Reproductive Vaccination- Deciphering the MLV impact on fertility

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1 Reproductive Vaccination- Deciphering the MLV impact on fertility

2 Safety Decision Efficacy Prebreeding Vaccination of Cattle should Provide fetal & abortive protection (BVD and BoHV-1) Not impede reproduction Impact of MLV vaccine prior to estrus synchronization?

3 Percentage of Calves Born Calving Distribution C Ranch O Ranch W Ranch S Ranch Day of Calving Season Which ranch is likely to be more profitable? Which ranch is better able to take advantage of selling truckload lots? Which ranch is best able to take advantage of early weaning?

4 Timeline For IBR and Effects on Reproduction Infertility: Infection of ovaries, interference with cyclicity Spontaneous Abortion Sporadic Abortions in Vaccinated Herds Abortion Storms in Susceptible Herds Months of Gestation Adapted from Youngquist, Current Therapy in Large Animal Theriogenology, Ch 48, 1997.

5 Decision Efficacy Safety

6 Phases of Estrous Cycle Senger, P.L. Pathways to Pregnancy and Parturition Current Conceptions Inc. 2 nd Edition

7 Infertility in heifers inoculated with modified-live bovine herpesvirus-1 vaccinal strains against infectious bovine rhinotracheitis on postbreeding day 14 J.M. Miller, DVM PhD; M.J. Van Der Maaten, DVMm PhD: C.A. Whetstone, Ph D Am J. Vet Res, Vol 50, No. 4, April 1989

8 Materials and Methods Inocula Four BHV-1 strains-originated from a repository of expired MLV-1 vaccines against IBR Heifers 10 originated from a herd with no history of vaccination for IBR Mated to a seronegative bull by natural service Experimental Design On postbreeding day (PBD) 14 2 heifers inoculated IV with 5 ml of 1 of 4 strains of BHV-1 (total of 8 heifers) Controls-2 heifers inoculated IV with 5 ml of noninfected cell culture Serurm was obtained prior to inoculation to check SN titers Blood was collected for plasma progesterone at 1 to 3 day intervals beginning on day of inoculation and continued till PBD 60

9 Results BHV-1 was isolated from at least 1 nasal, vaginal swab, and blood sample from each of the 8 heifers inoculated with a BHV-1 vaccinal strain Plasma progesterone tests indicated Control heifers remained pregnant 2 months post breeding 4 of 8 inoculated heifers remained pregnant 2 months post breeding Pregnancy failure was observed in 4 heifers Conclusion MLV BHV-1 vaccine may result in loss of pregnancy

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11 Case History 55 healthy excellently managed, confirmed pregnant Angus-cross heifers from the University of Wyoming herd vaccinated at 7-8 months of gestation Vaccinated with MLV in May 2010 prebreeding

12 Observations Abortions 32 days post vaccination Diagnostics conducted on six of seven aborted fetuses and one heifer that died Six heifers confirmed pregnant by ultrasound on vaccination found open at calving Lossed 14 pregnancies

13 Conclusion Diagnostic tests found numerous expressions of IBR symptoms and BoHV-1 antigens present in aborted fetuses NO BVDV was detected in aborted fetuses Abortions and pregnancy losses among the heifers in this study were observed following the use of a BoHV-1 MLV vaccine

14 The effects of vaccination on serum hormone concentrations and conception rates in synchronized naïve beef heifers Perry GA, et al., Theriogenology 2012

15 Materials and methods 59 heifers naïve to BoHV-1 and BVD Group 1 (n=21): 2 doses inactivated vaccine* 36 & 8 days prior to AI Group 2 (n=7): 1 dose inactivated vaccine* 8 days prior to AI Group 3 (n=21): 1 dose MLV vaccine^ 8 days prior to AI Group 4 (n=10): 2 doses placebo 36 & 8 day prior to AI All, bred AI and then with bulls 14 days *ViraShield 6+VL5 HB, Ǐnactivated Sterile Water Placebo, Novartis Animal Health US, Inc. ^Bovi-Shield GOLD FP 5 VL5, Zoetis Inc. Perry, et al., Theriogenology 2012

16 Measurements Abnormal estrus cycle (<15 days) Plasma P4 concentrations During the synchronization period After AI Plasma E2 concentrations Pregnancy rates Perry, et al., Theriogenology 2012

17 Outcome MLV vaccinated heifers had higher % abnormal cycles MLV vaccinated heifers had lower E2 concentrations Pregnancy rates were lower in heifers that received MLV vaccine Perry, et al., Theriogenology 2012

18 Outcome Naïve heifers Vaccinated inside of time prior to breeding as on label directions

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20 Animals 60 Beef Heifers naïve to BVDV/BoHV-1 with reproductive tract scores 3 (scale 1-5) Heifers randomly assigned to groups and vaccinated 2 days after Express initial FP detected 2 Days After estrus: Detected Group Product 1 st Vaccination 2 nd Vaccination A (n=20) B (n=20) VL5 Express FP VL5 Estrus 2 Days After Detected Estrus C (n=10) Citadel VL5 2 Days After Detected Estrus 10 Days Prior to Breeding 31 Days Prior to Breeding 10 Days Prior to Breeding D (n=10) Citadel VL5 2 Days After Detected Estrus 31 Days Prior to Breeding Walz et al. Theriogenology 2015

21 Fig. 1. Experimental design and timeline for vaccine administration, collection of samples, synchronization of estrus, and submission to breeding group. Events occurring after submission to the breeding group are not included. Group A heifers (n=20) were revaccinated with Express FP 5 VL5 at 10 days before synchronized natural breeding ((short prebreeding interval). Group B heifers (n=10) were revaccinated with Express FP 5 VL5 at 31 days before synchronized natural breeding (long prebreeding interval). Group C heifers (n=10) were administered Citadel VL5 at 10 days before synchronized natural breeding (control short prebreeding interval). Group D heifers (n=10) were administered Citadel VL5 at 31 days before synchronized natural breeding (control long prebreeding interval). BP,=breeding pen; CIDR-controlled internal drug release; P4=porgesterone. Walz et al. Theriogenology 2015

22 Measurements Interestral intervals Proportion of heifers exhibiting estrus within 5 days after synchronization Serum progesterone & estrogen Pregnancy rates end of the study first 5 days of the breeding season Mean day of conception Embryonic loss Ovarian and conceptus tissues were assayed for BVDV and BoHV-1 Walz et al. Theriogenology 2015

23 Group Results: Interestral Intervals and Response to Estrus Synchronization First interestrus interval (days) Second interestrus interval (days) Heifers exhibiting estrus in first 5 days of breeding season Group A 19.2 (n=20) 22.5 (n=19) 19/20 (95%) Group B 19.1 (n=20) 22.1 (n=20) 17/20 (85%) Group C 20.0 (n=10) 21.3 (n=10) 9/10 (90%) Group D 20.1 (n=10) 20.6 (n=10) 9/10 (90%) p-value P=0.449 P=0.801 P=0.774 Walz et al. Theriogenology 2015

24 Group Results: Interestral Intervals and Response to Estrus Synchronization First interestrus Second interestrus Vaccination with Express FP 5-VL5 did not interval (days) interval (days) result in negative reproductive impact based on: Duration of 1 st or 2 nd interestrus intervals Proportion of heifers exhibiting estrus within 5 days of synchronization Mean day of conception Pregnancies resulting from the first five days of the breeding season Heifers exhibiting estrus in first 5 days of breeding season Group A 19.2 (n=20) 22.5 (n=19) 19/20 (95%) Group B 19.1 (n=20) 22.1 (n=20) 17/20 (85%) Group C 20.0 (n=10) 21.3 (n=10) 9/10 (90%) Group D 20.1 (n=10) 20.6 (n=10) 9/10 (90%) p-value P=0.449 P=0.801 P=0.774 Walz et al. Theriogenology 2015

25 Results: Pregnancy Rates and Mean Day of Conception Within Breeding Season Group Embryonic loss detected prior to study end date Pregnant at study end date Pregnant at study end from first 5 days of breeding season Mean day of conception within breeding season Group A 2/20 (10%) 14/20 (70%) 12/20 (60%) Group B 1/20 (5%) 17/20 (85%) 15/20 (75%) Group C 1/10 (10%) 9/10 (90%) 6/10 (60%) 5.3 Group D 0/10 (0%) 10/10 (100%) 5/10 (50%) 6.3 Walz et al. Theriogenology 2015 p-value P=0.72 P=0.177 P=0.556 P=0.459

26 Group Results: Pregnancy Rates and Mean Day of Conception Within Breeding Season Embryonic loss detected prior to study end date Pregnant at study end date Pregnant at study end from first 5 days of breeding season Vaccination with Express FP 5-VL5 did not result in negative reproductive impact based on: Embryonic loss detected prior to the end of the study Pregnancy rates at the end of the study Group A 2/20 (10%) 14/20 (70%) 12/20 (60%) Group B 1/20 (5%) 17/20 (85%) 15/20 (75%) Mean day of conception within breeding season Group C 1/10 (10%) 9/10 (90%) 6/10 (60%) 5.3 Group D 0/10 (0%) 10/10 (100%) 5/10 (50%) 6.3 Walz et al. Theriogenology 2015 p-value P=0.72 P=0.177 P=0.556 P=0.459

27 Results Vaccination with Express FP 5-VL5 did not result in negative reproductive impact based on: Serum progesterone concentrations during estrus and diestrus Serum estrogen concentrations following initial vaccination or in the breeding pen BVDV was not detected in luteal tissue, ovarian tissue, or fetal tissues BoHV-1 was not detected in luteal tissue, ovarian tissue, or fetal tissues Walz et al. Theriogenology 2015

28 First Service Conception Rates Following Vaccination with Express FP 5 C. Jones, K. Haden, D. Robbins BIVI Tech Bulletin R-1

29 Effect of Vaccination on First Service Conception Rates Study conducted in a commercial cow/calf operation that was on a routine MLV vaccination program.

30 Rationale for Study First Service Conception Rates Following Vaccination with Breed-Back FP 5 (Express FP 5) Vaccine Previous studies Vaccination of sero-negative cows with MLV vaccine just prior to breeding, may reduce fertility This has impacted pre-breeding vaccination practices in beef and dairy cows.

31 Background Modified live IBR and BVD are commonly used to vaccinate cows prior to breeding An immune response is stimulated following replication of the modified live viruses There is a concern that the replicating viruses may invade the ovary, interfere with ovarian function, and result in infertility

32 Background (continued) Grooms DL, et al. J Vet Diagn Invest 1998; 10: Isolated BVD virus from ovaries of sero-negative heifers on day 12 following vaccination with MLV Showed presence of BVD antigen in the ovaries of seronegative cows 30 days post-vaccination with MLV Chiang BC, et al. Theriogeniology 1990; 33: Reduction in conception rate when sero-negative heifers were vaccinated with a modified live IBR just prior to turning with bulls.

33 Objective To evaluate if Express FP 5 administered 10 days prior to breeding will reduce first service conception rates and overall pregnancy rates in cows that had been vaccinated with a modified live IBR and BVD vaccine prior to previous breeding seasons.

34 Protocol 191 cows were sorted into two groups based on age and days post-calving All cows were 2 years of age All cows had received at least two MLV vaccines as heifers and had been vaccinated with MLV vaccine prior to each of the previous breeding seasons All were synchronized with the 7-11 Synch program and were time bred 60 hours following the second prostaglandin injection

35 Treatment Groups N Vaccination Timing Vaccines Group weeks prior to AI Group days prior to AI Express FP 5 Vibrio-Lepto-5 Express FP 5 Vibrio-Lepto-5

36 Vaccination and Synchronization Timeline 8 Days 7 Days 1 Day 3 Days 7 Days 60 hours MGA.5mg/hd/d Group 1 Vaccinated Start MGA Stop MGA 1st PGF 2ά GnRH Group 2 Vaccinated 10 Days 2 nd PGF 2ά GnRH and A.I. 28 Days All cows were fed MGA and injected with PGF2ά and GnRH.

37 Protocol (continued) Bulls were turned with cows six days following AI. All cows were pregnancy checked using ultrasound 33 days after AI. Cows open 33 days following AI were pregnancy checked via ultrasound 35 days after removal of bulls.

38 Results First Service Conception Rate # Pregnant # Open Total % Pregnant a Group % Group b 52.1% a No significant difference between groups 1 and 2 (p>.05). b One cow culled prior to pregnancy check. Note: The first service conception rates were consistent with previous years in which the same synchronization and fixed-time breeding program were used in this herd.

39 Results Overall Pregnancy Rate # Pregnant # Open Total % Pregnant a Group % Group % a No significant difference between groups 1 and 2 (p>.05).

40 Summary The first service conception rate and overall pregnancy rate were not significantly different in cows vaccinated with Express FP 5 ten days prior to artificial insemination versus cows vaccinated four weeks prior to artificial insemination. Cows utilized in this study had received a yearly prebreeding MLV vaccine in the years prior to the study.

41 Decision Safety Efficacy

42 Timeline of BVDV Effects on Reproduction I N F E R T I L I T Y EED Persistent Infection Congenital Defects Congenital Infections ( Cl) Abortion Months of Gestation Adapted from Grooms, 2004

43 Express FP Vaccines Prevent BVDV Persistent Infection Prevention of persistent infection caused by BVDV Type 1 (including 1b) & Type 2 4 different non-cytopathic BVDV challenge viruses 2 BVDV Type 1b 2 BVDV Type 2 7 different challenge studies

44 Summary of All BVDV Label Studies Challenge Virus Treatment Group # Positive/ Total Total % Protected BVDV Type 1b (3 Studies) Vaccinates Controls 2 of of 41 96% 7% BVDV Type 2 (4 Studies) Vaccinates Controls 2 of of 51 97% 2%

45 Express FP Vaccines First vaccine labeled for prevention of persistently infected calves First vaccine with written financial guarantee

46 Protection Against Persistent Infection 1 Year After Vaccination Challenge Virus Treatment Group PI Positive BVDV A single Type dose 1bof Express Vaccinates FP 5-VL5 administered 1/22 (4.5%) one Controls year prior to challenge with BVDV Type 1b or Type 2: BVDV Type 2 Vaccinates 0/18 (0%) 20/23 (87.0%) Demonstrated fetal protection against persistent infection Controls 21/22 (95.5%) Zimmerman A., et al, The Bovine Practitioner 47, 1 (2013)

47 IBR Abortion Challenge Challenge Virus Treatment Group Abortions Cooper IBR Controls 18/19 (94.7%) A single dose of Express FP 5-VL5 administered one Cooper year prior IBRto challenge Vaccinated with 12 IBR Cooper 2/13 Strain: months (15.4%) p< Demonstrated protection against IBR abortion for 12 months Zimmerman A., et al, The Bovine Practitioner 47, 2 (2013)

48 Decision IBR vaccination of pregnant cows & heifers is potentially the highest risk of causing abortions. Safety Conclusion Efficacy Modified live IBR vaccine should be given to heifers When designing heifer, pre-breeding at least 30 days prior to breeding. vaccination programs, vaccination history should be carefully considered and multivalent MLV vaccines should be used according to label directions. If heifers are not properly vaccinated they should not be vaccinated with MLV vaccines during pregnancy

49 Decision IBR vaccination of pregnant cows & heifers is potentially the highest risk of causing abortions. Safety Efficacy Modified live IBR vaccine should be given to heifers at least 30 days prior to breeding. If heifers are not properly vaccinated they should not be vaccinated with MLV vaccines during pregnancy

50 Decision IBR vaccination of pregnant cows & heifers is potentially the highest risk of causing abortions. Safety Conclusion Efficacy Modified live IBR vaccine should be given to heifers When designing heifer, pre-breeding at least 30 days prior to breeding. vaccination programs, vaccination history should be carefully considered and multivalent MLV vaccines should be used according to label directions. If heifers are not properly vaccinated they should not be vaccinated with MLV vaccines during pregnancy

51 Thank you! Final questions?