Professor Bonnie MallardOntario Veterinary College

Centre of Genetic Improvement of Livestock

FarmSmart ConferenceJan 18 2020Guelph, ON

Breeding Livestock for Resilience:The High Immune Response Technology

FarmSmart Learner Outcomes

A farm to fork perspective on how state-of-the-art genetic & genomics technologies play a important role in managing disease in livestock.

How these methods contribute to economically and environmentally sustainable food production.

How breeding livestock for resilience can be used by industry to improve livestock health and increase farm profit.

Outline

1. Immuno-genetic approaches to health

2. The High Immune Response (HIR™) technology

3. Heritability of immune response traits

4. Economic benefits of selecting for improved immunity

5. Commercial tests for immune responsiveness – Immunity+

6. First genomics test for immunity

7. Other genomics tests for disease resistance (e.g. Zoetis Clarifide

and UK bTB Advantage)

What is the High Immune Response (HIR™) Technology?

Overview of HIR™

HIR IS A PATENTED TEST METHOD THAT PROVIDES A WAY TO IDENTIFY ANIMALS WITH INHERENTLY SUPERIOR IMMUNITY AND ENHANCED DISEASE RESISTANCE.

HIR CAN BE USED BY LIVESTOCK PRODUCERS AS A MANAGEMENT AND BREEDING TOOL TO NATURALLY IMPROVE THE HEALTH OF THEIR HERD.

HIR PROVIDES BENEFITS TO THE PRODUCER, THE CONSUMER AND THE ANIMAL THROUGH REDUCED USE OF ANTIBIOTICS AND OTHER THERAPEUTICS RESULTING IN A HEALTHY SUSTAINABLE FOOD CHAIN.

MARKETED BY SEMEX ALLIANCE INC AS, Immunity+™

Mallard et al. 1998. Proc. WCGALP 27:257

Immune

Response

Traits

Antibody to Test

Antigen

(HEWL)

Delayed-type

hypersensitivity

(PPD)

Lymphocyte

Proliferation

(ConA)

Serum

Immunoglobulin

(IgG)

Yorkshire Pigs Selected for

High & Low Immune

Responses based on EBVs

CONTROL

-1.5

-1

-0.5

0

0.5

1

1.5

0 1 2 3 4 5 6 7 8

GENERATION

EB

Vs

HIGH

LOW

1980’s – 1990’s

Estimated Breeding Values of Pigs Ranked

Within High, Control & Low Immune Response Lines

Wilkie and Mallard. 1999. Selection for High Immune Response. Vet Immunol Immunopath 72(1-2):231

ANTIBODY RESPONSE toA. pleuropneumoniae Bacterin Vaccine

G4 Pigs Selected for High and Low IR

NON RESPONDERS

High = 4%

Low = 19%

Control = 22%0

0.1

0.2

0.3

0.4

0.5

0.6

day 0 day 14 day 21

HighControlLow

Log o

f O

D @

1/8

00d

il’n

of

sera a

b ba

b

c

Wilkie and Mallard. 1999. Adv. Vet. Med. 41:39

0 1 2 3 4 5 6 7

HIGH

CONTROL

LOW

140

145

150

155

160

165

170

175

180

DAYS

GENERATION

HIGH

CONTROL

LOW

Average Days to 100 Kg of Pigs Selected

For High & Low Immune Responses

Wilkie and Mallard. 1999. Vet Immunol Immunopath 72(1-2):231

Lo

w A

MI R

Av

er a

ge

AM

I R

Hi g

h A

MI R

0

2 0

4 0

6 0

7 0

7 2

7 4

7 6

7 8

8 0

S u r v i v a l R a t e o f ~ 1 9 0 0 I m m u n e R e s p o n s e P h e n o t y p e d

F 1 B a r r o w s : A n t i b o d y - m e d i a t e d I m m u n e R e s p o n s e

% M

or

ta

lity

L o w A M I R

A v e r a g e A M I R

H i g h A M I R

p = 0 . 0 4 ( C h i - s q u a r e T e s t f o r T r e n d )

Pigs with High Immune Response Survive Better in the Face of Natural Disease Challenge

PigGen Canada Project 2017

% S

urv

ival

Could Immuno-Genetic Approaches be used to Improve

Immunity in Dairy Cattle

We focussed on selecting for broad-based

disease resistance (rather than on single diseases)

based on Estimated Breeding Values (EBVs) of immune response traits used in a Selection Index

0

10

20

30

40

50

60

1996 2001 2007 2014

Repro (Metritis)

Retained Placenta

Respiratory

Lameness

Mastitis

NAHMS Dairy 2007 Part II: Changes in the Dairy Cattle Industry 1991-2007 & NAHMS 2014 Health and Management Practices on US Dairy Operations

Understanding the Problem in DairyDisease Trends 1996-2014

Why are health traits so difficult to improve?

Low heritability

1. Complexity of the genetic regulation of disease resistance

2. Difficulty in measuring the relevant trait

3. Poor data quality & inconsistency in disease diagnosis and recording

Selection to fight one disease may be counter-productive to other diseases

Complexity of the Immune System

24%

77%

BOVINE GENOME

Immune Response Others

Approximately 5500 genes out of ~23,000 total genes with linear and non-linear

effects on immunity

Determining Disease Prone Animals

67%

33%

Producers and Vets identify that some animals are more

prone to disease than others?

Yes No

1%

44%

38%

25%

90%

0% 50% 100%

Genetic Tests

Herd Records

DHI Reports

Vet Reports

VisualInspection

Determining which animals are more prone to disease problems

% of Respondents

Survey 2010

ANTIBODY- MEDIATED IMMUNE RESPONSE

CELL-MEDIATED IMMUNE RESPONSE

Capturing the Performance of Immune System:

14 Days 1 Day

i. Blood Collectionii. IM Immunization

i. Blood Collectionii. ID Immunization

i. Skin Thickness measurement

STEP 1: The Phenotypic Test

HIR Ranks Cattle asHigh, Average or Low Immune Responders

Selection for Immune Response is Based on

Estimated Breeding Values

Studies in number of species show IR is highly heritabletherefore will respond to selection

Immune Response

~

Significance of being a High Immune Responder

Less likely to be seropositivefor paratuberculosis

Improved milk & colostrum quality

Improved response to vaccine

Beneficial associations with herd life and some

reproductive traits

Better hoof health – digital dermatitis

Decreased occurrence of mastitis, pneumonia, metritis,

ketosis, retained placenta

Altered miRNA profiles in colostrum/milk

(Epigenetics)

Unique genomic IR profiles

Increased heifer growth rate

Disease data from: Wagter, et al. 2000 J. Dairy Sci. 83:488-498; Thompson-Crispi, et al. 2012. J. Dairy Sci. 95:3888-3893; Thompson-Crispi, et al. 2013. Clin Vacc Immuno. 20:106-112.

Benefit - Lower Disease Incidence

IR vs Disease Incidence (Combined Diseases)

HIGH

16%

14%

12%

10%

8%

6%

4%

2%

0% AVERAGE LOW

7.5%

11.3%

14.4%

Recorded Diseases Include:

Mastitis, Metritis, Ketosis, Retained Placenta, Respiratory, Lameness

> than 100 herds tested in our research

PATHOGEN

E. coli,

S. aureus

+ others

LOW AMIR

n=86

AVE AMIR

n=289

HIGH AMIR

n=83

ALL

COWS

Incidence Rate

High Severity

30.7a

6.15c

27.9a

1.98d

17.1b

2.13

26.3

2.72

Reduction in Mastitis by High AMIR = (26.3 - 17.1)/ 26.3 = 35%

Reference: Thompson-Crispi et al Clin Vaccine Immunol 2013 vol 1 106-112

Incidence of clinical mastitis per 100 cow-yearsby EBV Low, Average and High AMIR

Mastitis Incidence on Canadian Farms

58 Herds

Benefit – Improvement in Lameness

High AMIR cows had less

Infectious Digital Dermatitis,

but more Non-Infectious

Hoof Lesions

High CMIR cows tended to

have less Interdigital

hyperplasia

2014-2016 Data from Mallard Group

Cartwright & Mallard et al., JDS 2017

Infectious Digital Dermatitis

H-AMIR

A-AMIR

L-AMIR

High23%

Low 50%

Ave 60%

N=190

Leading Cause of Culling

Discovery Questions

How might you use this information to improve your on-farm practises?

Who could help you to implement information about immune response into your herd?

What resources might you need to put these changes into practise?

Immune system: a strong chain of protection for cow and calf

PASSIVE IMMUNITY

MATERNAL ANTIBODY

AMIR – Extracellular

ex. E. coli, Staph MastitisScours

CMIR – Intracellular

ex. Johne’sTB

Viruses

0

0.5

1

1.5

2

2.5

3

wk 0 wk 2 wk 3 wk 4 wk 6

Optical D

ensity V

alu

e (

DO

)

Specific Antibody in Colostrum and Milk

High

Ave

Low

Wagter LC. 2000 J. Dairy Sci. 83(3):488

*

*

* **

Benefit – Improved Colostrum and Milk

Correlations Between Specific Antibodyin Cow Colostrum vs Calf Sera Post-suckling

Correlation between Ab in Colostrum and Calf Blood = 0.74, p<0.04*N = 8 Cow/Calf pairs Wagter-Lesperance PhD thesis - 2016

Calves getting the colostrum from High Responders have more antibody in their blood.

Estimated cost savings for High vs Average Responder

for a common set of diseases –

(mastitis, metritis, ketosis,retained placenta, Johnes),

plus improved vaccine and colostrum responses is:

$247.91/cow/lactation.

Economic Benefit for Common Diseases per Standard Deviation of HIR

Cost:Benefit Analysis

Cost of HIR Test $20-$80/cow

HIR Benefit $247.91/cow/lacation

Cost:Benefit Year 1 3:1 or $248/cow

Cost:Benefit Year 2 6:1 or $496/cow

Cost:Benefit Year 3 9:1 or $992/cow

Agri-Studies Inc

Discovery Questions

How might you use this information on colostrum to improve your calf management?

Does information on HIR open up different disease treatment strategies?

How might your veterinarian help you put these changes into practise?

How can HIR be used as both a breeding and management tool?

Semex Exclusive Patented Technology

From the University of Guelph

December 2012

2012 –Semex Licences the HIR Technology from UoG

Bulls Designated as Immunity+

Approximately 10% of sires

PROVEN ON FARMS AROUND THE GLOBE:35 commercial herds totaling 30,000 Immunity+ daughters

Building a Stronger Herd

Dr Chesnais, Senior Geneticist, Semex

~12% Less

Disease on Farm

>

GWAS of Immune Response

Is a Genomics Test based on HIR™ Test System Possible?

Thompson-Crispi et al 2014, BMC Genomics

Reference Population (n ~ 6000)

HIR™ Phenotyped Genotyped (50K SNPs)

Step 1 – The Reference Population

+

Figure2:

The genomic analysis for AMIR detected four significant

SNPs on chromosomes 2, 11, and 14 (5% FDR),

and associations on chromosomes 21 and 23 (1% FDR)

GWAS: 2500 cows (60 herds) + 1000 bulls (4 Semex herds)50K imputed to 777K using another 3000 Reference Animals

Ref: Mallard et al 2018 Proc WCGALP

ELEVATE WITH SEMEX

Only Semex Can Leverage Immunity+ Rankings & Testing

June 2018Semex Launches First Genomics Test for Females

ELEVATE WITH SEMEX

Immune Genomics Validation• Gathered genotypes and health records

from 15 large US dairies

• Calculated disease incidence after adjusting for age and lactation effects of all genotyped animals (N=6,500)

• Used this information to determine how to display Immune Genomics values

• Significant differences (p<0.05) found for lameness, mastitis, persistent mastitis and overall disease frequency

Validation in the Field

Using genomically tested cows, instead of simply the sire

status, we can see that those cows with a stronger immune

system resist disease even better.

These High Immune Response cows have on average

30% less disease than their herdmates with either

average or low immune response genetics.

DISEASE DATA ON ~10,000 GENOMICALLY-TESTED COWS

High Immune Response (HIR) for DairyMore than 7 Awards since 2013

U of G Innovation of the Year 2018

Governor General Innovation Award 2017

Other Genomic Indices

1 – Based on Clinical Disease Recorded Data(e.g. Zoetis, CDN, Other)

2 - Based on Diagnostic Tests(e.g. bovine TB skin test)

Low Heritability

Canadian Compass will be similar

TB Advantage launched 2016 –

a genetic index aimed to help UK dairy farmers improve resistance against bovine tuberculosis (bTB).

Now available for Holsteins following research at Roslin Inst., with Genus ABS and UK Dairy Genetics Advisory Forum showing genetic variation between animals in response to TB skin test.

Like other indexes the scale ranges from -3 to +3, with a positive number predicting daughters with greater resistance. For every +1 point, 1% fewer daughters are expected to become infected.

Heritability of this trait is low (9%)

UK – Bovine Tuberculosis IndexTB Advantage

Badger buries calf carcass

Discovery Questions

What are the practical advantages to a genomics test for immunity?

What role does heritability play in genomic selection for health?

Do genomic tests for health open up new opportunities for breeding within your herd?

Adapting the High Immune Response (HIR™) Technology to Improve

Beef Cattle Health

Bovine Respiratory Disease (BRD) is the Most Costly Disease in Canadian Beef Industry

The Problem –Disease Risk and Over Use of Antibiotics

BRD accounts for up to 80% of feedlot sickness and costs

the US industry $700M annually!

Could Selecting for High Immune Responders

Reduce BRD and Drug Use?

We believe so!

Incidence of BRD/Pneumonia in Dairy

Herd A – 265 head

Herd B – 1267 head

Herd C – 2724 head

Pneumonic Nonpneumonic Percent P valueHigh Responders

2 34 5.6%

Vs. p = 0.09Herdmates 35 194 15.3%

Pneumonic Nonpneumonic Percent P value

High Responders

11 149 6.9%

Vs p = 0.22

Herdmates 101 1006 9.1%

Pneumonic Nonpneumonic Percent P valueHigh Responders

45 186 19.5%

Vs. p = 0.005Herdmates 683 1810 27.4%

Stakeholder Opportunity & Value

In order to secure this opportunity we are:

1 - establishing an HIR test system for beef calves well-suited to feedlots settings

2 – obtaining data on whether HIR/Immunity+ can reduce BRD in Canadian and American Angus

MORE TO COME……..

HIR will provide the same valuefor the beef industry?

Resilient animals are defined as having better immunity and are better adapted to stress, such as climate change.

Objective: Evaluate the Effects of Heat Stress on the Resilience of HIR Classified Cattle.

Resilience to Climate Change Project

Rectal Temperatures of 36 Ontario Beef Cows of Mixed Breeds during Normal THI (< 74) and above Normal THI (≥ 74)

Effect of Temperature Humidity Index (THI) on Body Temperature of Cattle

1 columns with different letters differ significantly 1

Ref: Nasrin Husseini, MSc Thesis, 2020

62.5% of cows had rectal temperature ≥39.5 when THI was 74 or greater

High Antibody Responders Regulate Body TemperatureBetter than Herd-mates during Hot Days in Ontario

H-AMIR A-AMIR L-AMIR

TN

4 HR -H

S1

24 H

R- H

S1

4 HR- H

S2

24 H

R -

HS2

0

5

10

15

HSP70 Concentration by Immune Response Phenotype

Treatment

HS

P70

Co

nce

ntr

ati

on

(n

g/m

l) High (n=15)

Average (n=15)

Low (n=15)

p = 0.07

p = 0.02

p = 0.04 p = 0.06

p = 0.04

p = 0.05

Thermo-neutral = TN(in vitro 37 degrees)

Heat Treatment 1 = HS1(in vitro 42 degrees, 4hr)

Rest 18hr then,

Heat Treatment 2 = HS2(in vitro 42 degrees, 4hr)

Heat Shock Protein 70 (HSP70) Protects Cells during Heat Stress

Shannon Cartwright, PhD Thesis

Discovery Questions

Would it be helpful to identify resilient animals in your herd?

Would resilience apply equally whether you are a dairy or beef producer?

Some Answers to the Discovery Questions to Improve Animal Health

1) Selectively breed your High/High females to Immunity+ sires

2) Super-ovulate your High/High females and use average or low as recipients

3) Low responders dairy cows could be bred for beef or culled

4) Discuss with your vet how to group livestock by immune response for treatments (eg vaccinations and antibiotic use)

5) Consider using immuno-stimulants to boost immunity of average and low cows (eg Imrestor, Cr yeasts…)

6) Bank colostrum from high immune responders

7) Purchase powdered colostrum from HIR females

8) Provide additional cooling for low responder cows

Funding is gratefully acknowledged from:

NSERC

OMAFRA

DFO

CFREF – Food from Thought

Corporate Sponsor - Semex Alliance

Thanks to our High Immune Response Teamand to our Funding Agencies

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