A field comparison of heterologous and homologous routes of administration of modified live vaccines for the control of bovine respiratory disease in recently weaned beef calves

Abstract

The use of metaphylactic antimicrobials to control bovine respiratory disease (BRD) is under increased scrutiny; therefore, effective immunization is becoming a priority. Stimulation of an effective immune response is challenging because calves are often primed with injectable (IJ) vaccines, in the face of maternal antibodies which can interfere with the immune response. Maternal antibody interference may be bypassed with use of intranasal (IN) vaccines. This study represents one of few independent vaccine field trials and it demonstrated no significant differences in post-weaning BRD morbidity/mortality or average daily gain in beef calves primed with either an IN or IJ vaccine.

Bovine respiratory disease (BRD) is important to the beef industry as it can cause large economic losses as a result of treatment costs, reduction in feed efficiency, decreased carcass value, and mortality (1). Data reported by commercial feedlots show the average BRD morbidity rate across US feedlots is 16% and that mortality ranges from 1% to 2% on average, depending on calf age (2,3).

Bovine respiratory disease is thought to be initiated by viral infections that cause lesions in the upper and lower respiratory tracts and compromise the immune system, allowing secondary bacterial infections to become established (4). Bovine respiratory syncytial virus (BRSV), bovine herpesvirus type 1 (BHV1), and bovine parainfluenza virus type 3 (BPI3) are viruses that cause direct disease in the upper and/or lower respiratory tract (3). Vaccination is an important method of controlling these viruses.

Parenteral and mucosal vaccines are commonly used on cowcalf operations to prime immunity against pathogens associated with BRD (5). Prime-boost vaccination is an effective method of stimulating the immune system; prime-boost is the administration of a priming vaccine followed by a second or “booster” dose (6). Homologous prime-boost route of administration is a common method of vaccination in beef calf production (5). Homologous route prime-boost uses an injectable modified live viral (MLV) vaccine for both the primer and the booster. This approach may result in failure of immune stimulation because calves are often primed at ~2 mo of age when circulating maternal antibodies (MatAb) have decayed, but are still present in moderate concentrations and are capable of interfering with the immune response to the vaccine (7). A heterologous route prime-boost method uses mucosal priming, by the intranasal (IN) route and systemic boosting through injection (IJ). The IN route of vaccination may be more effective as a priming vaccine in young calves, because IN vaccines bypass MatAb interference, allowing priming to occur in the face of MatAb (8). Intranasal vaccines have been shown to stimulate similar protection against disease as IJ vaccines in challenge models (9,10). While IN vaccines have been shown to be effective in challenge models there are no large-scale field studies showing the effectiveness of heterologous route prime-boost. In order to compare heterologous to homologous route protocols, 645 privately owned beef heifer and steer calves, born to multiparous cows in April and May of 2017, and identified at birth by unique radio frequency identification tags and visual ear tags, were recruited as a study population. The cow-calf pairs were owned by 1 ranch but were pastured in 7 groups. At ~2 mo of age, calves were randomly allocated, by coin flip, into either the homologous injectable modified live vaccine (IJ-MLV), IJ primed and boosted, group, or the heterologous intranasal modified live vaccine (IN-MLV), IN primed and IJ boosted group by systematic sampling, stratified by pasture.

Upon allocation, in June, calves received a 2-mL subcutaneous (SQ) dose of vaccine (Bovishield Gold FP 5; Zoetis Canada, Kirkland, Quebec) or a 2-mL intranasal dose (Inforce 3; Zoetis Canada) MLV vaccine, a 5-mL SQ multivalent Clostridium spp. vaccine (Ultrabac 7; Zoetis Canada), and a non-steroidal anti-inflammatory drug (Metacam; Boehringer-Ingelhiem, Burlington, Ontario) at label dose SQ. Calves in each pasture remained comingled as they were at enrolment and were managed extensively on 7 pastures until weaning in late September of 2017 when they were moved to a nearby feedlot. The vaccine groups were commingled and housed in 4 dirt floor single gender pens after moving to the feedlot. At weaning, the IJ-MLV group included 163 steers and 155 heifers, while the IN-MLV group consisted of 169 steers and 150 heifers. Upon arrival at the feedlot, all calves received a SQ 2-mL dose of the same IJ vaccine the IJ-MLV group was primed with as a booster vaccine. All calves also received a growth implant (Revalor G; Merck Animal Health, Kirkland, Quebec), a SQ multivalent Clostridium spp. booster vaccine, and a metaphylactic antibiotic SQ at label dose (Draxxin; Zoetis Canada) upon arrival. In the pens, study calves were comingled with non-trial calves, sourced from the same producer and vaccinated similarly to the IJ-MLV group. The number of calves from each vaccine group were similar within each of the pens; pen 1: 75, 78; pen 2: 88, 91; pen 3: 67, 61; pen 4: 88, 89, IJ-MLV, and IN-MLV, respectively. Effectiveness of the vaccine protocol was observed through comparison of morbidity and mortality due to BRD, and average daily gain (ADG).

Calves were monitored on a weekly basis by ranch staff, who were blinded to the calves’ vaccination status, for signs of BRD when on pasture and daily by blinded feedlot staff after weaning. Bovine respiratory disease cases were defined as calves that had a rectal temperature above or equal to 40°C as well as having at least 2 of the following signs: moderate depression (drooping head and ears), reluctance to move, tucking of the flank/abdomen, rapid shallow breathing, or increased respiratory effort. If a calf met the case criteria it was treated by staff and morbidity data were recorded.

All calves that died in the feedlot had a gross necropsy performed and digital photographs recorded within 24 h to determine cause of death. Standard digital photographs and clinical history were provided to the blinded consulting veterinarian who established the mortality diagnosis. All causes of mortality were recorded; however, only BRD mortality was included in the data analysis. For calculation of ADG, body weights were collected upon arrival at the feedlot and at reapplication of a growth promoting implant, averaging 68 days-on-feed, ranging from 52 to 73 d.

Statistical analyses were conducted using STATA Version 15 (Stata Corp., College Station, Texas, USA). Post-weaning mortality and morbidity were analyzed using a generalized linear mixed model equation with a logit link function and binomial distribution. Vaccine and gender were independent variables, while pen and pasture were included as random effects variables. The analysis for ADG was similar with the exception of distribution which was normal for the ADG. A P-value of ≤ 0.05 was considered significant.

Pre-weaning BRD morbidity of the calves, from day of priming vaccine to day of weaning were identical (1.2%) for each of the vaccine groups. It is important to note that the pre-weaning mortality is total mortality because no diagnoses were made; the remains of all calves were severely scavenged and unfit for postmortem. The total pre-weaning mortality for each vaccine group was also 1.2%.

With regard to post-weaning ADG, no numerical difference in post-weaning ADG was observed between the vaccine groups. The ADG was 1.6 kg/d for both the IJ-MLV and IN-MLV groups; this is similar to a study that also found no difference in ADG between IN- and IJ-MLV vaccine primed calves (11). However, the Ollivett et al study (11) was a multi-site study and found that 2 of 3 sites had either a significant increase or decrease in ADG for the IN groups compared to the IJ groups. This may indicate that IN vaccination does not have a meaningful impact on ADG or that ADG is an inconsistent variable for the comparison of vaccine protocol effectiveness.

Post-weaning BRD morbidity for the IN-MLV and IJ-MLV vaccine groups were 10% and 9%, respectively (Table 1). Given that the pens were populated by single gender cohorts, data were also analyzed with gender as a confounding variable. No significant differences in BRD morbidity were observed for vaccine group (P = 0.7) or gender (P = 0.8) (Table 2). Post-weaning BRD mortality was compared by vaccine group and gender. No significant difference (P = 0.1) was observed between the vaccine groups, though a large numerical difference was found; IJ-MLV 0.3% versus IN-MLV 1.6% (Table 1). The odds ratio comparing the risk of BRD mortality demonstrated that IN-MLV calves had over 5 times the odds of BRD related mortality (Table 2). Gender was not associated with mortality due to BRD (P = 0.6).

Table 1.

Comparison of bovine respiratory disease (BRD) morbidity, mortality, and average daily gain (ADG) between treatment groups after placement at the feedlot until re-implantation. Treatment groups are further subdivided by gender and combined.

	Injectable			Intranasal
	Steer	Heifer	Combined	Steer	Heifer	Combined
BRD morbidity	18 (11%)	11 (7%)	29 (9%)	19 (11%)	13 (9%)	32 (10%)
BRD mortality	1 (0.6%)	0 (0.0%)	1 (0.3%)	3 (1.8%)	2 (1.3%)	5 (1.6%)
ADG (kg/d)	1.6	1.6	1.6	1.6	1.6	1.6

Table 2.

The effect of gender and vaccine on bovine respiratory disease (BRD) morbidity and mortality.

	Odds ratio	Standard error	Confidence interval		P-value
			Lower	Upper
Post-wean BRD morbidity
Gender	0.84	1.86	0.25	2.86	0.8
Vaccine	1.11	1.31	0.65	1.90	0.7
Post-wean BRD mortality
Gender	0.54	3.39	0.05	5.87	0.6
Vaccine	5.16	3.00	0.59	45.15	0.1

For comparisons, the group used as the basis for comparison for gender was the steer group, and for vaccine was the injectable vaccine group.

Few field studies have observed a difference in BRD morbidity between IN- and IJ-MLV primed beef calves. One study compared IN- versus IJ-MLV priming of recently weaned beef calves and also found no difference in first treatment BRD morbidity rates (12). The BRD morbidity rates were much higher in the previous study, between 42% to 46%; however, the calves were auction derived and at higher risk for BRD treatment, and no metaphylaxis was administered which likely increased the risk of treatment (12). The calves in the current study were weaned and then directly delivered to a feedlot that was geographically close to the ranch of origin. Previous research has shown that calves that undergo less transport time and are not moved through auction marts have lower risk of BRD; therefore, it is likely that the calves in these 2 vaccine studies were of different risk levels of BRD treatment (13). Also, the risk of BRD morbidity was reduced through administration of antimicrobials for metaphylaxis upon arrival at the feedlot.

With regard to BRD mortality, IN primed calves were previously described as having a trend toward lower mortality than the IJ primed group (12), which is contrary to the current study’s finding. The contrary trends may be due to the difference in risk level of the calves in the 2 studies. The previous study’s calves were high risk and it is possible that rapid, local immunity conferred by the IN-MLV priming vaccine resulted in better priming in the face of a disease challenge. By contrast, the current study’s calves were lower risk ranch direct calves that were primed with an IN vaccine as neonates; priming of this type of calf with an IN vaccine may not have resulted in a sufficient systemic immune response to result in an adequate anamnestic response at weaning. If the systemic priming was not sufficient, the calves receiving the IN priming dose would have been at greater risk of a more severe form of BRD resulting in a numerically higher mortality rate.

It should be noted that only a trend toward difference in BRD mortality rates was observed and the BRD mortality rates were low overall. In this study, only 6 deaths in total (1%), due to BRD were observed in the post-weaning period. Average mortality rates due to BRD in feedlots have been reported between 1% and 2%, indicating that the mortality rates in this study were at the low end of the expected range for an “average” commercial feedlot (3). The IN-MLV and IJ-MLV groups individually had BRD mortality rates of 1.6% and 0.3%, respectively. The difference in BRD mortality was not statistically significant (OR = 5.16, P = 0.1), but may be clinically or economically important as the magnitude of the difference was quite large. It therefore would be valuable to repeat this trial with greater power to determine if the difference in mortality is repeatable and significant.

The higher mortality rates of the IN primed calves could be related to the difference in BVDV antigen exposure. Only the IJ-MLV group received BVDV antigens at ~2 mo of age/branding vaccination due to lack of a commercially available monovalent BVDV vaccine in Canada to use with the IN vaccine. However, the effect of the BVDV antigen’s absence from the vaccine may not be important because the calves likely had high passively acquired BVDV antigen at the time of priming. Cows in the herd from which the calves originated were administered an annual pre-breeding booster of a MLV 5-way viral vaccine (BRSV, BHV1, PI3, BVDV types 1 & 2) to the dams. It is likely that the herd level of passive transfer amongst the calves was good and that the calves were seropositive for BVDV. It has been observed that seropositive calves have the same risk of disease due to BVDV as non-vaccinated controls (14). Therefore, it is likely that both groups of calves in the current study had the same risk of disease due to BVDV regardless of their priming vaccine type.

Despite the current study finding no difference between heterologous and homologous vaccination route prime-boost, it is important to continue to investigate IN-MLV priming within different vaccine protocols. The investigators of this study have found that IN-MLV primed and IJ inactivated vaccine boosted calves had reduced risk of disease after challenge with BRSV, compared to IJ-MLV boosted calves (15). Therefore, future BRD control research should include field studies comparing the effectiveness of IN-MLV primed and inactivated vaccine boosted vaccine protocols to the current vaccination approach which uses MLV vaccines for priming and boosting. CVJ