OIE Collaborating CenterMember of OIE SCAD
Mechanism of FMD outbreaks and the Control of FMD in East Asia
Exotic Disease Research DivisionNational Institute of Animal Health
6-20-1 Kodaira, Tokyo 187-0022, Japan
Kenichi Sakamoto
Symposium on Prevention and Control of Foot and Mouth Disease
December 1, 2011
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General Information of Asia
1. Human PopulationWorld population 7.0 billions (2011.11)More than 60% 4.2 billions in Asia
2. Populations of domestic animals(2007 FAO)
World Population Ratio of AsiaCattle 1.38 billion 33.3%
Pigs 0.92 billion 58.5%
Sheep 1.09 billion 35.5%
3. Rapid Increase of economic activities in Asia RegionActive movements of people, animals, animal commodities
billion
Red line: Total populationBar: increasing population year by year
POOL 1O,A,Asia1
POOL 7O&A
POOL 5O,A,SAT1,2
POOL 3O,A,Asia1
POOL 2O,A,Asia1
POOL 6O,A,SAT1,2,3
POOL4O,A,SAT1,2,3
Model of related FMDVs Distribution
(OIE/FAO_WRLFMD、;OIE/FAO Global Conf. on FMD, Paraguay, 2009)
3 pools covering Europe, Middle-East and Asia3 pools covering Africa1 pool for the Americas
FMD virus in Asia
POOL 1O,A,Asia1
POOL 2O,A,Asia1
Asia1(G-V)
Asia1(G-IV)
AASIA
AASIA
OCathay
OSEA
OME-SA
(PanAsia-2)OME-SA
(PanAsia)Asia1(G-III)
( Hammond et al. http://web.oie.int/eng/A_FMD2009/FMD_presentation/Session%202_1/2_1_1_Hammond.pdf)
The recent characteristic of FMD outbreaks in the region
• The FMD spreads more quickly than before.
• FMD outbreaks are predominantly caused by FMDV serotype O.
• The two main topotypes involved are South-East Asia (SEA) and Middle East – South Asia (ME-SA).
• FMDV of the SEA topotype (Mya-98 lineage) is widespread in South-East Asia and East Asia.
• The economic impact of FMD in East Asia (People’s Republic of China, Japan and Korea) has been severe in 2010–2011.
• FMD outbreaks due to serotype A have been sporadically observed in recent years.
• Serotype Asia 1 newly appeared in Pakistan from 2010 and Bahrain and Iran in 2011.
FMD situation in the region (2009-2011)Type O
SEA topotype (Mya-98 lineage), Currently widely circulating in Asia. Lao PDR (2008-2009), Myanmar (2008-2009) , Thailand (2009), Malaysia (2009), Hong Kong SAR (2010), China (2010). In East Asia the Republic of Korea (South Korea)(2010.4, 2010.11-2011.4), Japan (2010.4), Russia (2010. 7), Mongolia (2010. 8), The Democratic People‘s Republic of Korea (North Korea) (2010.12- 2011).
CATHAY topotypeVietnam (2008), Taiwan (2009-2011) .
ME-SA topotypeBangladesh (2009), Malaysia (2009), (PanAsia lineage). Bhutan, Bangladesh and Nepal (2010), (the O-Ind-2001 lineage). China (2011.3) (PanAsia lineage closely related to Vietnam isolates).Afghanistan, Iran, Pakistan and Turkey (O-PanAsia-2)
Unknown topotypeKazakhstan (2011.5)
FMD situation in the region (2009-2011)Type A, Asia 1, C
Type AFMD type A (ASIA topotype): wide circulation in the region. Lao PDR (2008), Thailand (2009), Vietnam (2008-2009), P.R. China (2009), the Republic of Korea (2010.1-3).
Myanmar (2010. 9), very close to the border with Bangladesh.By the phylogenetic analysis the virus was most closely related to viruses occurring in India in 2000.
Asia 1The recent appearance of new Asia 1, Pakistan (2010) Bahrain and Iran (2011).
C No outbreak in the region in 2009-2011
RT-PCR
Virus Isolation
negative
positive
Antigen detection ELISA
Isolatedvirus
Neg
Cont.OACSAT1SAT2SAT3Asia1SVD
Strong Weak
Cont.
RT-PCR
Antigen ELISA
Virus isolation
2.5 ~ 6 hour
4 ~ 6 hour
2~7days
Consuming time for diagnosis
FMD Diagnosis Methods in Japan
Antibody Detection(in outbreaks and surveillances)•LPB ELISA•NT (in necessary)
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1 12
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7 7 78
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12
1 1 1 12 2
1 1 1 1
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292 outbreaks(including 1 goat
farm)
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【0例】
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【0例】
7/3
牛発生農場数 豚発生農場数
(戸) (戸)
発生事例数
No. of Outbreaks per day
Number of outbreaks (Cattle and Swine)
Total No. of Outbreaks
No. of Outbreaks in cattle
No. of Outbreaks in swine
Date
More wider spread
Large number of animals were waiting to be slaughtered
Japan decided FMD vaccination
May 19Restriction Area
Start vaccination to all the animals in movement control region (in Red circles) to control the speed of FMD
May 22Restriction Area
- 181 cases
40km
First time Vaccination in Japan
• All cloven-hoofed animals in the movement restriction zone (10 km radius)
• 6 PD50 O Manisa (oil adjuvant killed vaccine)
• Estimated r1 value 0.7
• Purified inactivated
• Destruction of the vaccinated animals
Cattle 45,950
Pigs 79,606
Others 118
Total 125,556
Number of vaccinated animals
1,066 farms
Vaccine matching of FMD in the region
• O SEA topotype (Mya-98): O Manisa, O Ind R2/75 and O Taw 98(some isolates from Hong Kong (2011) : not matching O Manisa, O Taw 98)
• ME-SA topotype (PanAsia-2) (2009-2010) : O Manisa, O IND R2/75, O TAW 98 and O BFS.
• FMDV A from Iran (2009-2010) : A TUR 06.
• FMDV A from Afghanistan (2010-2011): A IRAN 05, A TUR 06.
• A from the People’s Republic of China and the Republic of Korea: Mya-97.
• Asia 1 from Bahrain, Pakistan and Iran (2010-2011):
not matching with Asia 1 IND 8/79, Asia 1 Shamir, Asia 1 WBN
17
Foot-and-Mouth Disease Virus
7 immunologically distinct serotypes
Capsid Non-structural proteins
AAAAAAAAAn
L P1 P2 P35’ UTR 3’ UTRVPg
VP4 VP2 VP3 VP12A 2B 2C 3A 3B 3C 3DPoly C
~8.2 kb
IRES
O, A, C, Asia 1, SAT 1, SAT 2, SAT 3
FMD Differentiation of Infection and Vaccination
FMD VaccineInactivated Vaccine (concentrated purified)Potency:Normal 3PD50
For emergency 6~12PD50
Differentiated Infected VaccinatedAnimal
1)LPB ELISA ○ ○
2)NSP ELISA ○ ×
The conditions for FMD vaccine
•The FMD vaccine must be an inactivated vaccine.
•The vaccine selected should be a good antigenic match for field isolates. It is very important to send samples to FMD Reference Laboratories for virus isolation and sequencing.
•Whenever FMD vaccine is used, in an emergency to control FMD outbreaks or routinely, it is essential to be able to determine whether FMDV antibodies are the result of infection or vaccination.
•The vaccine should be produced in accordance with the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals.
•Cooperation and research collaboration on FMD diagnosis and vaccine production are important between Member Countries to control FMD in the region.
•In order to be able to differentiate between antibodies by infection and by vaccination, there is an urgent need to continue striving to produce pure vaccines to limit the effect of NSP’s when evaluating surveillance results.
Empty Capsid
Intact FMDV
Empty Capsid of FMDV as vaccine antigen
Virus Genome
One Copy of 3D Protein
No Genome
No NS proteins
Only Outer Shell
Genetic engineering technique
A new generation FMD vaccine
1. Sharing Disease Information in Pool 1 - 3(South East and East, Central and Middle-East Asia)
2. Early notification of the FMD to Members in the region and OIE
3. Strengthen the border control to prevent FMD virus entry 4. Scientific research collaborations of the FMD laboratories
to control the disease among the member countries in the region.
5. Technical supports to the developing countries in the region for diagnosis of FMD
6. Financial and economic supports to provide good matching FMD vaccines to FMD epidemic countries
To reduce FMD outbreaks in the regionProposals
The epidemiological roles of susceptible animals in FMD
Cattle:The most susceptible livestock to FMDV.
(Detector)
Pigs:Pigs excrete very large quantities of the virus (100- to 2000-fold more than cattle and sheep).
(Amplifier)
Sheep:Mild or un-apparent clinical signs, making early detection of FMDV infection difficult.
(Transporter ?)
An example of Detector
• Japan in 2000: PanAsia of O ME-SA topotype• FMD in only cattle
• Miyazaki, Hokkaido killed 740 cattle• Only Japanese black cattle created atypical
clinical signs. No vesicles in mouth or nasal cavity
• Pigs form typical symptom of vesicle in foot by animal experiments
• The source of the virus was considered to be imported hay or straw from the Asia region.
Excretion of virus
Minimal effectiveinfecting dose 101.0 ID50 102.6 ID50
105 ID50 108 ID50
Detector Amplifier
Epidemiology of FMD
Epidemiological role
Examples of Amplifier
• Taiwan 1997, UK 2001, South Korea 2002
• Recently Japan 2010, South Korea 2010-2011
• O type Cathay, ME-SA and SEA topotypes
• Accumulation of FMDV in the environments makes new outbreaks.
• FMD outbreaks in pigs are often on a very large scale.
• The FMD can cause serious economic damage.
Economic Impact in Recent FMD Outbreaks
Year Country No. of Animal Destroy Economic Damage
1997 Taipei China Swine 4 million 3.6 Billion US$ in first year
2000 Japan Bovine 740 72.7 Million US$
2000 S. Korea Bovine 2200 273 Million US$(FMD Vaccine to 850,000 Bovine)
2002 S. Korea Swine 160,000 225 Million US$
2001 UK Susceptible Animals 14.4 Billion US$6 million
2010 Japan Swine & Bovine 290,000 3 Billion US$ for complete recovery
2010- S. Korea Swine & Bovine 3.5 Million 3 Billion US$
Samples of Transporter
• UK in 2001, Cyprus in 2007
• The clinical signs are sometimes mild or unapparent.
• It makes early detection of FMDV infection difficult.
• Possibility of huge FMD outbreaks
• Serological tests are important for the diagnosis of FMD in sheep.
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発生農場数
英国の口蹄疫発生(MAFF UK, 2001~2002)
累積発生数
1日の発生数Numbers of slaughtered animals
2002. 1.14
Cases:2026
slaughtered 4.05 Million
species cattle 0.6 M
sheep 3.3 M
pig 0.14 M
goat 2 Thousand
others 2 T
由来農場Freshwater / Isle of Wight
発見されたと畜場(27頭)Brentwood / Essex
2001.2.21.
由来農場Great Horwood / Buckinghamshire
由来農場Freshwater / Isle of Wight
発生と畜場・農場(4件)Essex州
UK FMD outbreaks in 2001
2001.2.25
e
発生農場(3件)Devon州
発生農場(3件)Northumberland州
移動制限地域Berwick-on-Tweed / Northumberland州
移動制限地域Fyvie / Abardeen州
移動制限地域Woodchester 及びKington
/ Gloucestershire州
発生農場(1件)Hereford州
Epidemiological findings of 2001 UK FMD outbreaks
19 heads of sheep
Livestock markets
Distance between A B 400km
C happened before A and B
A Initial outbreak (Tyne and Wear state)
Pig Farm
Origin of the FMDV
Unknown(Airborn infection)
C Cumbria stateDevon state
Expansion of Nationwide infection
B First find Essex state Slaughter house
(Airborn infection)
Cattle near by the slaughter house
(Epiological Investigation)
To prevent pandemic outbreaks and to inhibit huge economic catastrophes in the region
1. Early Detection
2. Early Extinguishment
3. Early notification
4. Good matching Vaccine
However….
Infected pigs excrete FMD viruses within 2 - 4 days after FMD infection
And it takes about 7 days before the animals can induce protective antibodies by vaccination.
Prompt effective tools are strongly desired
◎ Anti-FMDV Agents in vitroGroup of Compound Agent IC50(μg/ml)
Anti-HIV agents (Non-Nucleotide Efavirenz 20 - 40Reverse Transcriptase Inhibitors)
Pyrazinecarboxamide derivatives T-705 14T-1105 1.6T-1106 17
Virus : FMDV O/JPN/2000 Cells : IBRS-2
FMDV Serotype Challenge dose EC50(μg/ml)
A 22 Iraq 10TCID50 0.44
C Philippine 10TCID50 1.76
Asia 1 Shamir 101.5TCID50 0.88
◎ Anti-FMDV Activities of T-1105 to FMDV serotypes in vitro
Mechanism of Action :
Inhibition of viral RNA polymerase
Plas
ma
conc
. (µg
/mL
)
Pig Cattle Sheep
Pharmacokinetics of T-1105 in domestic animals
0.01
0.1
1
10
100
0 10 20 30hour
T-1105T-1105M1
0.01
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1
10
100
0 10 20 30hour
T-1105T-1105M1
0.01
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1
10
100
0 10 20 30hour
T-1105T-1105M1
T-1105 Oral single Administration
100mg/kg Body Weight
Concentration of T-1105 in pig is high and poor in cattle
T-1105 (Twice a day, 200mg/kg)
1 dpi 2 dpi 3dpi 4dpi 6dpi 8dpi0 dpi 5dpi 7dpi
Collection of plasma, serum and nasal swabs
Virus inoculation
Experimental Schedule
Initial Administration of T-1105 is just one hour before FMDV inoculation
Oral administration (blended in feed)
Virus: O/JPN/2000, 106 TCID50/ml
Site of injection: Left front heel bulb intradermal
T-1105 Administrated Group・ No Clinical signs
・ No virus Excretion
Control group・ Typical Clinical signs
Clinical Signs after the virus inoculation
+Creation of vesicular legion++ Rupture of vesicle Lameness and difficulty in standing
0 1 2 3 4 5 6 7 81 - - - - - - - - -2 - - - - - - - - -3 - - - - - - - - -4 - - - - - - - - -
5 - - + ++ ++ ++ ++ ++ ++6 - - - + + ++ ++ ++ ++
T-1105
Control
Treatment No.Days post inoculation
In vivo test with virulent FMDV O/TAW/1997Assay of the pathogenicity of the virus by * PHID50
*50 % Pig Heel infectious Dose : The creation of vesicula in the injection site within 48 hours
Virus PHID50 (pfu) Ratio of virulence
O/JPN/2000 2.5 x 105 1
O/TAW/1997 9.4 x 101 2.5 x 103
O/SKR/2000 2.2 x 103 102
O/UKG/2001 1.9 x 103 10 2
“ O/JPN/2000 is a low virulent FMD virus to pigs”
Introduction of O/TAW/1997 for the in vivo efficacy test of T-1105 in pigs
1 2 3 4 5 6 7 8 9
1 + + ++ ++ ++ ++ ++ ++ ++6 + + ++ ++ ++ ++ ++ ++ ++
T-1105Admin.
Non-admin.
+ Creation of vesicular legion++ Rupture of vesicle
Pig No.Days post infection
2 - + + + ++ ++ - - -3 - - - - - - - - -4 - - - - - - - - -5 - + + + ++ ++ - - -
Lameness / Difficulty in standing
Summary of clinical signs in O/Taiwan/97 infection
No Lameness / No Difficulty in standing
1
10
102
103
104
105
106
0dpi 1dpi 2dpi 3dpi 4dpi 5dpi 6dpi 7dpidays post infection
PFU
/0.1
ml
#1
#6
Non-admin. group
Virus excretion in saliva from pigs infected with O/Taw/97
1
10
102
103
104
105
106
0dpi 1dpi 2dpi 3dpi 4dpi 5dpi 6dpi 7dpidays post infection
PFU
/0.1
ml
T-1105 admin. group
#2 #3#4#5
Clinical signs in pigs infectedwith O/Taiwan/97
Two of admin. pigs made vesicle at the only inoculation site.
The low level of virus was detected from saliva of some pigs.
Brief and lower level of viremia were detected in some pigs.
One pig did not show viremia as well as clinical signs.
FMDV excretion and viremia were controlled by administration of the T-1105
Minimum Effective dose of T-1105On Day 7
Group Concentration of T-1105(mg/kg)
No. of pigsTested / Protected
Protection(%)
A 3.125 6/5 84
B 12.5 6/3 50
C 50 6/6 100
D 200 6/6 100
E (Control) 0 6/1 16
Minimum effective doses of T-1105 conclusion
・ Day 7: Group C (50mg) Protection 100%
Group D (200mg) 100%
・ Day 10 : Group C Protection 84%
Group D 100%
・ 50 - 100mg/kg is the minimum dose to control
FMD in pigs
Virus : FMDV O IND R2/75
Conclusion
T-1105 administrated pigs with FMDV challenge・ No Viremia, low level fo viremia with highly virulent strain
・ No Clinical Signs (No Vesicles or only injection site, No Lameness)
・ No virus Excretion or very low level
Advantage of anti-FMDV compound, T-1105・Prompt effect ( In one hour)
・Independence from FMDV serotypes or strains
・ Administrating with food
Model for utilization of T-1105
FMD outbreaks in pig* Early stage of the outbreak
Objective: Reduction of FMD spread
Result: Decreasing the FMDV in the zoon
and infection in pig farms and the cattle farms
A
B
C
D
E
Zoon
F
3 km
Administration of the antiviral agent T-1105 to all pigs inPig farms within 3 km (Farm A, B, C, D, E, F)
Recommendation to use the antiviral agent
T-1105 should be used in the following conditions
1. In FMD outbreaks in pigs
2. Emergency use
3. To the normal pigs surrounding of an infected pig farm
4. Administrated pigs should be slaughtered to reduce the risk of emerging a mutant virus
5. T-1105 is administrated with food orally6. Administrated pigs should not be used for human consumption
until T-1105 is proved to be safe for human health
7. Strictly regulated by the countries and regions like as the emergency FMD vaccine
POOL 1O,A,Asia1
POOL 7O&A
POOL 5O,A,SAT1,2
POOL 3O,A,Asia1
POOL 2O,A,Asia1
POOL 6O,A,SAT1,2,3
POOL4O,A,SAT1,2,3
Model of related FMDVs Distribution
(OIE/FAO_WRLFMD、;OIE/FAO Global Conf. on FMD, Paraguay, 2009)
3 pools covering Europe, Middle-East and Asia3 pools covering Africa1 pool for the Americas
FMD virus in Asia
POOL 1O,A,Asia1
POOL 2O,A,Asia1
Asia1(G-V)
Asia1(G-IV)
AASIA
AASIA
OCathay
OSEA
OME-SA
(PanAsia-2)OME-SA
(PanAsia)Asia1(G-III)
( Hammond et al. http://web.oie.int/eng/A_FMD2009/FMD_presentation/Session%202_1/2_1_1_Hammond.pdf)
Cattle (millions)
Buffalo(millions)
Import Export Comparative Unit Price Ranking
Cambodia 3.34 0.72
- +++ **Moderate
LowLao PDR 1.35 1.16
- +++ **Moderate
LowMalaysia 0.8 0.14
+++ - ***** HighMyanmar 12.63 2.84
- ++++ * LowThailand 9.34 1.58
++ ++ *** Moderate Vietnam 6.88 3
+++ - ****Moderate
High
Cattle/Buffalo Trade vs. population and price
Recent FMD outbreaks in East Asia
1)1997- O: Cathay topotype: Taiwan (Nationwide) Illegal Movement of pigs from China
2) 1999-2002 O: ME-SA topotype, PanAsia lineage: China, Taiwan, Japan, Korea, Amur region of Russia, Mongolia
3) 2005- Asia 1:Hong Kong, China, Amur region of Russia, Mongolia, North Korea
4) 2009- A: ASIA topotype, China, South Korea
5) 2010-2011 O,SEA topotype, Mya-98 lineage: China, South Korea, Japan, Amur region of Russia, Mongolia, North Korea
China has the important role of the FMD outbreaks in East Asia1) Long border with FMD epidemic countries in South East and Central Asia2) Large numbers of susceptible animals (pigs, sheep, cattle)3) Rapid increase of economic activities (A raising nation)4) Active cross border movement of people and animal commodities
FMDV
The Scheme of FMD virus spread in East Asia
Mechanism of FMD spread in East Asia
FMD (Epidemic countries) China East Asia countries
199019911992199319941995199619971998199920002001
FMD – 10 year evolution of Asia topotype O
FAO warns same may happen again near future
1. Sharing Disease Information in Asian Region(South East, Central and East Asia)
2. Early notification of the FMD to Members in the region and OIE
3. Strengthen the border control to prevent FMD virus entry 4. Scientific research collaborations of the FMD laboratories
to control the disease among China, Japan, Korea and Taiwan
5. Technical support to South East Asian countries for diagnosis of FMD
6. Financial and economic supports to provide good matching FMD vaccines to SEA countries
To reduce FMD outbreaks in the regionProposals
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