FMD Reference Laboratory

Global Status Report for FMD:Tracking the emergence and spread of new viral lineages

Donald King

Acknowledgements: Valerie Mioulet, Nick Knowles, Anna Ludi, Ginette Wilsden, Mehreen Azhar, Hannah Baker, Kasia Bachanek-Bankowska, Antonello Di Nardo,

Bob Statham, Lissie Henry, Jemma Wadsworth, Clare Browning, Britta Wood, Alison Morris, David Paton, Abid Bin-Tarif, Ashley Gray, Beth Johns, Mark Henstock,

Nick Lyons, Dexter Wiseman, Julie Maryan, Sarah Belgrave

Seven endemic pools• Maintain specific FMD virus strains• Control via (tailored) vaccination and supporting diagnostics

• No reported serotype C outbreaks since 2004 (Kenya and Brazil)

Conjectured global status

• Global surveillance and changing patterns in risk

• Harmonised and improved lab capacity

• MoU now signed by all “core members”

• Meeting and annual reports available: http://www.foot-and-mouth.org/

Pretoria– November 2017

Core Network Members and affiliates:

Page | 4

1.2 Reporting Period

1st January 2016 - 31st December 2016

1.3 Collated input from

Figure 1-1: Participating laboratories

OIE Reference Laboratory for Foot and Mouth Disease, Dirección de Laboratorio

Animal

SENASA, Argentina

OIE collaborating centre for validation, quality assessment and quality control of diagnostic assays and vaccine testing for vesicular diseases in Europe, and FAO

Reference Centre for vesicular Diseases

CODA-CERVA, Ukkel, Belgium

OIE Regional Reference Laboratory for Sub-Saharan Africa (RRLSSA)

BVI, Gabarone, Botswana

Centro Panamericano de Fiebre Aftosa (PANAFTOSA) and OIE Reference

Laboratory for FMD

Rio de Janeiro, Brazil

FAO FMD Reference Laboratory

National Centre for Foreign Animal Disease National Centres for Animal Disease, Canadian Food

Inspection Agency, Winnipeg, Manitoba, Canada

OIE and China National FMD Reference Laboratory

Lanzhou Veterinary Research Institute (LVRI), CAAS, Gansu, People’s Republic of China

OIE FMD Reference Laboratory

French Agency for Food and, Environmental and Occupational Health & Safety (ANSES), Maisons-

Alfort, Paris, France

FAO Reference Centre for FMD in South Asia

Project Directorate on FMD (PDFMD), Indian Council for Agricultural Research, Mukteswar,

Nainital (Uttarakhand), India

OIE/FAO FMD Reference Laboratory

Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna (IZSLER), Italy

OIE Reference laboratory for Foot and Mouth Disease

Animal and Plant Quarantine Agency (QIA), Anyang city, Gyeonggi-do, Republic of Korea

OIE/FAO FMD Laboratory Network

Global surveillance via the OIE/FAO FMD Laboratory Network

• Since 2014 >2000 virological samples tested per year

• High proportion of samples that are ”no virus detected [NVD]”

• Gaps in surveillance remain in West/Central (and East Africa)

• Review geographical distribution and spread of transboundary FMDV lineages

• new way to highlight future risksInd-2001d

PanAsia

PanAsia-2

Mya-98

EA-3

Conjectured distribution of important

serotype O FMDV lineages. The extent of current distribution for each of the viral

lineages is represented within the black

lines, while the location of individual outbreaks (dots) and affected countries

(shaded in red, according to dates) are

shown. NB: Arrows are drawn to highlight the regions that are threatened by these

lineages

2017 data:

OA

NVD

FMDV serotypes detected

Pool 1

Pool 2Pool 3

Pool 4

Pool 6

Pool 5

Pool 7

OIE Global status

• Two sub-lineages (d and e)

• Since 2013, full genomic sequence data indicates that there have been multiple “escapes” from Pool 2

O/ME-SA/Ind-2001: a new pandemic lineage?

Libya(2013)

TunisiaAlgeria

Morocco

Mauritius (2016)

Pool 2

Saudi Arabia (2015)UAE (2015)

Jordan (2017)Vietnam (2016)Thailand (2016)

Myanmar (2017)China (2017)

Russia (2016)Mongolia (2015/17)South Korea (2017)

Malaysia (2018)

Saudi Arabia (2016) Myanmar (2015)

Myanmar (2017)

Saudi Arabia (2013)

Sri Lanka (2014/13)

UAE (2014)

Bahrain (2015x2) Vietnam (2015)Laos (2015)

d

e

(Bachanek-Bankowska et al., 2018)

Spread of A/ASIA/G-VII:

(Bachanek-Bankowska et al., 2018)

Pool 2

Saudi ArabiaTurkey

IranArmenia

Israel

• Emerged in 2015 from Pool 2

• Rapid spread into parts of West Eurasia (most recently Israel in 2017)

• Poor in vitro and in vivo responses for vaccines that are used in West Eurasia

• Gap in the coverage of vaccines have led to the development of new tailored vaccine strains

A/S

AU

/1/2

01

5

A/S

AU

/2/2

01

5

A/I

RN

/8/2

01

5

A/I

RN

/12

/20

15

A/I

RN

/25

/20

15

A-Iran-05 0 0 0 0 0

A-Tur-20-06 0.03 0.06 0.01 0.15 0.01

A-22 0.11 0.11 0.13 nd 0

A-Iran-87 0 0.04 nd nd nd

A-Iran-96 0.04 0.06 nd nd nd

A-Iran-99 0.01 0.01 nd nd nd

A-Sau-95* 0.20 0.19 0.26 0.16 nd

A-May-97 0.14 0.23 0.15 0.23 nd

A-Tur-11 0.01 nd 0.10 0.04 nd

A-Tur-14 0 nd 0 0 nd

A-IND-40-2000* 0.26 nd 0.03 0.24 nd

r-values:

Vac

cin

es

Pool 2 Myanmar

G-V

Sindh-08 G-I

G-VIb

G-III

G-VIII

IND/63/72* IND/18/80

YNBS/CHA/58*72

88

PAK/8/2008 AFG/1/2001

100

Shamir/ISR/89*IRN/10/2004

IND/14/95*IND/762/2003*

IND/18/2011* IND/7/2011*

100

IND 227/07*IND175/2007*

IND 97/08*IND 93/08*

IND 95/08*10010I0ND 96/08*10I0ND 137/08*

100IND96/2008*100

BAR/8/2009 IND 32/08*

IND 121/07*

IND78(177)/2011* IND/78/2011*

10086

IND 12/07*IND341/2008*

10076

IND/155/2010* IND/341/2008*

BD BAU ML5 2013* BD BAU ML6 2013*

IND356/2007*

100

BAN JE Mf-06 2012*

100 BAN JE Mf-03 2012*

10B0AN JE Mf-05 2012*

10B0AN JE Mf-01 2012* BAN JE Mf-02 2012*100

75

IND/148/2011* IND/248/2009*

100 BAN JE Mf-04 2012*

IND148(330)/2011*IND148(323)/2011*IND148(326)/2011*

IND148(322)/2011* IND148(324)/2011*

IND148(327)/2011* IND148(331)/2011*

100

IND/65/2010*IND65(140)/2010*

99

IND327/2009* IND/327/2009*

IND/787/2009*

IND205(508)/2010* IND/205/2010*

IND/509/2010*

IND/68/2012* IND68(128)/2012*

100

IND285(640)/2012*IND/285/2012*

100

76

IND131(255)/2012*IND157(336)/2013*

IND403(826)/2012*

BD SI 2 2013* IND/292/2012*

IND/294/2012* IND413(852)/2012* IND400(822)/2012*

86IND120(225)/2012*IND/120/2012*

IND/121/2012* IND/16/2012* IND119(223)/2012* IND118(222)/2012* IND15(24)/2012* IND/118/2012* IND/283/2012*IND/305/2012*

IND156(335)/2013*IND/115/2012* IND/119/2012* IND119(224)/2012* IND114(214)/2012* IND/114/2012* IND300(655)/2012* IND/300/2012*

IND115(217)/2012*

IND/306/2012* IND288(643)/2012*

88 IND411(846)/2012* IND411(845)/2012*

IND/288/2012* IND/291/2012*

IND163(334)/2012* IND163(333)/2012*

IND162(331)/2012* IND109(208)/2012*

86 IND/303/2012*IND303(658)/2012*

BAN GA Sr-187 2013*MYA/14/2017*93

90

85

99

71

98

0.00 0.04 0.08

*, not a WRLFMD Reference Number

• Serotype Asia 1 not reported in Southeast Asia since 2006/7(?)

• February 2017: FMD outbreaks in cattle in Myanmar

• Sequence data from RRL-SEA in Pakchong, Thailand

• New introduction of the virus from Pool 2

Onward risks?SEACFMD – 2017:

• ~500,000 head/year move from Mynamar into Yunnan Province of PR China

• 5% infected with FMDV

SEA: New outbreaks of Serotype Asia 1

Analyses of samples from NepalHighlights gaps in regional/National surveillance?

Serotype O:~94% identity with closest VP1 sequences

Serotype Asia 1:~91% identity with closest VP1 sequences

How do we interpret these trees?1. Rapid evolutionary

change2. Un-sampled cases

Pool 1

Pool 2Pool 3

Pool 4

Pool 6

Pool 5

Pool 7

FMD outbreaks in North AfricaNorth AfricaNo FMD outbreaks 1999-2013

Near EastSerotype O/SAT 2Serotype APrevious SAT 2 outbreaks in Egypt/Libya/Palestine 2012

March – April 2017: FMD cases in Algeria and Tunisia

• >100 outbreaks in cattle

• Due to a new FMD virus strain for the region (A/AFRICA/G-IV)

• Sequences from Algeria (March) and Tunisia (April) >99% identity

• Most closely related to FMD viruses from Nigeria

• First cases of Serotype A in the Maghreb > 30 years• Algeria 1977

• Tunisia 1984

• in-vitro vaccine matching data for provides candidates vaccines that now need testing

VACCINE STRAINSA/ERI/3/98 A/TUR/20/06 A22/IRQ/64 A/IRN/05

ALG/2/2017 0.41 0.00 0.31 0.00ALG/3/2017 0.32 0.00 0.32 0.00

• Due to the O/EA-3 topotype

• >50 outbreaks

• >99% nt identity to sequences from Guinea (generated by for samples collected in July 2018)

• July-September 2018: Reports to OIE of FMD outbreaks elsewhere in West Africa (The Gambia, Guinea-Bissau, and Sierra Leone { + Burkina Faso and Senegal -not reported to OIE})

• Are these cases linked? – and do they represent the likely origins of the viruses that help us understand how FMDV has recently spread into North Africa?

June 2018: FMD cases in Algeria

• Sequences from West Africa/Algeria are different to Egypt/ Palestine/Israel

• Western-clade most similar to sequences from Nigeria

• Similar picture to A/AFRICA/G-IV

Different O/EA-3 sub-lineages in Africa

Cameroon 2016

O/CAR/G4258/2013* (KY581680)

O/CAR/G4260/2013* (KY581679)

Nigeria 2014

O/GNA/18Z005582/18* (ANSES)

O/GNA/18Z005587/18* (ANSES)

O/GNA/18Z005583/18* (ANSES)

O/ALG/2/2018

O/ALG/1/2018

O/GNA/18Z005588/18* (ANSES)

Nigeria 2016

O/NIG/1/2007 (KX258020)

O/SUD/1/2005 (GU566056)

O/SUD/3/2005 (GU566058)

Egypt / Palestine / Israel 2017

O/SUD/2/86 (DQ165075)

O/ETH/2/2006 (FJ798127)

O/ETH/3/2004 (FJ798109)

O/ETH/1/2007 (FJ798137)

“East Africa” Clade

“West Africa” Clade

xxxxxxxxxxxxxxxxxxxxxxxx

UgandaKenyaBurundiRwandaTanzaniaDRC

ImportantInfrequent

Conjectured regional connections in Africa

SudanS. SudanEthiopiaSomaliaEritrea

West Africa

Pool 5

Southern Africa

Pool 6

Malawi

Maghreb countries West Eurasia

Pool 3

• Viral sequences highlight most frequent connections between countries (reflect trade and animal movements)

• Trans-Saharan spread of FMD is infrequent (previously occurred in 1999)

• New pathways into countries in North Africa (Maghreb)?

Cattle density map

EgyptLibya

Samples tested

2017/18 FMD situation – ”headlines”

ColombiaSerotype O

East AsiaSerotype O

MyanmarSerotype Asia 1

Algeria (Tunisia)Serotype ASerotype O

Near EastSerotype O (O/EA-3)Serotype A (A/ASIA/G-VII)Serotype SAT 2

RussiaSerotype O

ZambiaSerotype O

South KoreaSerotypes O/A

PakistanSerotype O

Selecting vaccines to cover risk?European Perspective

2010-2011• Outbreaks in Bulgaria• FMD-free buffer zone

in Turkish Thrace

• Outbreaks in UK in 2001• Increased FMD circulation

in East Asia

% o

f to

tal r

isk

NRL Workshop for FMD – Ascot, UK - May 2016

• New FMD lineages in North Africa

• Outbreaks in FMD-free countries

Vaccine Antigen Prioritisation: Europe

SELECTING VACCINES

September 2018

NB: Analyses uses best available data, however there are gaps in surveillance and vaccine coverage data

Insufficient Data: C3 Oberbayern [LOW];SAT2 SAU [HIGH];SAT3 ZIM 2/83 [LOW]

Risk Profile:

O-TUR/5/2009 [HIGH]O-3039 [HIGH]O1-Manisa [HIGH]O1-Campos [HIGH]O-BFS/1860 [LOW]O-SKR/7/2010 [LOW]O-TAW/98 [↓ LOW]

A-TUR/2006 [HIGH]A22 Iraq [HIGH]

A-Iran-05 [HIGH]A-Malaysia 97 [↑ HIGH]

A-Eritrea [MEDIUM]A-SAU 95 [LOW]

A24 Cruzeiro [↓LOW]Asia1-Shamir [HIGH]

SAT2 Eritrea 3218 [HIGH]SAT2-ZIM [MEDIUM]

SAT-1 Rho/78 [MEDIUM]

Vaccine Coverage:

DEFINING RISK

O/ME-SA/Ind2001A/ASIA/G-VII

40%

0%

Regional risks:

Viral lineages:

FMDV vaccines: evidence gaps Particularly for Africa (from OIE/FAO and EALN-FMD Network Meetings)

[1] in vivo potency tests are rarely done, particularly those that define cross-protective responses

[2] Immunogenicity studies for monovalent (or multivalent vaccines) are rarely reported

[3] Reference reagents (such as validated BVS) from vaccines suppliers are not readily available to the Reference laboratory community

[4] Not clear that batch serological testing data is always supplied

[5] Studies that assess vaccine performance under field conditions are often lacking

Production batches(Batch control)

Formulated product(Customer requirements)

Licensed vaccine(Registration)

• Biosecurity and containment procedures

• GMP and in process controls• MSV records• Homologous potency testing in

cattle• Sterility, adventitious agent and

inocuity testing• Purity and safety testing• Stability and duration of immunity• Confirmation of MSV identity

• Sterility and inocuity tests• Safety test• Indirect potency test• Monitoring of long-term storage

conditions• Verification of Ag integrity of

batch• Confirmation of batch identity• Purity testing

• Defining/validating heterologous correlates (cattle and other species)

• Batch testing to generate sera• Confirmation that batch sera

passes threshold heterologous responses

• Field studies of post-vaccination responses

• Vaccination coverage and outcomes

• Investigation of vaccine failure

• Selection of reference viruses (to cover regional risks)

• Generation of reference BVS• Application of in vitro vaccine

matching tests• Development of harmonised

test formats• In vivo studies (where required)• Identification of vaccine gaps

• Tender requirements• Shelf life• Antigenic relevance• Potency• Purity• Duration of immunity• Correlate of immunity

threshold • Verification /calibration studies

Vx Producers (with audit at registration/purchase)AU-PANVAC (with assistance from WRLFMD)Vx producer (with supervision/audit by AU-PANVAC) – or AU-PANVACCustomer (with support from FMD Reference labs/AU-PANVAC – where needed)OIE/FAO FMD Lab Network

KEY

VACCINATION PLANV

acci

ne

QA

/QC

Ho

mo

logo

us

pro

tect

ion

Vac

cin

e p

erf

orm

ance

Het

ero

logo

us

(fie

ld)

pro

tect

ion

FMDV vaccine QA/QC pipeline for Africa

Defining responsibilities:

• Epidemiology of FMD is very dynamic• New unpredictable patterns in Asia (East and West)

and North Africa• Threats to FMD-free countries in Europe and

Turkish Thrace

• Sampling of field outbreaks is critical• Importance of an active FMD Reference

Laboratory Network to facilitate sample collection from FMD outbreaks in the field– to feed real-time lab data back to FMD control programmes

• Impact upon selection and deployment of vaccines

Talk summary

Upcoming events….

• 60th Symposium and celebration on 5th-6th November 2018• Previous anniversary events……

• OIE/FAO FMD Laboratory Network Meeting @ Pirbright - 7th-8th

November 2018• E-learning course on FMD Diagnostics – Jan/Feb 2019• Practical training course on FMD diagnostics for East Africa – Jan 2019

Royal Society, London, 2008John Brooksby (first head of WRLFMD), Pirbright, 1998

40 years 50 years

Acknowledgements

• Support for the WRLFMD and research projects

• Collaborating FMD Reference Laboratories and field teams

• Partners within the OIE/FAO FMD Lab Network

New FMD outbreaks in Republic of Korea

A/I

ran

-05

A/M

ay 9

7

A T

UR

20

/06

A/G

-VII

A2

2

A2

4 (

1)

A2

4 (

2)

SKR/5/2008 0.45 0.12 0 0.47 0.43 0.19 0.35

1PANAFTOSA BVS2BI BVS

• March 2018: Two FMD outbreaks in pigs due to A/ASIA/Sea-97

• 2017: One outbreak due to A/ASIA/Sea-97• 2017: Eight outbreaks due to O/ME-SA/Ind-

2001• Samples tested at QIA and WRLFMD• Represent new introductions of FMD into

South Korea from an East/Southeast Asian country?

• Vaccine matching:

• 2018: 24 FMD outbreaks reported to OIE in DPR Korea (serotype O - tbc)

• 5 FMD outbreaks reported in Bashkortostan (in the FMD-free zone without vaccination)

• Reported cases in cattle, sheep and goats

• New FMDV lineage in ME-SA topotype(not PanAsia or PanAsia-2)

• Most closely related to FMD viruses in Pakistan and Iran (2014)

• Reporting of cases in “central Asia”?

O/ME-SA lineage in RussiaOctober 2017

• Two isolates in a new genetic clade within O/ME-SA/PanAsia-2ANT-10

• Discrete from other ANT-10 viruses

• Collected in Punjab, Pakistan (2016/17) from cattle and water buffalo

• No neutralization in VNT with BVS for O-Manisa, O-3039 or O-TUR-5-09

• New antigenic variant?

• Spread of this lineage needs to be closely monitored – esp. wrt evidence of vaccine failure in the field

Poor Ag-match for serotype O viruses from Pakistan

10 20 30 40 50 60 70 80

....|....|....|....|....|....|....|....|....|....|....|....|....|....|....|....|

Ag site 3

O/PAK/14/2017 TTSAGESSDPVTATVENYGGETQVQRRQHTDVSFILDRFVKVTPKDQINVLDLMQTPAHTLVGALLRTATYYFADLEVAV

O/PAK/10/2016 .......A....T...................................................................

O/PAK/4/2017 .......A........................................................................

90 100 110 120 130 140 150 160

....|....|....|....|....|....|....|....|....|....|....|....|....|....|....|....|

Ag site 1

O/PAK/14/2017 KHEGNLTWVPNGAPEAALDNTTNPTAYHKAPLTRLALPYTAPHRVLATVYNGNCKYGESHVPNVRGDLQVLAQKAARALP

O/PAK/10/2016 ....D..........T.............................................T..................

O/PAK/4/2017 ....D..........T........................................S....T...............T..

170 180 190 200 210

....|....|....|....|....|....|....|....|....|....|...

Ag site 1

O/PAK/14/2017 TSFNYGAIKATRVTELLYRMKRAETYCPRPLLAIHPDAARHKQKIVAPVKQLL

O/PAK/10/2016 .................................V..NE...............

O/PAK/4/2017 ....................................NE...............

• VP1

• Complete genome sequences will also be determined using the Illumina MiSeq

Known type O antigenically important residues are underlined

Vaccine matching O 3039 O Manisa O TUR/5/2009

O/PAK/14/2017 0.62 0.32 0.48

O/PAK/10/2016 0 0 0

O/PAK/4/2017 0 0.10 0

Residue 198 has been shown to be part of site 1 in type A viruses

↑

Preliminary analyses:

FMD Cases in Colombia

• First clinical case reported in South America since 2013 (Venezuela)

• 7 outbreaks (June and July 2017)

• 5 Outbreaks (October 2018)

• Some close to border with Venezuela

• Cases in vaccinated cattle

• Sequence data consistent with indigenous strains from the region

• Lineage 6 described by Maliratet al., 2011

Report on FMDV O in Zambia in 2018

Batch: WRLFMD/2018/00013

ISA-1

ME-SA

FAR-09ANT-10 PanAsia-2

PUN-10

Ind-2001PanAsia

bSEA

EA-2

ISA/1/62

IRN/31/2009 IRN/8/2005

IRN/88/200976

PAK/16/201072

OMN/7/2001 UKG/35/2001

77

TAI/189/87*96

KEN/5/2002

K11/93* K130/00*100

MAL/1/98

ZAM/2/2000 ZAM/1/2000

100

TAN/2/2004K117/00*

UGA/3/200271

TAN-CVL-2009-0040*

100TAN/5/2009 TAN/44/2009100

86 UGA/3/2004 UGA/1/2004

76 UGA/18/2004

UGA/8/2004UGA/6/2004

94 UGA/7/2004 UGA/5/2004

UGA/18/2007UGA/4/2004

COD/13/2006 COD/101/2006 COD/99/2006 COD/57/2006 COD/53/2006 COD/93/2006 COD/92/2006 COD/91/2006 COD/66/2006 COD/100/2006 COD/104/2006 COD/55/2006 COD/58/2006 COD/64/2006 COD/21/2006 COD/65/2006 COD/10/2006 COD/106/2006 COD/102/2006

COD/3/2006

COD/47/2006 COD/11/2006 COD/51/2006 COD/59/2006 COD/60/2006 COD/105/2006 87 COD/95/2006COD/90/2006

COD/68/2006 COD/77/2006 COD/19/2006 COD/81/2006COD/83/2006

COD/82/2006 COD/80/2006COD/15/2006 COD/63/2006

COD/7/2006

94COD/71/2006 COD/36/2006

94 COD/6/2006

73

TAN-CVL-2013-0378* TAN-CVL-2013-0376*

100

COD/3/2010 COD/1/2010 COD/2/2010TAN-CVL-2011-0106*

ZAM/4/2010 ZAM/1/2010

76 COD/4/2010

95 ZAM/3/2010

TAN/5/2014TAN/9/2014TAN/3/2014TAN/10/2014

100

TAN-CVL-2012-0318* UGA/1/2017

TAN/6/2014 TAN/8/2014

TAN/4/2014 TAN/7/2014

TAN-CVL-2013-0364* TAN-CVL-2012-0321*

TAN-CVL-2013-0362*100TAN-CVL-2013-0366*

100

93

ZAM/3/2018ZAM10/2018*ZAM12/2018*

ZAM/2/2018 ZAM/1/2018

100

96

99

74

98

82

100

0.00 0.04 0.08 0.12

• April 2018: FMD outbreaks reported in cattle - Chisamba and Chibomboin the Central Province

• Samples received to WRLFMD (and sequences from BVI) from Chisamba

• Sequenced as O/EA-2

• Represent new south westerly movement of serotype O into central Zambia?

• Previous O/EA-2 outbreaks in 2010 close to the border with Tanzania (Mbala)

FMD outbreaks in Zambia

EA-1

EA-2

EA-3

EA-4

WA

ME-SA (Ind-2001d)

Topotypes

©d-m

aps.

com

1000 km

600 mi

OS18