PRE-HARVEST INTERVENTIONS: The cost benefit ratio of E. coli vaccines.

PRE-HARVEST INTERVENTIONS:

The cost benefit ratio of E. coli vaccines

MODERATOR Mike FieldingManaging Editor of Technical Content,Meatingplace

Efficacy of Pre-harvest Technologies and Interest in Best Practices

Guy H. Loneragan, BVSc, PhDProfessor of Food Safety & Public HealthTexas Tech University, Lubbock, Texas

Poll Question

Is E. coli O157 predominantly a food-safety challenge in North American?

1. Yes2. No

Outline of Presentation

• Control of food-borne pathogens in beef production

• Interest in reducing burden of pathogens in groups of cattle sent to harvest

• Efficacy of available technologies– Limited discussion based on available time

• Summary

Control of E. coli O157• Informed regulatory oversight and industry

implementation of PR/HACCP plans have resulted in greatly improved microbial process control– Impact observed across various metrics

'96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09 '10 '110

0.51

1.52

2.53

CDC FoodNet Estimate 2010 HP Objective 2020 HP Objective

Inci

denc

e of

E. c

oli O

157 • 50% decline from baseline years (CDC)

• 90% reduction in USDA/FSIS ground beef positives

Control of E. coli O157• Many slaughter plants are now excelling at

microbial process control– Diminishing opportunities for further meaningful

improvement in microbial process control during slaughter/fabrication

• Currently there is very little microbiological control of raw commodity (i.e., cattle)– Can pre-harvest control of pathogens further

improve (i.e., impact) process control?

Pre-harvest control of E. coli O157• Initial focus on the way we manage & raise cattle

– Efforts to date have been largely unsatisfactory• E. coli O157 well-adapted to the ruminant gut

– Commensal bacterium• Worldwide distribution (poll question)

– Argentina, UK, Denmark, Australia, Canada, France• Incidence greater in Argentina, Scotland, etc., than US

– Relationship between cattle and E. coli O157 is robust across various management & rearing systems

Pre-harvest control of E. coli O157• Tremendous governmental interest in pre-

harvest control of E. coli O157• 1994 Public Meeting


harvest control of E. coli O157• 2010 USDA/FSIS Significant Guidance

document

Pre-harvest control of E. coli O157

• Industry investment and innovation• Technologies developed to modify

relationship between E. coli O157 & cattle– In-feed (e.g., probiotics, sodium chlorate)– Vaccination– Hide intervention (e.g., bacteriophage)

Efficacy of Pre-harvest Technologies• Majority of efficacy data about STEC O157

Pre-Harvest Slaughter/Fab

In-p

lant

PR/

HAC

CP

plan

t pro

cess

ing

aids

and

in

terv

entio

ns

Efficacy of Pre-harvest Technologies• Majority of efficacy data about STEC O157

VaccinesDirect-fed Microbials (aka probiotics)

Na

chlo

rate

Phag

e

Slaughter/FabPre-Harvest

In-p

lant

PR/

HAC

CP

plan

t pro

cess

ing

aids

and

in

terv

entio

ns

Direct-Fed Microbials

• Frequently referred to as probiotics• GRAS (approval) for use in cattle

– No label claim against food-borne pathogens• Thoroughly evaluated against E. coli O157

– Strain specific (NP51)– Dose response

• High-dose most effective against E. coli O157

Fecal: Relative Risk.1 .5 .75 1 2 4

Combined

R1

T1

C1

J2

J1

N1

A4

A3

A2

A1

U3

U2

U1

Relative Risk Efficacy Lower 95% CL Upper 95% CL P valueFeces 0.53 47% 0.44 0.63 <0.01Hides 0.60 40% 0.49 0.75 <0.01

Direct-Fed Microbials

Direct-Fed Microbials• NP51 strain, included in commercially available product,

works consistently– When used at the higher dose

• Reduces prevalence & concentration of E. coli O157– Brashears et al., 2012

Control Lower dose Higher dose-1

1

3

Log1

0 M

PN/g a

abb

• Type III Secretion System (T3SS)• Fully licensed in Canada as Econiche

– Label indication: ‘For vaccination of healthy cattle as an aid in the reduction of shedding of Escherichia coli O157’

• Not yet licensed in the US– Conditional or full license

• Peer-reviewed publications published in respected journals support efficacy

Vaccine Technologies

Reference Regimen Study Design Outcome OR P-valueVaccination Sampling

Potter et al 2004 3 dose Day 0, 21 and 42 Daily for 14 days post challenge Feces 0.35 0.04

6 samples: wks 0, 3, 6, 9, 12, 15 Feces 0.36 0.04

Peterson et al 2007 0 dose n/a 7 samples: wks 0, 3, 6, 9, 12, 15 and 18

Feces 0.36 <0.01

1 dose Day 42 0.25 <0.01

2 dose Day 0 and 42 0.27 <0.01

3 dose Day 0, 21 and 42 0.21 <0.01

Peterson et al 2007 3 dose Day 0, 21 and 42 5 samples: wks 0, 8, 10, 13, 14 Feces 0.81 0.57

TRM 0.01 <0.01

Smith et al 2008 2 dose 14 – 104 days apart 4 samples: 3 wks apart ROPES 0.59 <0.01

Smith et al 2009 2 dose Day 0 and 32 3 samples: wks 11, 13, 16 Feces 0.35 <0.01

4 samples: wks 11, 13, pre and post shipping

Hides 0.43 0.01

Regional vaccination TRM 0.69 0.63

2 dose Day 0 and 32 Comingling Feces 0.48 0.01

Hides 0.67 0.33

Smith et al 2009 3 dose Day 0, 21 and 42 5 samples: wks 0, 9, 11, 13, 15 Feces 0.5 <0.01

Smith et al 2009 2 dose Day 0 and 42 5 samples: wks 0, 9, 11, 13, 15 TRM 0.07 <0.01

Moxley et al 2009 2 dose Day 0 and 42 5 samples: wks 0, 9, 11, 13, 15 Feces 0.66 0.20

3 dose Day 0, 21 and 42 5 samples: wks 0, 9, 11, 13, 15 Feces 0.34 <0.01

Allen et al 2011 3 dose Day 0, 21 and 42 Daily for 14 days post challenge Feces 0.18 <0.05

Vaccine TechnologiesSo

urce

of s

lide:

Dav

id S

mith

, UN

L

• Siderophore receptor and porin proteins– SRP® Technology

• Developed to control Salmonella in turkey layer flocks– Very effective

• Approach used to make an SRP-based E. coli O157 vaccine– Epitopix, LLC– Pfizer Animal Health

Vaccine Technologies

Field Studies of E. coli SRP Vaccine• 2006 feedlot study

– 20-pen study across 2 feedlots in NE• Thomson et al. FPD 6:871-7 2009

– 50% reduction in fecal prevalence over time, P=0.03– Prevalence at harvest was low

• Feces: 1.4 vs 2.8% VE=50% P=0.18• TRM: 1.0 vs 2.3% VE=57% P=0.16• Hides: 0.5 vs 1.7% VE=71% P=0.06

– E. coli O157 recovered from 63% fewer animals at harvest (feces, TRM, or hides; P=0.02)

• 2.5 vs 6.8%

Field Studies of E. coli SRP Vaccine• 2007 field trial in a commercial feedlot

– 3 doses or SRP vaccine or 3 doses of placebo– Vaccine efficacy=85%; 98% reduction in concentration

• Granted conditional license in early 2009

d0 d42 d980

10

20

30

Vaccinates Placebo

Prev

alen

ce

Field Studies of E. coli SRP Vaccine• 2007 field trial in a commercial feedlot

– 3 doses or SRP vaccine or 3 doses of placebo– Vaccine efficacy=85%; 98% reduction in concentration

• Granted conditional license in early 2009

d0 d42 d980

10

20

30

Vaccinates Placebo

Prev

alen

ce

Concentration on d98-1

1

3

0.9

2.53

Log1

0 M

PN/g

Field Studies of E. coli SRP Vaccine• 2 industry-initiated studies in 2010• Population intervention studies

– Study A 2-dose study• 40% reduction in feces• No impact observed on hides• Associated with reduced total combos of beef trimmings

microbially lotted with a positive test

– Study B 1-dose study• Reduced prevalence in feces at beginning of study• 67% reduction in prevalence on hides• Only 1 positive combo (in control) so precluded analysis

Field Studies of E. coli SRP Vaccine

• 2 field studies conducted in 2011 – Vaccinates and controls in same feedlots

• 3-dose study (multiple feedlots)• 2-dose study (Renter et al., from K State)

• 2 cohorts of animals– Pens of vaccinated animals– Non-vaccinated pens – usual feedlot practices

• In 3-dose study, evidence of effect modification due to need for prerequisite programs

• 3-dose, multi-feedlot study• Sample-level data

– No treatment*time interaction (P=0.42)

– Significant association with vaccination (P=0.03)

• 12.3% in controls versus 5.9% in vaccinates

• VE = 52% over study duration • No effect in single feedlot in need

prerequisite programs

Cohort0

10

20

30 VaccinatesControls

Prev

alen

ce

P=0.03


• 3-dose, multi-feedlot study• Pen-level

– Detected in 70.0% of control pens vs 35.0% of vaccinate pens

– 50% reduction• Random pool of 5

– Detected in 60.0% of control pens vs 15.0% of vaccinate pens

– 75% reduction• No effect in single feedlot in need

prerequisite programs

Cohort0

20

40

60

80


Prev

alen

ce

P=0.04

Cohort0

20

40

60

80


Prev

alen

ce

P=0.01


• Single feedlot study– Renter et al., K State

• Two-dose regimen

• E. coli O157 in feces of 37% of controls compared to 17.4% of vaccinates– 53% reduction

• Prevalence of high shedders was 4.2% in controls compared to 0.95% of vaccinates– 77% reduction


Cohort0

20

40

60VaccinatesControls

Prev

alen

ceCohort

0

2

4

6

8

Hig

h Sh

edde

rs

• Considered strongest form of evidence support a causal relationship– Snedeker et al. ZPH doi: 10.1111/j.1863-2378.2011.01426

Systematic Review and Meta-analysis

• Summary measure of vaccine efficacy ~60%

Summary of Efficacy StudiesA variety of effective pre-harvest technologies have emerged (or emerging). Are not silver bullets but efficacy is detectable and repeatable (prevalence & concentration)

1

Efficacy robust across a variety of settings and study designs. Evidence of a dose response and must also consider pre-requisite programs to set the stage for intervention success

3

SRP® E. coli Bacterial Extract Vaccine conditionally licensed and available. Product has a labeled claim as an aid in the control of E. coli O157 in groups of cattle

2

Efficacy of SRP E. coli O157 vaccine ranged from a low of 40% to a high of 85%. Concentration reduced as well. Is this level of efficacy sufficient to have an Impact?

4

Poll Question Results

Is E. coli O157 predominantly a food-safety challenge in North American?1. Yes2. No

An Outcomes Model to Evaluate Risks and Benefits of Escherichia coli Vaccination in Beef Cattle

H. Scott Hurd and Sasidhar MalladiCollege of Veterinary Medicine, Department of Production Animal Medicine Former Deputy Undersecretary of Food Safety, USDA

The Need for This AnalysisAvailability of Vaccine

Effective at Reducing On-farm Prevalence

Relative Value of Pre-harvest(On-farm) Interventions?

Hurdle Technology = “Shotgun” – Not Efficient

Vaccine is Not Competitive with Current Post-harvest Interventions

Funded by Pfizer Animal Health, 2011

Unvaccinated

Methods: Mathematical Model “Converts” 0157:H7 Shedding Cattle to Human Illnesses

Production Slaughter Consumption

= Contaminated

Vaccinated

Methods: Mathematical Model “Converts” 0157:H7 Shedding Cattle to Human Illnesses

Production Slaughter Consumption

= Fewer Contaminated

Methods: Three Scenarios Evaluated

Additionally, Simulated for Various Levels of Product Adoption by Producers 0%, 40%, 80%, 100%

Details of the Scenarios for the Impact of Vaccination on Prevalence and Concentration of E. coli 0157:H7 in Cattle Feces

Scenario Percentage Reduction in Feedlot

Log10 CFU/g Reduction in Average E. coli 0157:H7

A 80 1.0

B 60 0.3

C 40 0.3

Results: Four Outcome Measures Considered

Mean annual number of human E. coli O157:H7 illnesses due to consumption of ground beef from steers and heifers (Public Health)

1

Probability of detecting E. coli O157:H7 per ground beef or ground beef trim sample tested by FSIS (in a 10,000 lb lot) (Regulatory)2

Mean annual number of events where multiple E. coli 0157:H7 human illnesses (outbreaks) occur due to consumption of ground beef from a single production lot (Outbreak)

3

Mean annual number of a “hot” production lots (hot lot = more than 1,000 E. coli O157:H7 contaminated ground beef servings from a single lot) (Event Days)

4

Outcome: Annual Number ofE. coli O157:H7 Illnesses

Annual 0157 Illnesses by Efficacy an Adoption

0% 40% 80% 100%0

5,000

10,000

15,000

20,000

25,000 Efficacy 80%Efficacy 60%Efficacy 40%

Vaccine Adoption

Num

ber o

f Illn

esse

s

Discussion of Results:Annual Number of Illnesses

• If vaccine is 80% effective and used by all producers, the projected number of cases is reduced from 20,000 to 8,000 (60% decrease)

• However, partial adoption is also useful– 80% effective with 40% adoption 23%

reduction in illness– 60% effective with 80% adoption 36%

reduction in illness

Outcome: Annual E. coli O157:H7 Illnesses Decreases with Adoption Number of E. coli 0157:h7 Illnesses Due to Consumption

of Ground Beef from Feedlot Cattle

0% 40% 80% 100%0

5,000

10,000

15,000

20,000

25,000Efficacy 80%Efficacy 60%Efficacy 40%

Vaccine Adoption

Num

ber o

f Illn

esse

s

Number of Human Cases Decreases Due to Both Reduced Prevalenceand Amount of O157 on the Carcass

Reduction of Cattle Prevalence and Concentration on Carcass

0

0.3

0.6

0.9

05,000

10,00015,00020,000

0.3

0.45

0.6

0.8

Fraction Reduction in Prevalence

Log CFU/g Reduction in Concentration of E. coli 0157: H7 in

Feces

Num

ber o

f Hum

an

Case

s

Outcome: Probability of Detection viaFSIS Sampling (Regulatory)

• Assumed FSIS testing of raw ground beef detects 1 CFUin a 325 g sample

• Based on average probability of detection per sample tested for different slaughter plants and for different production lots from the same plant

• Impact of additional industry test and hold is not considered

Outcome: Detection by FSISProbability of Detection via FSIS Testing

per Sample of Raw Ground Beef

0% 40% 80% 100%0.000%

0.050%

0.100%

0.150%

0.200%

0.250%

0.300%

0.350%

0.400%Efficacy 80%Efficacy 60%Efficacy 40%

Vaccine Adoption

Num

ber o

f Det

ectio

n by

FSI

S

Outcome: Detection by FSISProbability of Regulatory Positive by Efficacy and Adoption

0% 40% 80% 100%0.000%

0.050%

0.100%

0.150%

0.200%

0.250%

0.300%

0.350%

0.400% Efficacy 80%Efficacy 60%Efficacy 40%

Vaccine Adoption

Prob

abili

ty o

f Det

ectio

n by

FSI

S

Discussion of Results: Detection by FSIS

• Full adoption of 80% effective vaccine virtually eliminates chance of FSIS detection (97% reduction)

• 40% adoption of an 80% effective vaccine results in 37% reduction in probability of detection by FSIS

• 80% adoption of 60% effective vaccine results in 57% reduction in probability of detection by FSIS

What does Event DayCost You$

$

Hot Lots

Distributions are non-normal

● Prevalence and concentration of E. coli in cattle is not abell curve

● It is Poisson distributed

● Occasional HIGH levels

6% 7% 8% 9% 10% 11% 12% 13% 14% 15% 16% 17% 18% 19% 20%-0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

Prevalence

Prob

abili

ty

Poisson Distribution of E. coli Prevalences

6% 7% 8% 9% 10%

11%

12%

13%

14%

15%

16%

17%

18%

19%

20%-0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

6%

7%

8%

9%

10%

11%

12%

13%

14%

15%

16%

17%

18%

19%

20%-0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

6%

7%

8%

9%

10%

11%

12%

13%

14%

15%

16%

17%

18%

19%

20%-0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

Why do “Hot Lots” Happen?Prevalence and Concentration are NOT Normally Distributed (Poisson)

Cattle Prevalence Carcass Prevalence Concentration

Event Day

Outcome: Hot Lots (>1,000 servings in 10,000# lot) if Produce 16,000 Lots Per Year

Annual Number Hot Lots for Large Plant by Efficacy and Adoption

0% 40% 80% 100%0

20

40

60

80

100

120

140

160Efficacy 80%Efficacy 60%Efficacy 40%

Vaccine Adoption

Num

ber P

er Y

ear

Outcome: Hot Lots for a Plant Producing 16,000 Production Lots Per Year

Annual Number Hot Lots for Large Plant by Efficacy and Adoption

0% 40% 80% 100%0

20

40

60

80

100

120

140

160 Efficacy 80%Efficacy 60%Efficacy 40%

Vaccine Adoption

Num

ber P

er Y

ear

Discussion of Results: Hot Lots

• All levels of efficacy and adoption reduce the risk to packer

• Full adoption of 80% effective vaccine virtually eliminates chance of Hot Lots (96% reduction)

• 40% adoption of an 80% effective vaccine results in 43% reduction in probability of Hot Lots

• 80% adoption of 60% effective vaccine results in 49% reduction in probability of detection by FSIS

• What is a 20%, 30%, 40% reduction in risk worth?

Annual Hot Lots: Vaccine Reduces Variation and Extreme Doses

Box-Whisker Plot Comparison

More Variation and More

“Event Days”Vaccinated –40% Scenario

Unvaccinated

0 20 40 60 80 100 120 140 160 180 200

TAIL-END OF HISTOGRAM SHOWING IMPACT OF VACCINATION ON NUMBER OF PRODUCTION LOTS WITH HIGH E. COLI O157 PREVALENCE (>5%) IN 325 GM

SAMPLES

5.00% 28.75% 52.50% 76.25% 100.00%0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07Series1

Unvaccinated Vaccinated 60% Efficacy

57

Summary

• Analysis included impact of biological variation and uncertainty in parameters

• Modeled from “farm to fork” using best available scientific data

• Showed that vaccination reduces:– Human 0157:H7 cases– Risk of FSIS regulatory detection– Frequency and magnitude of “event days”

QUESTIONS & ANSWERS

FOR MORE INFORMATION

Guy H Loneragan: [email protected] Hurd: [email protected]

Mike Fielding: [email protected]

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PRE-HARVEST INTERVENTIONS: The cost benefit ratio of E. coli vaccines.

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Transcript of PRE-HARVEST INTERVENTIONS: The cost benefit ratio of E. coli vaccines.