foreign animal disease research unit usda/ars...foreign animal disease research unit usda/ars...
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Foreign Animal Disease Research Unit
USDA/ARS
Agricultural Research Service, Plum Island Animal Disease Center
Overview USAHA – FED
2012
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APPROVED NEW CRIS PROJECTS 2012-2017
• Intervention Strategies to Support the Global Control and Eradication of FMD
• Countermeasures to Control Foreign Animal Diseases of Swine: CSF/ASF
• Ecology and pathogenesis of Re-Emerging VSV in North America
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Foot and Mouth Disease • FMD is considered number one
threat to American Agriculture and related industries (livestock, crops, farm supply, etc)
• FAO/OIE announced eradication from Americas by 2023 – global strategy key to eradication
• FMD is main barrier to international trade of animal products
• FMD is one of the main threats to global food security
Maasai Hearding; Painting By Kahare Miano
“Countries infected with FMD are more prone to food insecurity as a result of the impact of FMD at household level and through reduced access to local, national and international markets and of animal draught power for agriculture” OIE/FAO, 2009
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T.R. Doel / Virus Research 91 (2003) 81/99 86
Currrent vaccines
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Concerns with FMD Vaccines
• SAFETY: Require adaptation and growth of large volumes of wild type virus in cells è possibility of escape of virus from manufacturing facilities
• EFFICACY: • Narrow antigenic coverage (serotype / subtype) • Short duration of immunity <6 months • Vaccinated and exposed animals become
carriers
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Characteristics of an “Ideal” FMD Vaccine
• Effective, rapid and long-lasting protection with one inoculation
• Prevents viral transmission • Allow differentiation of infected from vaccinated
animals (DIVA) • Safe: produced without the need for virulent FMDV • No need for adaptation of field strains to cell culture • Prevent development of carrier state • Broad antigenic coverage • Stable antigen – long shelf life • Long duration of immunity
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2 Negative markers Targeting NSP
3Dpol ELISA 3B ELISA
3B 23 3’NTR IRES S
1A 1B 1C 1D 2A
2B 2C 3A 3C 3D A poly (C)
NON-STRUCTURAL STRUCTURAL δ L
5’NTR
RE1 RE2
Easy swap of capsid sequences Vaccine seed antigens
Deletion of Leader protein (543 bp) Attenuating factor
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Bovine # a Virus
Viremia, Maximum
Titer. b (DPI) c
Virus in Saliva, Maximum Titer b (DPI) c
Fever d (DPI) e
Maximum Clinical Score/
Maximum achievable f
(DPI) g
Neutralization Titer maximun (Starting DPI) h
Shedding in air. Maximun
Titer i (DPI) c
7109 A24WT 7.60 (3) 8.90 (3) Yes (2,3) 5/5 (7) 2.4 (5) 5.57 (5) 7110 A24WT 7.31 (4) 10.18 (3) Yes (2-5) 5/5 (5) 2.4 (6) ND 9143 A24WT3Bm3Dm 7.40 (4) 9.03 (5) Yes (3) 1/5 (5) 3.6 6.29 (6)
9144 A24WT3Bm3Dm 7.92 (4) 8.85 (5) Yes (4) 4/5 (7) 3.0 5.45 (7) 9145 A24LL3Bm3Dm Negative Negative No 0/5 1.5 ND j 9146 A24LL3Bm3Dm Negative Negative No 0/5 2.4 Negative
Safety Data Cattle
FMD-LL3B3D is fully attenuated in cattle!
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N=4 N=4 N=4 Commercial Tetravalent
FMDV Vaccine unvaccinated controls 1xBEI- Vx 1x BEI Marker virus
Naïve
Efficacy Data Cattle BEI-inactivated Vaccine formulated with montadine ISA 260 adjuvant
(Sepic-WOW) 21 dpv challenge with FMDV-A24
No clinical disease (0/4)*
No clinical disease (0/4)*
100 % clinical disease (4/4)
Inactivated vaccines prepared with FMD-LL3D and FMD-LL3B3D induced complete protection against challenge!
FMD-LL3D FMDV Vaccine
N=4
1x BEI Marker virus
No clinical disease (0/4)*
FMD-LL3B3D FMDV Vaccine
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Characteristics of an “Ideal” FMD Vaccine
• Effective, rapid and long-lasting protection with one inoculation
• Prevents viral transmission • Allow differentiation of infected from vaccinated
animals (DIVA) • Safe: produced without the need for virulent FMDV • No need for adaptation of field strains to cell culture • Prevent development of carrier state • Broad antigenic coverage • Stable antigen – long shelf life • Long duration of immunity
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Novel Ad5-FMD Vaccine • A novel FMD vaccine
was developed by ARS scientists under the leadership of Dr. Marvin Grubman
• This vaccine utilizes a defective human adenovirus vector to deliver genes coding for FMDV structural proteins
Human Defective Adenovirus 5 vector - Lacks necessary proteins for growth - Delivers and expresses transgenes in target cells
M. Grubman
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N=6
N=4
N=6
N=4
N=6
N=4 2o Vx
2o Naive 2o Naive
1o Vx 1o Vx 1o Naive
First Licensed Molecular FMD Vaccine
No clinical disease 100% protection
(10/10)
No clinical disease 100% protection
(10/10)
100 % clinical disease (10/10)
DHS- TAD Group
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Characteristics of an “Ideal” FMD Vaccine
• Effective, rapid and long-lasting protection with one inoculation
• Prevents viral transmission • Allow differentiation of infected from vaccinated
animals (DIVA) • Safe: produced without FMDV !! • No need for adaptation of field strains to cell culture • Prevent development of carrier state • Broad antigenic coverage • Stable antigen – long shelf life • Long duration of immunity
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Implications
• What does this vaccines add for US preparedness? – Possibility of domestic production – Rapid response to new strains – Opened regulatory path to other molecular
vaccines • Implications to the hemisphere?
– Potential application in final stages of eradication?
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APPROVED NEW CRIS PROJECTS 2012-2017
• Intervention Strategies to Support the Global Control and Eradication of FMD
• Countermeasures to Control Foreign Animal Diseases of Swine: CSF/ASF
• Ecology and pathogenesis of Re-Emerging VSV in North America
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ASF On The Move 2012
Beginning of 2007 in R. of Georgia and has since spread to the neighboring countries of Armenia, Azerbaijan, Ukraine and Russia
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ASFV Research Program
Develop intervention strategies to control ASF virus by identifying virus-host determinants of virulence and transmission and by developing technologies to enable the development of ASF vaccines that are efficacious against the most prevalent ASF strains.
– Development and standardization of a challenge model to assess ASFV experimental immunogens
– Comparative studies of early pathogenesis events in swine during infection with highly virulent and attenuated ASFV strains using a natural route of infection.
– Identification of immune mechanisms mediating protection induced by experimental live attenuated vaccine strains
– Functional Genomics and development of ASFV experimental vaccines
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Challenge model
Hypothesis: Oronasal (simulated natural) inoculation of pigs will allow elucidation of critical virus-host interactions which may be targeted by novel countermeasures
Standardized intra-oral deposition of ASFV under sedation
Dr. Jonathan Arzt
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LVR CVR RVR
Functional genomics
Structural proteins: p30, p72, p54
Immune response modulation: 5EL (IkB), 8CR (lectin), 8DR (CD2)
Prevention of apoptotic cell death: 5HL (Bcl2), 4CL (iap)
Host range and virulence associated genes NL, UK, 9GL, TK
Multigene family (MGF) 530 genes
Multigene family (MGF) 360 genes
Dr. Manuel Borca
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180kB ASFV
0kB X
X
PCR Amplify left flank Amplify right flank
INFECTION
ASFV
Macrophages
TV
TRANSFECTION
INSERT REPORTER GENE
Transfer Vector (TV)
P72 GUS
RECOMBINATION x
Genetic engineering of ASFV
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ASFV challenge (1,000-10,000 LD100)
Protection in pig
MAL (Malawi’83)
RSA1 (Pr4’96) TEN (Tengani’54)
YES NO NO
Immunization MAL∆9GL TEN∆9GL Pr4∆9GL
RSA2 (Pr5’96)
RSA3 (CR1’96)
RSA4 (CR3’96) RSA5 (O1’96)
NO NO
YES YES NO
NO
YES
YES
YES
YES
∆9GL confers strain-specific protection
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Production of recombinant Georgia ASFV ΔCD-2 like
Δ ASFV genes
9GL NL UK
MGF CD-2 like
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What next • Comparative studies of early pathogenesis events in swine during
infection with highly virulent and attenuated ASFV strains using a natural route of infection.
• Determine protection induced by experimental live attenuated vaccine strains
• Identification of immune mechanisms mediating protection induced by experimental live attenuated vaccine strains
• Expression of multiple ASFV immunogens in replicating viral vectors (e.g. vaccinia) to assess immune response and protection from challenge
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Strategic partnerships • Government: DHS, USDA/APHIS, EPA,
DOD, DOS, DOE • Stake holder: National Pork Board (>$2 M
in last 4 years) • Academia: UConn, Kansas State,
U.Georgia, Stonybrook, U. Wisconsin, U. Vermont, Texas A&M
• Industry: Pfizer, Merial, Intervet, GenVec
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“To establish and sustain global research partnerships to generate scientific knowledge and discover the tools to
successfully prevent and control FADs”
GLOBAL PARTNERSHIPS
• India Australia • Spain Pakistan • Vietnam South Africa • UK Argentina • Kenya Cameroon • Russia R. Georgia • S.Korea Japan • Mexico Uganda • Israel Denmark
Countries with current research collaborations
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