Defining Requirements and Execution of
International Field Trials for Next
Generation FMD Vaccines and Diagnostics M. Colby1, P. Hullinger, T. Beckham, and D. Brake
EU FMD Open Session
31 Oct 2014
1Michelle Colby, DVM, MS
Branch Chief, Agricultural Defense
Chemical and Biological Defense Division
Homeland Security Advanced Research Projects Agency
Science and Technology Directorate
Presenter‟s Name June 17, 2003
Introduction to DHS S&T
Overview of DHS S&T Vaccine and Diagnostic projects
Overview of approaches to proposed International Field Trials
for FMD Vaccines and Diagnostics
Overview
2
Presenter‟s Name June 17, 2003
Agricultural Defense Mission
The Agricultural Defense mission is to enhance current
capabilities and develop state-of-the-art
countermeasures for high-priority foreign animal
diseases (FAD). This includes near- and long-term
research and development for vaccines and
diagnostics, in coordination with internal and external
stakeholders.
HSPD-9 Paragraph 23: The Secretaries of [DHS, USDA,
HHS, EPA…] in consultation with the Director of the Office
of Science and Technology Policy, will accelerate and
expand development of current and new
countermeasures against the intentional introduction or
natural occurrence of catastrophic animal, plant, and
zoonotic diseases. The Secretary of Homeland Security will
coordinate these activities. 3
Presenter‟s Name June 17, 2003 4
Presenter‟s Name June 17, 2003
S&T’s Agricultural Defense Programs span
the entire outbreak spectrum
Agricultural Screening Tools
(AST) to verify disease free
status so uninfected animals
and products can continue to
move maintaining business
continuity w/in U.S.
Livestock Decontamination, Disposal and Depopulation (3D):
New methodologies and decision support tools for depopulation,
disposal and decontamination that facilitate rapid response and
prevent disease spread in a manner that minimizes waste,
environmental impact and negative public perception.
Enhanced Passive Surveillance
(EPS) includes diagnostic tests,
surveillance tools and data integration
procedures to identify infected
animals prior to overt symptoms and
improve our ability to detect diseases
that threaten the U.S. agricultural
critical infrastructure.
High throughput diagnostics (DX) allow more
rapid confirmation of disease status and
increased sample processing capabilities
enhancing our ability to contain outbreaks.
Vaccines (VX) to rapidly
prevent disease in
healthy animals prevents
disease spread among
healthy herd, maintaining
business continuity.
Tools to support planning and
response, drive requirements
for countermeasures
development and inform post-
outbreak response activities
by creating scalable (local to
national) simulation and
modeling tools to analyze
potential responses and
control options to minimize
FAD spread.
Diagnostics (DX) to distinguish
vaccinated from infected
animals may allow more rapid
return to trade status,
enhancing business continuity
and minimizing economic
impact.
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Presenter‟s Name June 17, 2003
FAD Vaccines and Diagnostics Project
Develop more effective vaccines
and diagnostic countermeasures for high priority
FADs, in partnership with the USDA and
industry 6
• FMD Vaccines (initiated 2005)
Near term - Enhanced characterization and import permits
for „Off the shelf‟ foreign-manufactured, inactivated FMD
vaccines *Import permit July 2011
Mid term - New serotype- and subtype-specific, marked,
molecular vaccines (pipeline) *Conditional License May
2012
Long term - Broad spectrum countermeasures:
multi/panvalent vaccines, biotherapeutics and
immunomodulators *Ongoing Projects
• Countermeasures for Other FAD
• Prioritized agents identified by key customer (USDA-APHIS
Emergency Management – NVS) and interagency working
groups (FADT)
• Includes near term, mid term and long term R&D funding
projects for African Swine Fever and Classical Swine Fever
• Diagnostics
• Differentiating infected from vaccinated animals (DIVA)
companion assays for vaccines in development
Presenter‟s Name June 17, 2003
FMD Virus Vaccine, Serotype A24, Live
Adenovirus Vector (USDA Code 1FM1.R0)
7 7
• Conditional license granted for use in cattle
on May 31, 2012
Recently renewed to May 6, 2016
Met the expiration potency after three years
in storage at -18+/-5oC.
• Included U.S. field safety study with 500
dairy and beef cattle
Included pregnant dairy
• Monovalent vaccine
• Public-private partnership between DHS,
USDA and industry
• Replication deficient viral vector
• Does not contain full FMDv genome, so
can be produced at BSL-2
• Recent PIADC studies
Cattle - Demonstrated 6 mo. duration of
immunity(experimental challenge)
Swine - Demonstrated proof-of-concept
efficacy (experimental challenge at 2
weeks post-vaccination)
Presenter‟s Name June 17, 2003
Ad5FMD Vaccine Candidate Pipeline
1. 14 AdFMD monovalent vaccine candidates efficacy tested
2. 9 AdFMD vaccine candidates have been identified for master seed virus
production
• 5 MSVs completed to date (CVB approvals in process)
3. AdFMD candidates for 6 of 7 major serotypes
• Multiple, serotype A candidates
• Multiple serotype O candidates
• Includes vaccine candidates for most recent outbreaks in S. Korea
(O/South Korea/2010) and Egypt (SAT2/Egypt/2012)
Pre-Master Seeds
Made/Tested
Master
Seeds
Planned
Master
Seeds
Made
Master
Seeds
Submitted
for
Approval
AdFMD
Construction
In Progress
2 5 14 4 3
8
Presenter‟s Name June 17, 2003 9
Additional FMD DIVA Vaccine
Platform Research Investments Replicon Particle (Harrisvaccines; SirraVax™)
• Basis of company‟s USDA licensed swine vaccine products (influenza, PRRS, PEDV)
• Only veterinary platform that currently qualifies as a „production platform‟ for USDA
CVB conditionally licensed products (VS Memo 800.213) – significantly reduces R&D
costs and timelines to licensure
• Single dose FMD vaccine candidate shown to be 100% efficacious in both cattle and
swine proof-of-concept efficacy studies (experimental challenge at 2 weeks post-
vaccination
Modified Vaccinia Ankara (Bavarian-Nordic; MVA-BN)
• Basis of company‟s EMEA licensed smallpox vaccine (IMVANEX®)
• Replication deficient in livestock
• 2-dose FMD vaccine candidate shown to be 100% efficacious in recently completed
cattle proof-of-concept study (experimental challenge at 21 days post-boost)
Presenter‟s Name June 17, 2003 10
3B Foot and Mouth Disease ELISA Kit
Collaborative project –
• Strong academic (Texas A&M) and government (USDA APHIS
and ARS) partnership
• Leveraging diagnostic industry (BIOO, VMRD) fee-for-service
expertise
Develop a new FMD serology Dx test based on the FMDV
non-structural protein 3B with performance equivalent
to/better than commercially available diagnostic assays
used for distinguishing vaccinated from infected animals
Develop a DIVA test to differentiate cattle vaccinated with
next generation FMD molecular vaccines
Supports FMD “vaccinate‐to‐live” policy to differentiate
vaccinated from infected animals, based on the detection
of antibodies to FMDV non structural proteins (NSP)
Shorter assay result time (hours vs. day)
Enables manufacturing of kits and reagents in U.S
Presenter‟s Name June 17, 2003
OVERVIEW OF APPROACH TO
THE PROPOSED
INTERNATIONAL FIELD
TRIALS FOR FMD VACCINES
AND DIAGNOSTICS
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Presenter‟s Name June 17, 2003
Why International FMD Vaccine Trials?
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Two-year, multi-herd study to compare DHS-funded Ad5 FMD vaccines and
new 3B ELISA test kit to traditional FMD vaccines and diagnostics in an
endemic country. • Cannot be done in field conditions in the U.S. due to absence of FMD
• Head-to-head natural challenge with traditional vaccines provides data supporting
the Ad5FMD vaccine‟s effectiveness in comparison to today’s “gold-
standard” vaccine
• The use of DHS-funded 3B ELISA test kit in conjunction with both vaccines
provides data to support use in a “vaccinate-to-live” strategy (vs. stamping out)
Establish relationships with the
FAO to facilitate future trials of
DHS products in transboundary
disease endemic countries.
Critical to establishing efficacy in a
production setting and promoting
commercial potential.
Presenter‟s Name June 17, 2003
Year 1 Year 2 Year 3 Year 4
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Technical Approach and Timeline
Objectives:
Demonstrate Ad5 vectored FMD vaccine is as effective as traditional killed vaccine
Demonstrate effectiveness of Ad5 vectored FMD vaccine in an FMD
outbreak/endemic situation
Demonstrate process for using vaccine and companion Differentiating Infected from
Vaccinated Animals (DIVA) diagnostic in a disease situation
Build international partnerships to facilitate future trials in endemic settings
1 - Workshop(s) to identify partner countries and detailed plan for case-control study and validating 3ABC DIVA diagnostic assay in endemic countries 2 - Production of additional master seed viruses needed for the bi- or tri-valent vaccine
Analysis of data and final report
Procurement of required vaccine and diagnostic kits
Begin field study, initial study period of 6 months
If vaccine efficacious at 6 months, continue study to 12 and 18 mo. time points to obtain information related to duration of immunity, effect of boostering, and serological response to vaccine
Future possibility of additional trials with African or Classical Swine Fever vaccines, or additional FMD vector platforms in other countries
Begin in-country planning for vaccine trial
Presenter‟s Name June 17, 2003
Comparable or better performance against traditional
killed vaccines in an outbreak/endemic field situation at
6, 12 and 18 months post-vaccination Number of animals diagnosed with FMD clinical disease at 6, 12 and 18
months post-vaccination
Number, severity and duration of post-vaccination injection site reactions
Serum virus neutralization (SVN) titers to each FMDV fraction in
multivalent vaccine at 3 days, 1, 2 and 3 weeks and 3, 6, 12 and 18
months
Onset of functional antibody response (mean days to 50%, 80% and >
90% herd seropositivity)
Assess viral load and shed by qPCR on sera, nasal swabs and probang
samples
Demonstrate duration of immunity of at least 6 months
(threshold), ideally 18 months (objective) Duration of response (number of animals that require re-vaccination at 6,
12 and 18 months)
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Vaccines and Diagnostics Trial Metrics (1)
Presenter‟s Name June 17, 2003
3B cELISA DIVA assay complementary to Ad5 FMD
vaccine Supports a differentiating infected from vaccinated animals strategy
(DIVA)
Sensitivity and Specificity equivalent or better than commercially
available diagnostic assays used for distinguishing vaccinated from
infected animals
Successful Repeatability and Reproducibility
≤ 15% coefficient of variation (within a single lab/among three labs,
respectively)
Cost lower by 33-50%
Time points evaluated; 3 days, 1, 2 and 3 weeks and 3, 6, 12 and 18
months
15 *3B is the immunodominant B-cell epitope of the 3ABC recombinant protein
Vaccines and Diagnostics Trial Metrics (2)
Presenter‟s Name June 17, 2003
A series of meetings/workshops to establish a common
understanding of DHS goals and objectives
Discuss logistical considerations and how to best succeed at
the execution of an international trial of the FMD Virus
Vaccine, Live Adenovirus Vector and the companion 3B ELISA
(short term)
Establish general recommendations for international field trials
Identify potential field trial locations and partners for current
and future collaborations
Release an “Expression of Interest” for potential partners to
respond to once the study requirements and design are
established
Vaccine and Diagnostic Trial Approach
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Presenter‟s Name June 17, 2003
Identify and foster the development of
collaborative opportunities for international
partnerships to further advance the state of the art
for FAD vaccines and diagnostics
Overarching Goal
17 Build enduring partnerships for the future
If interested in additional information please contact;
Michelle Colby, DVM, MS
Branch Chief, Agricultural Defense
Chemical and Biological Defense Division
Homeland Security Advanced Research Projects Agency
Science and Technology Directorate
Presenter‟s Name June 17, 2003
Back-up
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Presenter‟s Name June 17, 2003
1. 10X dose (calf) Acceptable - no local or systemic reactions
2. Backpassage/Reversion to Virulence (cattle) Inoculation of master seed virus (MSV) into 10 cattle showed
no reversion to virulence
Only a small amount of vaccine virus inoculum was isolated
from nasal swabs at 1-2 days post-administration in 4/10
animals
No amplification of vaccine virus was evident
3. Shed-spread (cattle, swine) MSV could not be isolated from either 10 cattle or 10 swine
after intramuscular administration.
Naive cattle and swine co-mingled with vaccinated cattle or
swine do not seroconvert to adenovirus or FMD seroconvert.
Portion of study published in Grubman, MJ, et. al. 2010. Future
Virol. 5(1):51-64.
FMD Virus Vaccine, Serotype A24, Live Adenovirus Vector:
USDA CVB Licensing Studies (Safety Related)
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Presenter‟s Name June 17, 2003
4. Field Safety (beef, dairy) 500 total
• 4 geographic, commercial sites
• Both sexes
• Young (19-22 weeks) and older (> 2yrs)
• Includes 100 lactating dairy; 58 pregnant (all trimesters)
96% experienced no recorded adverse events of any kind
during the 3 week post-vaccination observation period.
In the remaining 4%, there were no recorded instances of
serious, permanent or systemic adverse reaction attributable to
vaccination.
Study conclusion: Vaccine is safe for use in healthy cattle when
used per proposed label recommendations
FMD Virus Vaccine, Serotype A24, Live Adenovirus Vector:
USDA CVB Licensing Studies (Safety Related)
21
Presenter‟s Name June 17, 2003
5. Supplemental Safety Studies • Milk safety
10 lactating cows and nursing calves; milk collected
daily on days 0-4 and days 7, 10, and 14
None of the milk samples from any of the vaccinated
cattle tested positive for the adenovirus vector
Study conclusion: Vaccine is not shed in the mammary
tissue of cattle after IM inoculation
• Vaccine biodistribution and persistence in cattle Very low level of vaccine vector detected at inoculation
site and draining lymph node up to 72 hrs post-
inoculation
Results published: Montiel, NA. et. al. 2013. Vet. Immunol. Immunopathol.
151(1-2):37-48
Montiel, NA. et al. 2012. Vaccine. 30(9):1690-1701.
FMD Virus Vaccine, Serotype A24, Live Adenovirus Vector:
USDA CVB Licensing Studies (Safety Related)
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Presenter‟s Name June 17, 2003
Minimum Protective Dose (MPD) Studies: • 14 days post single dose vaccination (n=34 vaccinates)
94 % SVN positive
97% protection against generalized disease
91% protection against plasma viremia (VI, rRT-PCR)
• 7 days post single dose vaccination (n=10 vaccinates) 50% SVN positive
100% protection against generalized disease
90% protection against plasma virema (VI, rRT-PCR)
• Product release dose („normal potency‟) is 15.8 X MPD
Supplemental Information: • 100% (12/12) protected against generalized disease and viremia following
direct contact challenge at 1 week post-single dose vaccination Grubman, MJ, et. al. 2010. Future Virol. 5(1):51-64.
• 88% (91/104) of the vaccinated animals tested from the Field Safety Study
had positive FMDV SVN titers (>0.9 log10) at approximately 12 months post-
single dose vaccine administration
FMD Virus Vaccine, Serotype A24, Live Adenovirus Vector:
USDA CVB Licensing Studies (Efficacy Related)
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Presenter‟s Name June 17, 2003
3B Development
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Good separation of positive
and negative results
Enables diagnostic
serological testing of FMDV
susceptible species
Enables U.S.
manufacturing and
production of critical
reagent for protecting the
homeland
i.e. PrioCHECK® FMDV NS test
(Thermo Fisher Scientific;
formerly Prionics) is not
currently licensed by USDA
CVB for import, distribution, and
use
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