 3
Trueperella pyogenes
Mannheimia haemolytica
940
BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus; PI3, parainfluenza virus type 3
administration and 48 per cent administering the primary two-dose course at the incorrect interval. The proportion of vaccine courses not compliant with the SPC where no BRD was reported is unknown and not available for comparison. Nevertheless, vaccination not complying with the SPC could be expected to reduce vaccine efficacy in the field as recommendations made in the SPC are supported by experimental data approved by licensing authorities and deviations either reduce efficacy or supportive evidence is not available. It should be possible to correct the three commonest SPC breeches identified in this study (pneumonia outbreak starting before the onset of expected immunity, vaccination initiated in one or more cattle too young and unlicensed concurrent vaccine administration) on many farms by considering the choice of vaccine and timing of vaccine administration, including completing vaccination of calves sold for finishing before they are transferred to the finishing unit, along with training and education of veterinary practitioners and farmers. Of the 24 outbreaks investigated where vaccine use was compliant with the SPC, in six (25 per cent) pathogens contained in the vaccine were detected. This represented only 0.12 per cent of all courses sold. These findings might suggest that failure of respiratory vaccines to prevent significant disease where the vaccine is used according to the SPC is rare. However, the sensitivity and specificity of laboratory tests for BRD pathogens is often questioned (Allen and others 1991, Angen and others 2009, Lorenz and others 2011). The diagnostic methods employed may have been insufficiently sensitive and failed to detect pathogens that were present. For example, the nested PCR for BRSV, which
was not routinely available at the time of the study, has been shown to have a sensitivity of 89 per cent as opposed to 69 per cent for IFAT in the same clinical samples (Vilcek and others 1994). It is commonly agreed that sampling acute cases of BRD is essential to maximise the chances of detecting causative pathogens (Cooper and Brodersen 2010) and where an early investigation cannot be carried out the sensitivity of the diagnostic approach is reduced. However, Trueperella pyogenes, which is often associated with chronic pneumonia (Griffin and others 2010), was only detected in two outbreaks concurrent with other bacterial and viral pathogens. Furthermore, M. bovis, which has been associated with BRD of longer duration in feedlot cattle (Fulton and others 2009), was only detected in 5 of the 39 outbreaks tested for this pathogen. Both findings suggest that failing to sample acute cases was not common. Furthermore, as 30 of 35 outbreaks with available data were sampled within seven days of the first case, it is likely that most cases sampled were early cases and typical of the outbreak. Nevertheless, if tests of higher sensitivity had been employed, the number of outbreaks where a pathogen contained in the vaccine was detected may have been higher. On the other hand, vaccinated cattle if exposed to a pathogen contained in the vaccine will become infected, seroconvert and shed the pathogen in question although at a lower level than in unvaccinated cattle (Salt and others 2007, Vangeel and others 2007). Therefore, detection of a pathogen that was also contained in the vaccine does not necessarily imply that it had caused the respiratory tract pathology responsible for the clinical disease, particularly if other
TABLE 9: For 7 of the 45 BRD outbreaks with a standard laboratory investigation, where the diagnosis was a pathogen contained in one of the vaccines and vaccination was not compliant with the specific product characteristics (SPC); the vaccine used, number and class of cattle in the group, doses of vaccine used, the different diagnoses and reasons for non-compliance with the SPC
Vaccine 3, 6 and 9 1 and 3 5 1 1 1 1 Total
Number in group 65 80 25 105 25 55 110 465
Reason for non-compliance with the SPC
Number of vaccines used
Total courses used
Finisher
3
195
Suckled calves: spring born Finisher Finisher Suckled calves: autumn born Suckled calves: spring born Suckled calves: summer born
2 1 1 1 1 1
160 25 105 25 55 110 675
Class of cattle
Diagnosis 1
BRSV BoHV-1 BRSV BRSV BoHV-1 BoHV-1
Diagnosis 2
A
Mannheimia haemolytica
1
Mycoplasma bovis Mycoplasma bovis Mannheimia haemolytica Pasteurella multocida
1
B
C
D
E
F
1 1 1
1 1 4
0
1 1 1 3
1
2
0
A, pneumonia outbreak started before the expected onset of immunity stated in the SPC; B, pneumonia outbreak started after the duration of immunity stated in the SPC had elapsed; C, vaccination of one or more calves commenced at an earlier stage than stated in the SPC; D, the interval between vaccinations was different to that stated in the SPC; E, unlicensed concurrent vaccine administration. For vaccine 4, changes to the 2010 SPC applied retrospectively; F, the route of vaccine administration was different to that stated in the SPC BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus
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Paper pathogens were also present. Furthermore, recent studies have shown that 63 per cent of healthy calves were culture positive for bovine bacterial pathogens from BAL fluid (Angen and others 2009). However, a higher specificity for disease where two pathogens are detected in lung tissue has been reported and detection of P. multocida by culture was also found to be significantly associated with disease status (Allen and others 1991, Angen and others 2009). Furthermore, BRSV was only detected in diseased calves by antigen ELISA and not in healthy calves (Angen and others 2009). The incidence of M. bovis may have been underestimated because in six outbreaks this pathogen was not tested for. P. multocida was the most frequently detected pathogen in the investigated outbreaks with a frequency of almost half, and it is likely to have been of more significance than other bacterial isolates because as noted above the detection of this pathogen has been shown to be specific for disease (Allen and others 1991, Angen and others 2009). This bacterium was detected in five of the six outbreaks that also involved a pathogen contained in the vaccine used where the vaccine had been used in compliance with the SPC. It is likely that P. multocida played a significant role in these outbreaks. First, for the reason of disease association above, and secondly, because of the significantly greater frequency of occurrence in these outbreaks compared with the outbreaks where a pathogen contained in the vaccine used was present but where vaccine use had not been compliant with the SPC. From this field study of BRD vaccinated mainly beef cattle, there are four main conclusions. First, the cattle in groups reporting BRD outbreaks represented a very small proportion of the total cattle vaccinated as represented by the number of courses of vaccine used in the affected groups and sold during the study period. Secondly, almost half the BRD outbreaks as defined by this study were associated with vaccine usage outwith the SPC. Thirdly, the proportion of courses used in outbreaks where a pathogen contained in the vaccine was detected in the diseased cattle was relatively small. Fourthly, bacterial pathogens were commonly detected and the most common pathogen detected in all outbreaks of BRD in vaccinated cattle was P. multocida, which was likely to be a significant cause of disease, particularly in cattle where a pathogen contained in the vaccine used was present and vaccine use had been compliant with the SPC.
Acknowledgements This study was only possible through the willing cooperation of numerous colleagues in veterinary practice and within SAC Consulting Veterinary Services and Pfizer Animal Health to all of whom the authors would like to extend their thanks. Pfizer Animal Health funded the laboratory investigations carried out
by SAC Consulting: Veterinary Services. Pfizer Animal Health is thanked for use of its data. SAC Consulting: Veterinary Services receives financial support from the Scottish Government through the Veterinary and Advisory Services programme.
References ALLEN, J. W., VIEL, L., BATEMAN, K. G., ROSENDAL, S., SHEWEN, P. E. & PHYSICK-SHEARD, P. (1991) The microbial flora of the respiratory tract in feedlot calves: associations between nasopharyngeal and bronchoalveolar lavage cultures. Canadian Journal of Veterinary Research 55, 341–346 ANGEN, O., THOMSEN, J., LARSEN, L. E., LARSEN, J., KOKOTOVIC, B., HEEGAARD, P. M. H. & ENEMARK, J. M. D. (2009) Respiratory disease in calves: microbiological investigations on trans-tracheally aspirated bronchoalveolar fluid and acute phase protein response. Veterinary Microbiology 137, 165–171 COOPER, V. L. & BRODERSEN, B. W. (2010) Respiratory disease diagnostics of cattle. The Veterinary Clinics of North America. Food Animal Practice 26, 409–416 FULTON, R. W., BLOOD, K. S., PANCIERA, R. J., PAYTON, M. E., RIDPATH, J. F., CONFER, A. W., SALIKI, J. T., BURGE, L. T., WELSH, R. D., JOHNSON, B. J. & RECK, A. (2009) Lung pathology and infectious agents in fatal feedlot pneumonias and relationship with mortality, disease onset, and treatments. Journal of Veterinary Diagnostic Investigation 21, 464–477 GRIFFIN, D., CHENGAPPA, M. M., KUSZAK, J. & MCVEY, D. S. (2010) Bacterial pathogens of the bovine respiratory disease complex. The Veterinary Clinics of North America. Food Animal Practice 26, 381–394 LORENZ, I., EARLEY, B., GILMORE, J., HOGAN, I., KENNEDY, E. & MORE, S. J. (2011) Calf health from birth to weaning. III. Housing and management of calf pneumonia. Irish Veterinary Journal 64, 14–23 MEADOWS, D. (2010) A study to investigate the use and application of BVDV vaccine in UK cattle. Cattle Practice 18, 202–209 MOSIER, D. A., CONFER, A. W. & PANCIERA, R. J. (1989) The evolution of vaccines for bovine pneumonic pasteurellosis. Research in Veterinary Science 47, 1–10 PERINO, L. J. & HUNSAKER, B. D. (1997) A review of bovine respiratory disease vaccine field efficacy. Bovine Practitioner 31, 59–66 SALT, J. S., THEVASAGAYAM, S. J., WISEMAN, A. & PETERS, A. R. (2007) Efficacy of a quadrivalent vaccine against respiratory diseases caused by BHV-1, PI3V, BVDV and BRSV in experimentally infected calves. Veterinary Journal 174, 616–626 TAYLOR, J. D., FULTON, R. W., LEHENBAUER, T. W., STEP, D. L. & CONFER, A. W. (2010) The epidemiology of bovine respiratory disease: What is the evidence for preventive measures? The Canadian Veterinary Journal 51, 1351–1359 VANGEEL, I., ANTONIS, A. F. G., FLUESS, M., RIEGLER, L., PETERS, A. R. & HARMEYER, S. S. (2007) Efficacy of a modified live intranasal bovine respiratory syncytial virus vaccine in 3-week-old calves experimentally challenged with BRSV. Veterinary Journal 174, 627–635 VILCEK, S., ELVANDER, M., BALLAGI-PORDÁNY, A. & BELÁK, S. (1994) Development of nested PCR assays for detection of bovine respiratory syncytial virus in clinical samples. Journal of Clinical Microbiology 32, 2225–2231
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Field study of pneumonia in vaccinated cattle associated with incorrect vaccination and Pasteurella multocida infection W. M. Crawshaw and G. L. Caldow Veterinary Record published online February 27, 2015
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Paper Field study of pneumonia in vaccinated cattle associated with incorrect vaccination and Pasteurella multocida infection W. M. Crawshaw, G. L. Caldow This field study used data on the vaccine courses against bovine respiratory disease sold by one pharmaceutical company in conjunction with pharmacovigilance data to explore reported suspected lack of expected efficacy and the reasons for this. The study ran from May 1, 2007, to April 30, 2010, and covered vaccines sold in Scotland and part of Northumberland. In total, 83 groups of cattle reported suspected lack of expected efficacy, representing 1.6 per cent of the 804,618 vaccine courses sold. It was possible to investigate 45 of these outbreaks in depth using a standard questionnaire and diagnostic protocol. Vaccine usage outwith the specific product characteristics (SPC) occurred in 47 per cent of cases (21/45). The proportion of vaccination courses used where a pathogen contained in the vaccine was detected in the diseased cattle and vaccine use was consistent with the SPC was estimated at 0.12 per cent of the courses sold. Pasteurella multocida was the most common pathogen detected and was found in 21 of the outbreaks. For outbreaks where a pathogen contained in the vaccine was detected, P. multocida was found at a significantly greater frequency (P=0.03) where vaccine use was compliant with the SPC (five of six outbreaks) compared with outbreaks where vaccine use had not been compliant with the SPC (one of seven outbreaks). The limitations of the study, including the diagnostic tests employed and definition of vaccination outwith the SPC, are discussed.
Vaccination as a control method for bovine respiratory disease (BRD) has been increasingly adopted in the UK, as indicated by the number of BRD vaccine courses sold by all manufacturers in 2012 compared with 2002, which showed an estimated increase of 36 per cent over this period (Pfizer Animal Health (2002, 2012); Market Report, Walton-on-the-Hill, personal communication). The evidence to support vaccination as an intervention is largely based on experimental challenge trials that have assessed immune response, clinical disease and pathogen shedding, often with encouraging results (e.g. Vangeel and others 2007). In contrast, there are few field studies investigating BRD vaccine efficacy. Field studies are difficult to conduct due to the potential for extensive confounding, variability in risk factors for BRD between farms, the multifactorial nature of BRD and inadequate methods for diagnosis (Taylor and others 2010). Furthermore, in the UK, the relatively small group sizes and numbers of replicates typically available limit statistical power. Two reviews of
field studies of vaccination against BRD concluded that evidence of efficacy is equivocal (Mosier and others 1989, Perino and Hunsaker 1997). This study sought to estimate the proportion of cattle vaccinated against BRD using any of the nine vaccines marketed by one pharmaceutical company that were in groups spontaneously reported with BRD; to investigate how the vaccines had been used compared with the directions in their specific product characteristics (SPC) and also to investigate which BRD pathogens were present in affected cattle using a standard laboratory diagnostic protocol. Studies of this type have not been previously reported but have value in quantifying the failure rate of BRD vaccines and offering potential explanations for failure of vaccination to prevent BRD that could be the subject of further research.
Materials and methods Veterinary Record (2015) W. M. Crawshaw, BVetMed DCHP DipECBHM MRCVS, Pfizer Animal Health (now Zoetis UK Ltd), Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS, UK MBM Veterinary Group, 21 Hill Street, Kilmarnock, Ayrshire KA3 1HF, UK (current address) G. L. Caldow, BVM&S MSc DipECBHM CertCHP MRCVS FRAgS,
doi: 10.1136/vr.102701 SAC Consulting Veterinary Services, Greycrook, Melrose, St.Boswells, Roxburghshire TD6 0EU, UK E-mail for correspondence: [email protected] Provenance: not commissioned; externally peer reviewed Accepted February 9, 2015
All veterinary practices in Scotland and one in north Northumberland were included in the study. The study period was May 1, 2007, to April 30, 2010. The denominator for the proportion of vaccinated cattle that were identified in groups with BRD was estimated from the number of courses of the nine vaccines (Table 1) produced by one pharmaceutical company (Pfizer Animal Health) sold to these practices during the study period using sales data from the company. For vaccines licensed for a two-dose primary course only, or in the case of vaccine 7 where a single- or two-dose primary course was licensed, the number of vaccination courses was calculated by dividing the number of doses sold by two. 10.1136/vr.102701 | Veterinary Record | 1 of 7
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Paper TABLE 1: For the nine vaccines included in the study, the antigens and the number of doses for primary and booster vaccination recommended in the specific product characteristics of each vaccine Vaccine
Vaccine trade name
Live antigen(s)
1 2 3
Rispoval 4 Rispoval 3 Rispoval Pasteurella
BRSV, PI3 BRSV, PI3
4 5 6 7 8
Rispoval IntraNasal RS+PI3 Imuresp RP Tracherine Rispoval IBR marker live Rispoval IBR marker inactivated Rispoval RS
BRSV, PI3 BoHV-1, PI3 BoHV-1 BoHV-1 (gE deleted)
9
Inactivated antigen(s)
Primary course doses
Booster doses
BoHV-1, BVD BVD Leukotoxoid and capsular antigens of MAHA
2 2 1
None licensed None licensed None licensed
1 1 1 1 or 2 2
None licensed None licensed None licensed 1 1
2
None licensed
BoHV-1 (gE deleted) BRSV
BoHV-1, bovine herpesvirus 1; BRSV, bovine respiratory syncytial virus; BVDV, bovine virus diarrhoea virus; gE, glycoprotein E; MAHA, Mannheimia haemolytica; PI3, parainfluenza virus type 3
For the single-dose vaccines, the number of vaccination courses was equal to the number of doses of vaccine sold. The numerator for estimating the proportion of vaccinated cattle that were identified in groups with BRD was the sum of the number of vaccine courses administered to both affected and unaffected cattle in each affected group. An affected group was vaccinated with any of the nine BRD vaccines and was also reported to the UK Suspected Adverse Reaction Surveillance Scheme (SARSS) due to suspected lack of expected efficacy either directly to the company or via the UK Veterinary Medicines Directorate. For all outbreaks, an attempt was made to collect basic epidemiological information specific to the affected group from the reporting veterinary surgeon by the company’s pharmacovigilance staff using a standardised data collection form. The information included dates of vaccination, age range of calves when vaccinated, batch number of vaccine used, expiry date of vaccine, concurrent treatments or vaccinations, date of onset of first case of BRD, number of cattle in the affected group and production class of cattle (e.g. suckled calves, dairy calves, finishing cattle). Consistent collection of more detailed information from a large number of veterinarians and farmers managing disease outbreaks under commercial farming conditions was not considered possible. Where the reporting veterinary surgeon was unable to supply accurate information on group size (n=13), the median group size of all the other groups of cattle that were included in the study and in the same production class was used for the calculations for this group. The collected data were used to calculate the proportion of courses administered to groups that were recognised to have experienced BRD. For outbreaks where the attending veterinary practitioner and farmer were willing to supply complete epidemiological information, collect the diagnostic samples and animals that met the sampling criteria were available, a standard laboratory investigation was performed according to the following protocol. In live cattle in the affected group, the attending veterinary practitioner collected bronchoalveolar lavage (BAL) samples from two to four recently affected ( pyrexic temperature ≥39.5°C and clear nasal and/or ocular discharge) untreated cattle. From the same cattle, a nasopharyngeal swab was submitted in virus transport medium. In some outbreaks where fatalities occurred in the affected group, one to three fresh carcases of recently affected cattle were submitted in addition to the above or as an alternative. All laboratory investigations were conducted at the eight veterinary laboratories of the Scottish Agricultural College Consulting: Veterinary Services (SACCVS). Standard culture methods following the standard operating procedures (SOPs) in place at SACCVS for the detection of bacteria and mycoplasmas were used in all BAL samples, and where the lung of any carcase showed gross lesions of pneumonia, the surface of the lesion was seared and sampled aseptically. Indirect fluorescent antibody tests (IFAT) for bovine respiratory syncytial virus (BRSV) and parainfluenza virus type 3 (PI3) were 2 of 7 | Veterinary Record | 10.1136/vr.102701
performed on lung impression smears and cellular deposits from BAL samples and for bovine herpesvirus 1 (BoHV-1) on nasopharyngeal swabs by standard procedures following the SOPs in place at SACCVS. As there were concerns over the specificity of the BoHV-1 conjugate, an aliquot from all samples that yielded a positive BoHV-1 IFAT result was sent to a reference laboratory for further testing by virus isolation, immunocytochemistry or PCR. The diagnostic criteria employed were detection of a recognised pathogenic bacteria or Mycoplasma species by culture, detection of BRSV or PI3 by IFAT and detection of BoHV-1 by virus isolation or PCR or immunocytochemistry in at least one animal in the group that met the case selection criteria. Outbreaks with a standard laboratory investigation were also studied to compare the practice of vaccine administration with the recommendations in the SPC for the vaccine(s) used. For the purpose of analysis where the BRD incident had started before the expected onset of immunity from the vaccine, as detailed in the SPC, this was classified as ‘vaccine use not compliant with the SPC’. For vaccine 4, changes to the SPC made in 2010 in connection with age at vaccination (reduced from 21 to 9 days) and concurrent vaccine use (changed from contraindicated to veterinary judgement on a case-by-case basis) were applied retrospectively to all cases included in the study. Therefore, for this study, concurrent use of another vaccine was assessed as compliant with the SPC. The reported production classes of cattle involved in the BRD outbreaks were recorded.
Statistical analysis For all outbreaks with standard laboratory investigation, the two-tail Fisher’s exact test was used to assess the effect of the class of cattle on compliance with the SPC; if the frequency of 'no diagnosis' was affected by whether the vaccine(s) had been used in compliance with the SPC, detection of multiple pathogens, detection of two pathogens, detection of three pathogens and isolation of different pathogens. For those outbreaks where a pathogen was diagnosed that was also contained in the vaccine, the effect of whether the vaccine(s) had been used in compliance with the SPC on the frequency isolation of different pathogens was examined. The cut-off for statistical significance was taken to be probability greater than or equal to 0.05.
Results The total number of courses of vaccine sold during the study period of May 1, 2007, to April 30, 2010, was 804,618, ranging from 221,460 for vaccine 1 to 10,790 for vaccine 8 (Table 2). Notifications under the UK SARSS for BRD in cattle vaccinated with any of nine bovine respiratory vaccines marketed by the pharmaceutical company during the study period totalled 91 cases of the case type suspected lack of expected efficacy. Eight cases were excluded from analysis because the BRD outbreak had started before any vaccine had been administered (n=2); only one dose of a primary course requiring two doses had been
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Paper TABLE 2: Total number of vaccine courses sold and total courses used in all the 83 BRD outbreaks studied, the 45 outbreaks investigated with a standard laboratory investigation (SLI) and the six outbreaks where a diagnosed pathogen was also contained in the vaccine and the vaccine was used according to specific product characteristics (SPC) Vaccine 1 2 3 4 5 6 7 8 9 Total
Total vaccine courses sold
Total courses used in 83 groups reported with BRD
Total courses used in 45 groups investigated with an SLI
Total courses used in six groups where pathogen diagnosed contained in vaccine and vaccine used according to the SPC
221,460 20,098 101,665 152,820 71,200 199,835 11,120 10,790 15,630 804,618
4531 (2.0) 1850 (9.2) 2229 (2.2) 1476 (1.0) 175 (0.2) 2378 (1.2) 0 (0.0) 50 (0.5) 170 (1.1) 12859 (1.6)
2570 (1.2) 1800 (9.0) 2170 (2.1) 1091 (0.7) 175 (0.2) 2005 (1.0) 0 (0.0) 0 (0.0) 170 (1.1) 9981 (1.2)
440 (0.20) 0 (0.00) 250 (0.25) 165 (0.11) 150 (0.21) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 940 (0.12)
Figures in parenthesis are the percentage of courses of this vaccine sold BRD, bovine respiratory disease
given (n=1); investigation revealed that the disease was not BRD but another diagnosis (n=3); there was no additional information (n=1); or the same outbreak had been reported twice (n=1). This left 83 cases used in the study. The distribution of these cases by month of onset of BRD is shown in Fig 1. October to February showed the highest number of reports, with a peak in November. In 82 of the 83 cases, one or more of the nine vaccines had been used exclusively as respiratory vaccines. The exception was one outbreak where a vaccine from a second company had been used in combination with one of the company’s nine vaccines in 117 cattle. The absence of denominator data precluded these courses from the second company being included in the analysis. Group size information was missing in 13 outbreaks (16 per cent). Group size ranged from 5 to 1700 cattle, with a median of 65 (inter-quartile range: 40–119). In 12 outbreaks comprising 1038 cattle, two vaccines had been used; and in two outbreaks comprising 1765 cattle, three vaccines had been used. It was calculated that the 8408 cattle in 83 groups reported with BRD had received 12,859 courses of one of the nine vaccines from the company (Table 3) and 117 courses of a vaccine from the second company. In the 83 BRD outbreaks, 12,859 courses had been used, representing 1.6 per cent of courses sold over the whole nine vaccine range (Table 2). No standard laboratory investigation was carried out in 38 (42 per cent) of the 83 BRD outbreaks, and in 23 of these the epidemiological information was incomplete. These 38 outbreaks were used only to estimate the proportion of vaccinated cattle that were identified in groups with BRD. The standard laboratory investigation was completed in 45 (58 per cent) of the 83 BRD outbreaks. However, in six outbreaks, culture for Mycoplasma bovis was not carried out (due to laboratory error) and group size information was missing from 35 30
one outbreak. In these outbreaks, 5726 cattle (68.1 per cent of all the cattle in 83 groups where BRD was reported) received 9981 courses of vaccine (Table 3). Group size ranged from 5 to 1700 cattle, with a median of 70 (inter-quartile range: 48–110). In six outbreaks comprising 685 cattle, two vaccines had been used; and in two outbreaks comprising 1765 cattle, three vaccines had been used. The majority of outbreaks investigated involved beef cattle, particularly suckled calves (calves from beef cow herds) and most commonly spring-born calves (48.9 per cent) (Table 4). An approximation of age ranges at BRD onset for the different classes of cattle reported is shown in Table 4. In 21 of the 45 outbreaks (47 per cent), at least one failure to use the vaccine in accordance with the SPC was identified and a total of 27 failures to follow the SPC occurred in these 21 outbreaks (Table 4). However, in eight of these, one failing was that the BRD incident had started before the expected onset of immunity. In three outbreaks, this was the only non-compliance, and if these are excluded, then the number of outbreaks with failure to use the vaccine in accordance with the SPC is 18/45 (40 per cent). The other most common reasons for use outwith the SPC were vaccination of cattle at too early an age (8/21) and unlicensed concurrent vaccine administration (6/21). There was no statistically significant difference for cattle class and SPC compliance. The type of samples collected and examined in the 45 outbreaks where the standard laboratory investigation was carried out is shown in Table 5. In total, 38 carcases, 78 BAL samples and 103 nasopharyngeal swabs were examined. The time of sampling in relation to the first detected case in the outbreak was available for 35 cases and ranged from 0 to 58 days. However, all
TABLE 3: Number of vaccine courses used and number of cattle in all the 83 BRD outbreaks studied, the 45 outbreaks with a standard laboratory investigation (SLI) and the six outbreaks where a diagnosed pathogen was also contained in the vaccine and the vaccine was used according to specific product characteristics (SPC)
25
Total in 45 groups with an SLI (%)
Total in six groups where pathogen diagnosed contained in vaccine and vaccine used according to the SPC (%)
12,859 (100)
9981 (77.6)
940 (7.3)
8408 (100)
5726 (68.1)
650 (7.7)
20 Total in 83 groups reported with BRD (%)
15 10 5 0 Jan
Feb Mar
Apr May Jun
Jul
Aug Sep
Oct
Nov Dec
FIG 1: Month of onset of respiratory disease reported for all the 83 outbreaks studied 2007–2010. The black part of each bar represents the 45 outbreaks with a standard laboratory investigation
Number of courses of vaccine used in reported outbreaks Number of cattle in reported outbreaks
BRD, bovine respiratory disease
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Paper TABLE 4: The number of bovine respiratory disease (BRD) outbreaks by whether one or more of the vaccination courses used was compliant with the specific product characteristics (SPC), reasons for non-compliance, class of cattle and approximate age range in the 45 outbreaks with a standard laboratory investigation
Class of cattle
Reason for non-compliance with the SPC
Approximate age range at time of BRD onset (days)
Vaccinated according to the SPC (%)
Not vaccinated according to the SPC (%)
Total (%)
Fisher’s exact test P value
38–180 187–480 94 55–82
5 (20.8) 1 (4.2) 0 (0.0) 0 (0.0)
1 (4.8) 5 (23.8) 1 (4.8) 3 (14.3)
6 (13.3) 6 (13.3) 1 (2.2) 3 (6.7)
0.19 0.08 0.47 0.09
2 1 3
3
183–270
15 (62.5)
7 (33.3)
22 (48.9)
0.08
1
2
150–245
1 (4.2)
2 (9.5)
3 (6.7)
0.59
1
2
105–300 38–480
2 (8.3) 24 (100.0)
4 (8.9) 45 (100.0)
1.00 NA
8
Dairy bred Finishing unit Heifer rearer Suckled calves: autumn born Suckled calves: spring born Suckled calves: summer born Undefined Total
2 (9.5) 21 (100.0)
A
B
C
D
E
F
4
1
1
1 1
8
2
2
2
6
1 2
A, pneumonia outbreak started before the expected onset of immunity stated in the SPC; B, pneumonia outbreak started after the duration of immunity stated in the SPC had elapsed; C, vaccination of one or more calves commenced at an earlier stage than stated in the SPC; D, the interval between vaccinations was different to that stated in the SPC; E, unlicensed concurrent vaccine administration. For vaccine 4, changes to the 2010 SPC applied retrospectively; F, the route of vaccine administration was different to that stated in the SPC; NA, not applicable
but five outbreaks were sampled 0–7 days after the first detected case. The diagnostic results are presented in Table 6, showing the number of diagnoses by pathogen and whether the vaccine had been used according to the SPC. No diagnosis was made in 10 outbreaks (22.2 per cent). Multiple pathogens were detected in 19 outbreaks (42.2 per cent), most commonly two pathogens, which were detected in 17 outbreaks (37.8 per cent). Bacterial pathogens were detected in 32 of 35 outbreaks where a diagnosis was made; in one outbreak only BoHV-1 was detected and in two only BRSV. The frequency of detection of the different bacterial pathogens did not differ significantly whether or not vaccination was compliant with the SPC. The commonest diagnosis was Pasteurella multocida (a pathogen not included in any of the vaccines used), which was present in 21 (46.7 per cent) outbreaks. Of the agents included in the vaccines, Mannheimia haemolytica was identified in nine outbreaks (20.0 per cent), BoHV-1 and BRSV were each identified in five outbreaks (11.1 per cent) and PI3 in two outbreaks (4.4 per cent). However, the vaccines against these specific pathogens had not been necessarily used in all of these outbreaks. The details of the six outbreaks where the diagnosis was a pathogen contained in one of the vaccines used and the vaccination had been carried out according to the SPC are shown in Tables 7 and 8. Of the pathogens contained in the vaccines, BoHV-1 and BRSV were the commonest diagnoses in this category (each 2/6 outbreaks). P. multocida was also confirmed in 5/6 cases always concurrent with one or more other pathogens. M. bovis was not detected in any of these six outbreaks. In total, the number of vaccinated cattle in the investigated BRD outbreaks where a pathogen contained in the vaccine was diagnosed as a cause of respiratory disease and the vaccine was used in accordance with the SPC varied from 0.0 per cent (vaccines 2, 6, 7, 8 TABLE 5: The sample types submitted and the number of cattle sampled in the 45 outbreaks with a standard laboratory investigation No. of cattle sampled Sample type Total Carcase only Carcase and BAL Carcase and NPS BAL and NPS Carcase and BAL and NPS
No. of outbreaks
Carcase
BAL
NPS
45 19 0 4 19 3
38 25 0 7 NA 6
78 NA 0 NA 69 9
103 NA NA 19 74 10
BAL, bronchoalveolar lavage; NA, not applicable; NPS, nasopharyngeal swab
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and 9) to 0.25 per cent (vaccine 3) and totalled 0.12 per cent (940 courses) over the whole nine vaccine range (Tables 2 and 7). The details of the seven outbreaks where the diagnosis was a pathogen contained in one of the vaccines used and the vaccination had not been carried out according to the SPC are shown in Tables 7 and 9. Of the pathogens contained in the vaccines, BoHV-1 and BRSV were diagnosed in three outbreaks each. M. bovis was confirmed in two outbreaks. P. multocida was detected in one outbreak concurrent with BoHV-1. The three commonest reasons for use outwith the SPC were pneumonia outbreak started before the expected onset of immunity, calves vaccinated at too early an age and unlicensed concurrent vaccine administration. P. multocida was present in 5/6 (83 per cent) outbreaks where the vaccine was used according to the SPC but in only 1/7 (14 per cent) outbreaks where the vaccine was not used according to the SPC (Table 7) and this difference was significant (P=0.03). No other significant difference in the frequency of isolation of different pathogens was identified. BoHV-1 was diagnosed in three outbreaks that were not included in the 45 with a standard laboratory investigation because they were investigated for BoHV-1 only. In two of these outbreaks, vaccines including BoHV-1 had been used (vaccines 1 and 6) but only vaccine 1 had been used in compliance with the SPC.
Discussion The number of vaccine courses used in groups of cattle reported with BRD represented 1.6 per cent of the total courses of vaccine sold during the study period. The suspected adverse reactions surveillance scheme is widely publicised to the UK veterinary profession and is used frequently, particularly for significant BRD outbreaks in cattle vaccinated against BRD. However, it is accepted that not all cases of BRD occurring in vaccinated cattle were reported, particularly where veterinarians were unwilling to report or for groups of cattle experiencing a low incidence of BRD or cases where clinical disease was mild. Farms where BRD did not occur in vaccinated cattle were not studied, and the general prevalence of respiratory disease in cattle in the UK has not been reported. Therefore, it is not possible to compare the prevalence of BRD in the vaccinated cattle included in the study with unvaccinated cattle. The methodology used to estimate the proportion of vaccinated cattle that were identified in groups with BRD may result in four potential sources of error. First, it could not be determined whether all the vaccine doses sold were actually administered during the study period. Secondly, there was potential error associated with reports of BRD in cattle
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Paper TABLE 6: The number of different diagnoses for the 45 BRD outbreaks with a standard laboratory investigation Total outbreak cases No diagnosis Outbreaks with multiple pathogens Outbreaks with two pathogens Outbreaks with three pathogens BoHV-1 PI3 BRSV Histophilus somni Mannheimia haemolytica Mycoplasma bovis Pasteurella multocida Trueperella pyogenes
Vaccination compliant with the SPC (%)
Vaccination not compliant with the SPC (%)
Total (%)
Fisher’s exact test P value
24 (100.0) 7 (29.2) 9 (37.5) 7 (29.2) 2 (8.3) 2 (8.3) 1 (4.2) 2 (8.3) 5 (20.8) 5 (20.8) 1 (4.2) 10 (41.7) 2 (8.3)
21 (100.0) 3 (14.3) 10 (47.6) 10 (47.6) 0 (0.0) 3 (14.3) 1 (4.8) 3 (14.3) 2 (9.5) 4 (19.0) 4 (19.0) 11 (52.4) 0 (0.0)
45 (100.0) 10 (22.2) 19 (42.2) 17 (37.8) 2 (4.4) 5 (11.1) 2 (4.4) 5 (11.1) 7 (15.6) 9 (20.0) 5 (11.1) 21 (46.7) 2 (4.4)
NA 0.30 0.56 0.23 0.49 0.65 1.00 0.65 0.42 1.00 0.17 0.56 0.49
The diagnoses are categorised by whether the vaccination courses used in that group of cattle were compliant with the specific product characteristics (SPC). There was more than one diagnosis in outbreaks with multiple pathogens BoHV-1, BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus; PI3, parainfluenza virus type 3
vaccinated using vaccine sold before the start of the study period and reports of BRD not being included for cattle administered courses near the end of the study period. To minimise the first two potential sources of error, the study period began on May 1, 2007, and ended on April, 30, 2010, because the majority of cattle in the population under study were born in the beef cow herd and could be reasonably expected to be outside during the grazing season where the BRD risk was low and vaccination rarely carried out. This ensured that both the time period when cattle were most likely to be vaccinated and to experience BRD during the period of cover from that vaccination were included. Thirdly, when calculating the number of courses sold from the number of doses sold it was not known what proportions of doses were used for two- or single-dose primary courses or for single-dose boosters. However, the error here is likely to be low as 782,708 of 804,618 (97.3 per cent) of the vaccine doses sold were either licensed only for a two-dose primary course with no option for a single-dose booster (vaccines 1, 2 and 9) or a singledose primary course (vaccines 3, 4, 5 and 6). This methodology may overestimate the incidence of BRD in vaccinated cattle by underestimating the number of cattle vaccinated with vaccines 7 and 9, which could both be boosted with a single dose at sixmonthly intervals and for the former a single-dose primary course is also an option. However, vaccines 7 and 8 showed a low proportion of courses sold (2.7 per cent) during the study period (Table 2), so this error is likely to be small. Fourthly, movement of vaccinated cattle in and out of the region was not known and could not be taken into account; however, the error here is likely to be small also as vaccination before movement
was unusual in the UK during the study period (W. M. Crawshaw and G. L. Caldow, unpublished observations). A high proportion of the total reported BRD outbreaks in vaccinated cattle included in the study were subjected to the standard laboratory investigation (45 of 83 outbreaks comprising 68.1 per cent of the cattle and 77.6 per cent of the total vaccine courses used). Outbreaks with a standard laboratory investigation reported in this study primarily involved beef cattle (36 of 45 outbreaks), and the findings should be extrapolated to dairy cattle with caution. Non-SPC-compliant vaccine use was a frequent finding, accounting for 47 per cent of outbreaks with a standard laboratory investigation. Where this was due to one or more calves initially being vaccinated at too young an age, it should be noted that it was not possible to quantify the proportion of the group that was too young and therefore any influence this may have had. Exclusion of outbreaks where the only non-compliance with the SPC was that BRD occurred before the expected onset of vaccine immunity reduces outbreaks with non-SPC-compliant vaccine use to 40 per cent. Occurrence of BRD before the expected onset of immunity following vaccination stated in the SPC was classified as non-compliance with the SPC because it is stated in most BRD vaccine SPCs that the timing of vaccine administration should allow the onset of immunity before the BRD risk period. Similarly to other non-compliances with SPC, vaccine efficacy could be compromised in these circumstances. Likewise, Meadows (2010) reported that the use of bovine virus diarrhoea virus vaccines outwith the SPC was also common in 71 farms in England, with 21 per cent of farmers using the wrong dose or route of
TABLE 7: The number of different diagnoses for 13 of the 45 BRD outbreaks with a standard laboratory investigation where at least one diagnosis was a pathogen contained in one of the vaccines used Number of outbreak cases No diagnosis Outbreaks with multiple pathogens Outbreaks with two pathogens Outbreaks with three pathogens BoHV-1 PI3 BRSV Histophilus somni Mannheimia haemolytica Mycoplasma bovis Pasteurella multocida Trueperella pyogenes
Vaccination compliant with the SPC (%)
Vaccination not compliant with the SPC (%)
Total (%)
Fisher’s exact test P value
6 (100.0) 0 (0.0) 5 (83.3) 3 (50.0) 2 (33.3) 2 (33.3) 1 (16.7) 2 (33.3) 0 (0.0) 2 (33.3) 0 (0.0) 5 (83.3) 1 (16.7)
7 (100.0) 0 (0.0) 4 (57.1) 4 (57.1) 0 (0.0) 3 (42.9) 0 (0.0) 3 (42.9) 0 (0.0) 2 (28.6) 2 (28.6) 1 (14.2) 0 (0.0)
13 (100.0) 0 (0.0) 9 (69.2) 7 (53.8) 2 (4.4) 5 (38.5) 1 (7.7) 5 (38.5) 0 (0.0) 4 (30.8) 2 (15.4) 6 (46.2) 1 (4.7)
NA NA 0.56 1.00 0.19 1.00 0.46 1.00 NA 1.00 0.46 0.03 0.46
The diagnoses are categorised by whether the vaccination courses used in that group of cattle were compliant with the specific product characteristics (SPC). There was more than one diagnosis in outbreaks with multiple pathogens BoHV-1, BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus; NA, not applicable; PI3, parainfluenza virus type 3 Bold typeface indicates significance.
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Paper TABLE 8: For 6 of the 45 BRD outbreaks with a standard laboratory investigation, where the diagnosis was a pathogen contained in one of the vaccines and vaccination was compliant with the specific product characteristics; the vaccine used, number and class of cattle in the group, doses of vaccine used and the diagnoses Vaccine
Number in group
1 and 3
250
1 and 4 4
40 60
Class of cattle
Number of vaccines used
Total courses used
Suckled calves: summer born Dairy bred Dairy bred
2
500
2 1
80 60
Diagnosis 1
Diagnosis 2
Mannheimia haemolytica BRSV PI3
Pasteurella multocida
5
150
Suckled calves: undefined
1
150
BoHV-1
1
85
Suckled calves: spring born
1
85
BoHV-1
1
65
Suckled calves: spring born
1
65
BRSV
Total
650
Pasteurella multocida Pasteurella multocida Pasteurella multocida Pasteurella multocida
Diagnosis 3
Trueperella pyogenes
Mannheimia haemolytica
940
BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus; PI3, parainfluenza virus type 3
administration and 48 per cent administering the primary two-dose course at the incorrect interval. The proportion of vaccine courses not compliant with the SPC where no BRD was reported is unknown and not available for comparison. Nevertheless, vaccination not complying with the SPC could be expected to reduce vaccine efficacy in the field as recommendations made in the SPC are supported by experimental data approved by licensing authorities and deviations either reduce efficacy or supportive evidence is not available. It should be possible to correct the three commonest SPC breeches identified in this study (pneumonia outbreak starting before the onset of expected immunity, vaccination initiated in one or more cattle too young and unlicensed concurrent vaccine administration) on many farms by considering the choice of vaccine and timing of vaccine administration, including completing vaccination of calves sold for finishing before they are transferred to the finishing unit, along with training and education of veterinary practitioners and farmers. Of the 24 outbreaks investigated where vaccine use was compliant with the SPC, in six (25 per cent) pathogens contained in the vaccine were detected. This represented only 0.12 per cent of all courses sold. These findings might suggest that failure of respiratory vaccines to prevent significant disease where the vaccine is used according to the SPC is rare. However, the sensitivity and specificity of laboratory tests for BRD pathogens is often questioned (Allen and others 1991, Angen and others 2009, Lorenz and others 2011). The diagnostic methods employed may have been insufficiently sensitive and failed to detect pathogens that were present. For example, the nested PCR for BRSV, which
was not routinely available at the time of the study, has been shown to have a sensitivity of 89 per cent as opposed to 69 per cent for IFAT in the same clinical samples (Vilcek and others 1994). It is commonly agreed that sampling acute cases of BRD is essential to maximise the chances of detecting causative pathogens (Cooper and Brodersen 2010) and where an early investigation cannot be carried out the sensitivity of the diagnostic approach is reduced. However, Trueperella pyogenes, which is often associated with chronic pneumonia (Griffin and others 2010), was only detected in two outbreaks concurrent with other bacterial and viral pathogens. Furthermore, M. bovis, which has been associated with BRD of longer duration in feedlot cattle (Fulton and others 2009), was only detected in 5 of the 39 outbreaks tested for this pathogen. Both findings suggest that failing to sample acute cases was not common. Furthermore, as 30 of 35 outbreaks with available data were sampled within seven days of the first case, it is likely that most cases sampled were early cases and typical of the outbreak. Nevertheless, if tests of higher sensitivity had been employed, the number of outbreaks where a pathogen contained in the vaccine was detected may have been higher. On the other hand, vaccinated cattle if exposed to a pathogen contained in the vaccine will become infected, seroconvert and shed the pathogen in question although at a lower level than in unvaccinated cattle (Salt and others 2007, Vangeel and others 2007). Therefore, detection of a pathogen that was also contained in the vaccine does not necessarily imply that it had caused the respiratory tract pathology responsible for the clinical disease, particularly if other
TABLE 9: For 7 of the 45 BRD outbreaks with a standard laboratory investigation, where the diagnosis was a pathogen contained in one of the vaccines and vaccination was not compliant with the specific product characteristics (SPC); the vaccine used, number and class of cattle in the group, doses of vaccine used, the different diagnoses and reasons for non-compliance with the SPC
Vaccine 3, 6 and 9 1 and 3 5 1 1 1 1 Total
Number in group 65 80 25 105 25 55 110 465
Reason for non-compliance with the SPC
Number of vaccines used
Total courses used
Finisher
3
195
Suckled calves: spring born Finisher Finisher Suckled calves: autumn born Suckled calves: spring born Suckled calves: summer born
2 1 1 1 1 1
160 25 105 25 55 110 675
Class of cattle
Diagnosis 1
BRSV BoHV-1 BRSV BRSV BoHV-1 BoHV-1
Diagnosis 2
A
Mannheimia haemolytica
1
Mycoplasma bovis Mycoplasma bovis Mannheimia haemolytica Pasteurella multocida
1
B
C
D
E
F
1 1 1
1 1 4
0
1 1 1 3
1
2
0
A, pneumonia outbreak started before the expected onset of immunity stated in the SPC; B, pneumonia outbreak started after the duration of immunity stated in the SPC had elapsed; C, vaccination of one or more calves commenced at an earlier stage than stated in the SPC; D, the interval between vaccinations was different to that stated in the SPC; E, unlicensed concurrent vaccine administration. For vaccine 4, changes to the 2010 SPC applied retrospectively; F, the route of vaccine administration was different to that stated in the SPC BoHV-1, bovine herpesvirus 1; BRD, bovine respiratory disease; BRSV, bovine respiratory syncytial virus
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Paper pathogens were also present. Furthermore, recent studies have shown that 63 per cent of healthy calves were culture positive for bovine bacterial pathogens from BAL fluid (Angen and others 2009). However, a higher specificity for disease where two pathogens are detected in lung tissue has been reported and detection of P. multocida by culture was also found to be significantly associated with disease status (Allen and others 1991, Angen and others 2009). Furthermore, BRSV was only detected in diseased calves by antigen ELISA and not in healthy calves (Angen and others 2009). The incidence of M. bovis may have been underestimated because in six outbreaks this pathogen was not tested for. P. multocida was the most frequently detected pathogen in the investigated outbreaks with a frequency of almost half, and it is likely to have been of more significance than other bacterial isolates because as noted above the detection of this pathogen has been shown to be specific for disease (Allen and others 1991, Angen and others 2009). This bacterium was detected in five of the six outbreaks that also involved a pathogen contained in the vaccine used where the vaccine had been used in compliance with the SPC. It is likely that P. multocida played a significant role in these outbreaks. First, for the reason of disease association above, and secondly, because of the significantly greater frequency of occurrence in these outbreaks compared with the outbreaks where a pathogen contained in the vaccine used was present but where vaccine use had not been compliant with the SPC. From this field study of BRD vaccinated mainly beef cattle, there are four main conclusions. First, the cattle in groups reporting BRD outbreaks represented a very small proportion of the total cattle vaccinated as represented by the number of courses of vaccine used in the affected groups and sold during the study period. Secondly, almost half the BRD outbreaks as defined by this study were associated with vaccine usage outwith the SPC. Thirdly, the proportion of courses used in outbreaks where a pathogen contained in the vaccine was detected in the diseased cattle was relatively small. Fourthly, bacterial pathogens were commonly detected and the most common pathogen detected in all outbreaks of BRD in vaccinated cattle was P. multocida, which was likely to be a significant cause of disease, particularly in cattle where a pathogen contained in the vaccine used was present and vaccine use had been compliant with the SPC.
Acknowledgements This study was only possible through the willing cooperation of numerous colleagues in veterinary practice and within SAC Consulting Veterinary Services and Pfizer Animal Health to all of whom the authors would like to extend their thanks. Pfizer Animal Health funded the laboratory investigations carried out
by SAC Consulting: Veterinary Services. Pfizer Animal Health is thanked for use of its data. SAC Consulting: Veterinary Services receives financial support from the Scottish Government through the Veterinary and Advisory Services programme.
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Field study of pneumonia in vaccinated cattle associated with incorrect vaccination and Pasteurella multocida infection W. M. Crawshaw and G. L. Caldow Veterinary Record published online February 27, 2015
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