reproductive vaccination- -...

Reproductive Vaccination-

Deciphering the MLV

impact on fertility

Decision

•Prebreeding Vaccination of Cattle should• Provide fetal & abortive protection (BVD and

BoHV-1)

• Not impede reproduction

• Impact of MLV vaccine prior to estrus synchronization?

Safety Efficacy

0 10 20 30 40 50 60 70 80 90 100 110 120

C Ranch

O Ranch

W Ranch

S Ranch

Day of Calving Season

Perc

en

tag

e o

f C

alv

es B

orn

Which ranch is likely to be more profitable?

Calving Distribution

Which ranch is better able to take advantage of selling truckload lots?Which ranch is best able to take advantage of early weaning?

0 1 2 3 4 5 6 7 8

9 Months of Gestation

Infertility:

Infection of

ovaries,

interference

with

cyclicity

Sporadic Abortions in Vaccinated Herds

Timeline For IBR and Effects on Reproduction

Spontaneous Abortion

Abortion Storms in Susceptible Herds

Adapted from Youngquist, Current Therapy

in Large Animal Theriogenology, Ch 48, 1997.

Decision

Safety

Efficacy

Phases of Estrous Cycle

Senger, P.L. “Pathways to Pregnancy and Parturition” Current Conceptions Inc. 2nd Edition

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

• 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

Materials and Methods

• 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

Results

• 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

Case History

• 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

Observations

• 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

Conclusion

“The effects of vaccination on serum hormone concentrations and conception rates in synchronized naïve beef heifers”

Perry GA, et al., Theriogenology 2012

•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

Materials and methods

*ViraShield® 6+VL5 HB, ̌Inactivated Sterile Water Placebo, Novartis Animal Health US, Inc.

^Bovi-Shield GOLD® FP® 5 VL5, Zoetis Inc.Perry, et al., Theriogenology 2012

•Abnormal estrus cycle (<15 days)

•Plasma P4 concentrations• During the synchronization period

• After AI

•Plasma E2 concentrations

•Pregnancy rates

Measurements

Perry, et al., Theriogenology 2012

•MLV vaccinated heifers had higher % abnormal cycles

•MLV vaccinated heifers had lower E2 concentrations

•Pregnancy rates were lower in heifers that received MLV vaccine

Outcome

Perry, et al., Theriogenology 2012

•Naïve heifers

•Vaccinated inside of time prior to breeding as on label directions

Outcome

• 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 initial detected estrus:

Animals

Walz et al. Theriogenology 2015

Group Product 1st Vaccination 2nd Vaccination

A (n=20) Express® FP

VL5

2 Days After Detected

Estrus

10 Days Prior to Breeding

B (n=20) Express® FP

VL5

2 Days After Detected

Estrus


C (n=10) Citadel® VL5 2 Days After Detected

Estrus


D (n=10) Citadel® VL5 2 Days After Detected

Estrus


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.


• 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

Measurements


Results:Interestral Intervals and Response to Estrus Synchronization

Group 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


Results:Interestral Intervals and Response to Estrus Synchronization

Group 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

Vaccination with Express® FP 5-VL5 did not

result in negative reproductive impact based on:

• Duration of 1st or 2nd 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


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%)

4.2

Group B 1/20 (5%) 17/20 (85%) 15/20

(75%)

3.1

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

p-value P=0.72 P=0.177 P=0.556 P=0.459


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%)

4.2

Group B 1/20 (5%) 17/20 (85%) 15/20

(75%)

3.1

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

p-value P=0.72 P=0.177 P=0.556 P=0.459

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


•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

Results


First Service Conception Rates

Following Vaccination with

Express® FP 5

C. Jones, K. Haden, D. Robbins

BIVI Tech Bulletin 03-106R-1

Effect of Vaccination on First Service Conception Rates

Study conducted in a commercial

cow/calf operation that was on a

routine MLV vaccination program.

• 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.

Rationale for Study

• 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

Background

• Grooms DL, et al. J Vet Diagn Invest 1998; 10:130-134.• 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 sero-

negative cows 30 days post-vaccination with MLV

• Chiang BC, et al. Theriogeniology 1990; 33:1113-1120.• Reduction in conception rate when sero-negative heifers

were vaccinated with a modified live IBR just prior to turning with bulls.

Background (continued)

• 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.

Objective

• 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

Protocol

Treatment Groups

N Vaccination Timing Vaccines

Group 1 96 4 weeks prior to AI

Express® FP 5

Vibrio-Lepto-5

Group 2 95 10 days prior to AI

Express® FP 5

Vibrio-Lepto-5

MGA .5mg/hd/d

28 Days

10 Days

Vaccination and Synchronization Timeline

Group 1

Vaccinated

Sto

p M

GA

Start

MGAGnRH

Group 2

Vaccinated

2n

d

PG

F 2ά

GnRH

and A.I.

8 Days 7 Days 1 Day 3 Days 7 Days 60 hours

1st

PG

F 2ά

All cows were fed MGA and injected with PGF2ά and GnRH.

• 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.

Protocol (continued)

Results

First Service Conception Rate

# Pregnant # Open Total % Pregnanta

Group 1 51 45 96 53.1%

Group 2 49 45 94b 52.1%

aNo significant difference between groups 1 and 2 (p>.05).bOne 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.

Results

Overall Pregnancy Rate

# Pregnant # Open Total % Pregnanta

Group 1 92 4 96 95.8%

Group 2 87 7 94 92.5%

aNo significant difference between groups 1 and 2 (p>.05).

• 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 pre-breeding MLV vaccine in the years prior to the study.

Summary

Decision Safety

Efficacy

Timeline of BVDV Effects on Reproduction

0 1 2 3 4 5 6 7 8 9

Months of Gestation

Persistent Infection

Adapted from Grooms, 2004

EED

Abortion

Congenital Defects

Congenital Infections (

Cl)

INFERTILITY

• 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

Express® FP Vaccines PreventBVDV Persistent Infection

Challenge

Virus

Treatment

Group

# Positive/

Total

Total %

Protected

BVDV Type

1b

(3 Studies)

Vaccinates

Controls

2 of 51

38 of 41

96%

7%

BVDV Type 2

(4 Studies)

Vaccinates

Controls

2 of 64

50 of 51

97%

2%

Summary of All BVDV Label Studies

• First vaccine labeled for prevention of persistently infected calves

• First vaccine with written financial guarantee

Express® FP Vaccines

Challenge Virus Treatment Group PI Positive

BVDV Type 1b Vaccinates

Controls

1/22 (4.5%)

20/23 (87.0%)

BVDV Type 2 Vaccinates

Controls

0/18 (0%)

21/22 (95.5%)

Protection Against Persistent Infection1 Year After Vaccination

A single dose of Express® FP 5-VL5 administered one

year prior to challenge with BVDV Type 1b or Type 2:• Demonstrated fetal protection against persistent infection

Zimmerman A., et al, The Bovine Practitioner 47, 1 (2013)

Challenge

Virus

Treatment

Group

Abortions

Cooper IBR Controls 18/19 (94.7%)

Cooper IBR Vaccinated 12

months

2/13

(15.4%)

p<0.0001

IBR Abortion Challenge

A single dose of Express® FP 5-VL5 administered one

year prior to challenge with IBR Cooper Strain:• Demonstrated protection against IBR abortion for 12 months

Zimmerman A., et al, The Bovine Practitioner 47, 2 (2013)

Decision

Safety Efficacy

• IBR vaccination of pregnant cows & heifers is

potentially the highest risk of causing abortions.

• 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

Conclusion

When designing heifer, pre-breeding

vaccination programs, vaccination history

should be carefully considered and multivalent

MLV vaccines should be used according to

label directions.

Decision

Safety Efficacy







Decision

Safety Efficacy







Conclusion

When designing heifer, pre-breeding

vaccination programs, vaccination history

should be carefully considered and multivalent

MLV vaccines should be used according to

label directions.

Thank you!

Final questions?

reproductive vaccination- -...

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