Defining Requirements and Execution of International Field ... · Defining Requirements and Execution of International Field Trials for Next Generation FMD Vaccines and Diagnostics

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


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


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.

5


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


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)


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


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)


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


OVERVIEW OF APPROACH TO

THE PROPOSED

INTERNATIONAL FIELD

TRIALS FOR FMD VACCINES

AND DIAGNOSTICS

11


Why International FMD Vaccine Trials?

12

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.


Year 1 Year 2 Year 3 Year 4

13

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


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)

14

Vaccines and Diagnostics Trial Metrics (1)


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)


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

16


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

[email protected]


Back-up

19


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)

20


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



21


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.



22


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


USDA CVB Licensing Studies (Efficacy Related)

23


3B Development

24

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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Defining Requirements and Execution of International Field ... · Defining Requirements and Execution of International Field Trials for Next Generation FMD Vaccines and Diagnostics