Safety of Vatan Inactivated or Modified Live Viral Reproductive Vaccine When Compared to Sterile Saline in Beef Cows
Corresponding author: Dr. George A. Perry, Department of Animal and Range Science, South Dakota State University, Brookings, South Dakota,USA. Tel: 605 688 5456; Email: George.Perry@sdstate.edu
Vaccinating female beef cattle with a modified live virus (MLV) has been an effective tool for reducing the risk of reproductive failure and fetal loss due to infections with Bovine Viral Diar- rhea virus (BVDV) and Bovine Herpesvirus (BHV-1) infections. [1-4] Inactivated virus vaccines, while providing some protec- tion, have not demonstrated the same levels of reproductive protection [2,5]. However, vaccination of naïve heifers with a MLV vaccine around the onset of standing estrus has been shown to have negative effects on corpus luteum (CL) function [6, 7] and pregnancy success . The effect on luteal function was not seen in previously vaccinated heifers . This negative impact on pregnancy success has been reported on not only first service conception rates, but also on a low percentage of animals conceiving on second service [8, 10], and in some heif- ers infected with BHV-1 at or near estrus, normal estrous cy- cles could be delayed for up to two months . Furthermore, BVDV antigen has been detected in the ovary up to 30 days post-vaccination  although the impact of this finding is not clear.
The effects of vaccination on estrus synchronization and con- ception rates are highly variable. Animals vaccinated with a MLV vaccine at least two times prior to synchronization pro- tocol (second dose administered 90 days prior to peak breed- ing day), and then vaccinated again 40 or 3 days prior to peak breeding (three doses total) resulted in no difference in con- ception rates between treatments . In an additional study in which the vaccination history was not reported and titer concentrations were not determined, heifers were vaccinated with a MLV vaccine either 30 or 9 days prior to the start of the AI breeding program with no differences in estrous response or pregnancy success between treatments . A recent study compared MLV to inactivated vaccine in naive heifers report- ed non-significant differences in pregnancy success between treatments . These heifers were vaccinated with either a MLV or inactivated vaccine 40 and 10 days prior to a 45 day breeding season (n = 30) or 61 and 31 days prior to a 45 day breeding season (n = 30).
heifers vaccinated at 61 and 31 days prior to breeding with an inactivated vaccine had a 15% greater pregnancy success com- pared to heifers vaccinated at 61 and 31 days prior to breed- ing with a MLV vaccine. The same study showed no impact on reproductive parameters in BHV-1 sero-positive heifers .
In the previously mentioned study animal numbers were small, limiting the ability to detect small differences in pregnancy success. However, with the large numerical differences noted between those vaccinated with a MLV vaccine and non-vacci- nated controls, the question arises, does vaccination 30 days prior to the start of an AI breeding season negatively influence breeding season pregnancy success? Therefore, the objective of the present study was to examine the differences in preg- nancy success between beef females vaccinated with either a MLV vaccine or an inactivated vaccine when compared to a non-vaccinated control group, with sufficient power to detect a difference of less than 10 % in pregnancy success between groups.
Materials and Methods
Protocols were reviewed and approved by both the South Da- kota State University and the North Dakota State University institutional animal care and use committees. All animals were managed according to herd standard operating procedures utilizing routine animal husbandry procedures.
Well vaccinated mature post-partum beef cows and beef heif- ers (n = 1436) in seven unique herds over 2 years (Table 1) were vaccinated according to the label (30 days prebreeding) with 1) a modified live vaccine 2) an inactivated vaccine, or 3) saline (non-vaccinated control; Figure 1). Prior to year 1 all cows had previously received Bovi-Shield GOLD® FP® 5 L5 HB annually prior to the start of the breeding season. In year 1, cows were grouped by parity, stratified by calving date and randomly assigned to one of the three treatments. In year 2, animals in herds 5 and 6 received the same treatment as in year 1.
Figure 1. Timeline for synchronization events and vaccination. PG-Prostaglandin F-2alpha (Lutalyse); Prog-Progesterone
(EAZI-BREED™ CIDR® implants); GnRH-Gonadotropin releasing hormone; AI- Artificial Insemination
Among heifers vaccinated 40 and 10 days prior to breeding, heifersvaccinated with the inactivated vaccine hada 20% great- er pregnancy success compared to MLV vaccine, and among
In both years, all animals were synchronized with the 7-day CO-Synch + CIDR protocol and artificially inseminated at the appropriate time after CIDR removal (cows 60 to 66 hours;
(3 to 13)
(33 to 127)
(3 to 11)
(34 to 101)
(3 to 13)
(37 to 99)
(33 to 99)
(3 to 13)
(29 to 97)
(3 to 13)
(31 to 97)
(67 to 120)
(67 to 123)
(67 to 121)
(5 to 11)
(49 to 107)
(5 to 11)
(50 to 108)
(5 to 11)
(52 to 104)
(2 to 4)
(45 to 128)
(2 to 4)
(53 to 127)
(2 to 5)
(58 to 129)
(2 to 11)
(34 to 86)
(2 to 10)
(46 to 93)
(2 to 11)
(40 to 93)
(2 to 4)
(53 to 102)
(2 to 4)
(51 to 99)
(2 to 4)
(51 to 97)
1Days Postpartum (interval from calving to fixed-time AI)
2AI Conception Rate
3Percentage of animals pregnant on day 56 of the breeding season
4Percentage of animals pregnant at the end of the breeding season
Table 1. Selected characteristics of each herds.
heifers 52 to 56 hours). Cows remained separated from bulls for at least 10 days after AI. Pregnancy success and fetal age were determined by transrectal ultrasonography 28 days after AI (year 1 and 2), 56 days after AI (year 1), and > 30 days after the end of the breeding season (year 1 and 2).
In year 1, mature cows in group 1 were administered their treatment, sterile saline at 60 days prior to fixed-time AI and a commercially available MLV vaccine (Bovi-Shield GOLD FP 5 L5 HB, Zoetis, Parsippany, NJ) containing BHV- 1, BVDV (types 1 and 2), bovine parainfluenza-3, and bovine respiratory syn- cytial virus, as well as Leptospira canicola, L. gryppotyphosa, L. hardjo, L. pomona, and L. icterohaemorrhagiae bacterin at 30 days prior to fixed-time AI. Virgin heifers received the same vaccine (Bovi-Shield GOLD FP 5 L5 HB) 60 and 30 days prior to fixed-time AI. Mature cows and virgin heifers in group 2 were vaccinated at 60 and 30 days prior to fixed-time AI with a com- mercially available inactivated vaccine (Vira Shield® 6+L5 HB, Elanco, Greenfield, IN). The inactivated vaccine contained the following viral fractions: BHV-1, BVDV (types 1 and 2), bovine parainfluenza-3, and bovine respiratory syncytial virus, and the following bacterial fractions: Leptospira canicola, L. gryp- potyphosa, L. hardjo, L. pomona, and L. icterohaemorrhagiae. Cows in group 3 were vaccinated at 60 and 30 days prior to fixed-time AI with sterile saline.
In year 2, virgin heifers, and mature cows in group 1 were vac- cinated in the same way as year 1. However, mature cows in group 2 only received a single vaccine at 30 days prior to fixed- time AI.
Synchronization and Breeding
Ten days prior to the start of the breeding season, all animals were administered progesterone as a vaginal insert (EAZI- BREED ™ CIDR® Cattle Insert, Zoetis, Parsippany, NJ) and gonadorelin hydrochloride (GnRH; Factrel® Injection, Zoetis, Parsippany, NJ; Figure 1). Vaginal inserts were removed and the heifers were administered dinoprost tromethamine [Pros- taglandin F2-alpha (PGF); Lutalyse® Sterile Solution, Zoetis, Parsippany, NJ] IM on day -3. Artificial insemination occurred at the appropriate time after CIDR removal (cows 60 to 66 hrs; heifers 52 to 56 hrs) and an injection of GnRH was given con- current with insemination. All females remained separated from fertile bulls for at least 10 days after AI. Pregnancy suc- cess and fetal age was determined by transrectal ultrasonogra- phy on day 28 after AI (year 1 and 2), 56 days after AI (year 1), and > 30 after the end of the breeding season (year 1 and 2). Presence of a fetal heartbeat was used to determine fetal via- bility and crown-rump length was used to determine fetal age.
Data were initially analyzed using the GLIMMIX procedure in SAS and included treatment, year, and the treatment by year interaction in the model. There was no treatment by year inter- action (P > 0.66) therefore herd was included in the statistical model as a random variable to account for unknown differenc- es between herds/years. Therefore, data were analyzed using the GLIMMIX procedure in SAS and included treatment, day postpartum, and the treatment by day postpartum interaction in the model and using the treatment by herd interaction as the error term. The goal of analyzing the data this way was to enable valid data interpretation across all herds.
Some cows were sold prior to calving for non-reproductive reasons (age, health, and disposition; n = 132). Thus calving data was calculated on cows exposed to breeding with cows sold for non-reproductive reasons removed from the analysis (n = 1304). Data were analyzed using the GLIMMIX procedure in SAS and included treatment, day postpartum, and the treat- ment by day postpartum interaction in the model and using the treatment by herd interaction as the error term. All data are reported as means ± standard error of the mean.
Synchronization and breeding
Days postpartum influenced conception rates with heifers and short postpartum cows having decreased AI conception rates compared to cows that were further postpartum (P < 0.05; Ta- ble 2). At the day 56 pregnancy determination (AI and 1 es- trus cycle with the bull) the effect of postpartum interval on pregnancy rates remained, with short postpartum cows (< 80 days post-partum at the start of the breeding season) having decreased pregnancy rates compared to cows that were > 80 days postpartum. After the breeding season, heifers still had decreased pregnancy rates compared to cows that were > 120 days postpartum at the start of the breeding season, but there was no difference in pregnancy rates between any groups of cows.
|Days Postpartum||n||AI Conception (%)||Day 56 Pregnancy Success (%)||Breeding Season Pregnancy
|Heifers||251||33 ± 4a||90 ± 2ab||94 ± 2a||4 ± 2|
|< 80||481||35 ± 5a||88 ± 3a||96 ± 2ab||2 ± 1|
|81 to 100||361||43 ± 4b||92 ± 2bc||96 ± 1ab||1 ± 1|
|101 to 120||235||50 ± 4bc||93 ± 1c||98 ± 1b||1 ± 1|
|>120||171||57 ± 4c||91 ± 1abc||98 ± 1b||1 ± 1|
Means within a column having difference superscripts are different
abc P< 0.05
Table 2. Impact of Postpartum Interval on Pregnancy Success.
At 56 days after AI, MLV animals had decreased pregnancy success compared to the Control groups (P ≤ 0.01), but there was no difference between the Inactivated and Control group.
Cite this article: George A. Perry. Safety of Vaccination with an Inactivated or Modified Live Viral Reproductive Vaccine When Compared to Sterile Saline in Beef Cows. J J Vet Sci Res. 2016, 2(2): 035.
Following the breeding season, pregnancy success was similar between MLV and Control (P = 0.34; Table 3) as well as be- tween the Inactivated and Control (P = 0.14; Table 3). While not intended as a comparison between the two vaccine groups, day 28 conception rates tended to differ between MLV and In- activated groups (P = 0.055) and conception rates in the Inac- tivated group were greater (P = 0.01).
|Vaccine||n||AI Conception (%)||Day 56 Pregnancy
|Breeding Season Pregnancy
|Modified Live||489||40.0 ± 4a||88.9 ± 2c||95.2 ± 2c||2 ± 1|
|Inactivated||471||46.5 ± 4b||93.2 ± 2d||98.0 ± 1d||2 ± 1|
|Saline||476||43.3 ± 4ab||92.5 ± 2d||96.4 ±1cd||2 ± 1|
Means within a column having different superscripts are different
abP = 0.055, cdP ≤ 0.01
Table 3. Impact of Vaccine on Pregnancy Success.
The percentage of cows that calved between day 1 and 12 of the calving season did not differ between MLV and Control groups (P = 0.50; Table 4) or between Inactivated and Control groups (P = 0.31). There was no difference in the percentage of cows that calved between days 13 to 30 among treatments (P > 0.41). Furthermore, there was no difference in percentage of cows that calved after day 30 among treatments (P > 0.15). When cumulative calving data was evaluated (Table 4), the per- centage of cows that calved by day 30 of the calving season did not differ between MLV and Control groups (P = 0.16) or be- tween Inactivated and Control groups (P = 0.78). Furthermore, the total percentage of cows that calved did not differ between MLV and Control (P = 0.86), but was decreased (P ≤ 0.02) in MLV and Control groups compared to Inactivated group.
|Vaccine||n||Day 1 to 12||Day 13 to 30||Day >30||Day 1 to 30||Calving Season|
|Modified Live||489||50.0 ± 4a||21.3 ± 4||27.4 ± 6||69.5 ± 4a||94.8 ± 2c|
|Inactivated||471||56.0 ± 4b||23.5 ± 4||23.2 ± 5||74.4 ± 3b||97.3 ± 1d|
|Saline||476||52.4 ± 4ab||21.2 ± 3||26.4 ± 5||73.6 ± 4ab||95.0 ± 2c|
Means within a column having different superscripts are different
abP < 0.10, cdP ≤ 0.02
Table 4. Impact of Vaccine on Calving Distribution.
Days postpartum influenced conception rates with heifers and cows less than 80 days postpartum having decreased AI con- ception rates compared to cows that were greater than 100 days postpartum. This is similar to other published studies where conception rates were improved among animals with longer postpartum intervals compared to animals with short- er postpartum intervals [16, 17]. Furthermore, there was no
difference in AI or breeding season conception rates between animals vaccinated with MLV or saline or between animals vaccinated with an inactivated vaccine and saline. Few studies have attempted to measure the effect of vaccinating well vacci- nated (nonnaïve) beef animals [18, 19]. One deficiency in these studies is the lack of true control (non-vaccinated animal) against which to measure conception rates. In this regard, it is difficult to draw a conclusion regarding vaccination timing and its effect on ovarian function and conception rates in well vaccinated animals. A recent study in dairy cattle reported no difference in conception rates between vaccinating previously vaccinated primiparous dairy cows (3 MLV as calves and 1 pre- breeding as a heifer) with either a MLV or inactivated vaccine 45 days prior to FTAI .
In the present study there was only a significant difference between MLV and saline controls and between MLV and inac- tivated for the 56 day pregnancy success. The importance of the 56 day pregnancy determination is that this represents cows that will calve during the first 30 days of the calving season; numerous studies have reported that cows that calve early in the calving season are more likely to conceive during the subsequent breeding season, with increased longevity in the herd compared to animals that calve later in the calving season [20-22]. It was surprising that among well vaccinated animals, even though neither treatment group was statistically different from controls, there tended to be a difference in AI conception rates between animals vaccinated with a MLV and an inactivated vaccine. This difference was significant at day 56 and after the breeding season between animals vaccinated with a MLV and an inactivated vaccine. However, the reason for this difference is unknown since a similar difference was not seen between the MLV and controls.
Any discussion on vaccine safety must be coupled with the ability of the various vaccine options to provide reproductive and fetal protection. If disease challenge or the potential of ex- posure were not of concern then omitting reproductive vac- cination would be the ultimate “safe” intervention. However, the benefit of reproductive vaccines in breeding age animals has been shown by multiple studies indicating both better and longer protection when MLV BVDV and BoHV1 vaccines are used .
In summary, while vaccination with a MLV vaccine 30 days pre- breeding tended to decrease pregnancy success to AI, vacci- nation with either a MLV or inactivated reproductive vaccine 30 days pre-breeding resulted in similar pregnancy rates and calving distributions as non-vaccinated Controls. The find- ings suggest that the potential small decrease in reproduction caused by MLV vaccination should be balanced with the in- creased protection provided by these vaccines when making vaccine decisions.
The authors thank David Gay, Christina Mogck, Doug Young, for technical assistance. This study was supported by Zoetis.
- Givens MD, Marley MS, Jones CA, Ensley DT, Galik PK,et al. Protective effects against abortion and fetal infection following exposure to bovine viral diarrhea virus and bovine herpesvi- rus 1 during pregnancy in beef heifers that received two doses of a multivalent modified-live virus vaccine prior to breeding. J Am Vet Med Assoc,2012.241(4):484–495.
- Rodning SP, Marley MS, Zhang Y, Eason AB, Nunley CL,et al. Comparison of three commercial vaccines for preventing per- sistent infection with bovine viral diarrhea virus. Therio, 2010. 73:1154–1163.
- Ficken MD, Ellsworth MA, Tucker CM.Evaluation of the Effi- cacy of a Modified-Live Combination Vaccine against Abortion Caused by Virulent Bovine Herpesvirus Type 1 in a One-Year Duration-of-Immunity Study. Vet Ther, 2006; 7(3): 275-282.
- Ellsworth MA, Jackson JA, Goodyear M, Oien NL, Meinert TR.Fetal Protection Following Exposure to Calves Persistent- ly Infected with Bovine Viral Diarrhea Virus Type 2 Sixteen Months after Primary Vaccination in Dams. Veterinary Thera- peutics. 2006,7(3):295-305.
- ZimmermannAD, Buterbaugh RE, Herbert JM, Hass JM, Frank NE, Luempert III LG, Chase CCL. Efficacy of bovine herpsesvi- rus-1 inactivated vaccine against abortions and stillbirth in pregnant heifers. JAVMA 231(9) 1386-89, 2007.
- Van der Maaten, M.J. and J.M. Miller, Ovarian lesions in heifers exposed to infectious bovine rhinotracheitis virus by non-genital routes on the day after breeding. Vet Mi- cro,1985,10(2):155-163.
- Smith PC, Nusbaum KE,Kwapien.RP,Stringfellow DA,Drig- gers K.Necrotic oophoritis in heifers vaccinated intravenously with infectious bovine rhinotracheitis virus vaccine during es- trus. Am J Vet Res,1990;51(7): 969-72.
- Chiang BC,Smith PC,Nusbaum KEandStringfellow DA.The effect of infectious bovine rhinotracheitis vaccine on reproduc- tive efficiency in cattle vaccinated during estrus. Theriogenolo- gy.1990 33(5):1113-1120.
- Spire MF, Edwards JF, Leipold HW, Cortese VS. Absence of Ovarian Lesions in IBR Seropositive Heifers Subsequently vaccinated with a modified live IBR vaccine vaccinated with a Modified Live Virus Vaccine. Agripractice,1995.16(7): 33-38.
- Perry GA,Zimmerman AD,Daly RF,Buterbaugh RE,Rhoades J.The effects of vaccination on serum hormone concentrations and conception rates in synchronized naive beef heifers. Ther- iogenology,2013,79(1):200-205.
- Miller JMandVan der Maaten MJ.Effect of primary and re- current infections bovine rhinotracheitis virus infection on the bovine ovary. Am J Vet Res, 1985; 46(7): 1434-1437.
- Grooms DL,Brock KV,andWard LV.Detection of cytopathic bovine viral diarrhea virus in the ovaries of cattle following immunization with a modified live bovine viral diarrhea virus vaccine. J Vet Diagn Invest,1998,10(2):130-134.
- Bolton M,Brister D,Burdett B,Newcomb H,Nordstrom S,Re- productive safety of vaccination with Vista 5 L5 SQ near breed- ing time as determined by the effect on conception rates. Vet Ther. 2007,8(3):177-182.
- Stormshak F,Tucker CM,Beal WE,and Corah LR,Reproduc- tive responses of beef heifers after concurrent administration of vaccines, anthelmintic and progestogen. Theriogenology, 1997; 47(5):997-1001.
- Walz PH,Edmondson MA,Riddell KP,Braden TD,Gard JA.et al. Effect of vaccination with a multivalent modified-live viral vaccine on reproductive performance in synchronized beef heifers.Theriogenology, 2015,83(5):822-831.
- Larson JE,Lamb GC,Stevenson JS,Johnson SK,Day ML.Syn- chronization of estrus in suckled beef cows for detected estrus and artificial insemination and timed artificial insemination using gonadotropin-releasing hormone, prostaglandin F2al- pha, and progesterone. J Anim Sci, 2006, 84(2):332-342.
- Stevenson JS,Johnson Sk,Milliken GA. Symposium Paper: Incidence of postpartum anestrus in suckled beef cattle: Treat- ments to induce estrus, ovulation, and conception. Prof. Anim. Sci., 2003;19:124-134.
- Walz PH,Montgomery T,Passler T,Riddell KP,Braden TD. Comparison of reproductive performance of primiparous dairy cattle following revaccination with either modified-live or killed multivalent viral vaccines in early lactation.J Dairy Sci. 2015, 98(12):8753-8763.
- Burris MJ.and Priode BM. Effect of calving date on subse- quent calving performance. J. Anim. Sci., 1958; 17: 527- 533.
- Cushman RA,Kill LK,Funston RN,Mousel EM and Per- ry GA,Heifer calving date positively influences calf weaning weights through six parturitions. J Anim Sci, 2013; 91(9): 4486-4491.
- Lesmeister JL,Burfening PJand Blackwell RL,Date of first calving in beef cows and subsequent calf production. J. Anim. Sci.1973, 36:1-6.
- Cortese VS.Bovine vaccinesan herd vaccinatoon programs in Large Animal Internal Medicine 5th ed. Smith BP 2014 Else- vier, St. Louis MO 2012; 1465:1471.