Preparing for the unexpected: the response to foot-and-mouth disease outbreaks in 2007 in the United Kingdom

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1 Preparing for the unexpected: the response to foot-and-mouth disease outbreaks in 2007 in the United Kingdom Donald King Vesicular Disease Reference Laboratory Group FMD and SVD Reference Laboratories

2 Preparedness for an FMD outbreak?

3 Index Case IP1b (3 rd August 2007) (Wood lane, Normandy) Herd of 38 beef cattle held at pasture tongue lesion (Pictures by E. Ryan, J Gloster) Inter digital foot lesion

4 Characterisation of FMD virus responsible Strain characterisation (VP1) reported within 24 hours of first case 99.8% identical to O1 British Field Sample 1860 O1/BFS 1860 originally isolated from cattle in the UK during an FMD outbreak in 1967 Used as a reference strain by IAH (TPI) Used as a vaccine strain by Merial

5 Media impact Linda Dixon Linda Dixon Linda Dixon David Paton

6 FMD outbreaks (2007) In southeast England Located near Pirbright ( ) Occurred in 2 phases August and September 8 infected premises Multiple Holdings 9 holdings with clinical disease ( ) 2 holdings rrt PCR only ( ) Classical FMD lesions evident Affected mainly cattle M3 ALDERSHOT X M4 WINDSOR X GODALMING X WOKING X X HEATHROW EGHAM X X X GUILDFORD X KEY 10 km M25 FMD confirmed Preclinical (lab only) No evidence of infection

7 Laboratory support provided by IAH Pirbright FMD reference laboratory, Aug Oct 2007 Virological diagnostic tests on 52 report cases and high risk herds samples Sequencing of outbreak and related viruses Full genome sequencing Serology Cedi Type O kit, Cedi NSP kit, virus neutralisation 19,000+ blood samples at IAH (~60,000 in total) Visited 18 holdings Meteorological analyses

8 /08 08/08 13/08 18/08 23/08 28/08 02/09 07/09 12/09 17/09 22/09 27/09 02/10 07/10 12/10 17/10 Daily sample submissions: AUGUST 2007 SEPTEMBER 2007 Submitted samples (day) Date

9 Detection of FMD virus in clinical samples Laboratory based assays High through put rrt PCR (approx 4 5 hours) Ag ELISA (approx 4 hours) Virus isolation (1 4 days) Lateral flow devices (LFDs) Developed by IAH in collaboration with IZSLER (Brescia) and Svanova Used for rapid (<10 mins) confirmation of FMD in the lab and also used in the field (IP7) LFD marketed by

10 Laboratory test selection: rrt PCR was widely used to test submitted material Sample type Number submitted rrt-pcr Ag- ELISA VI Epithelial suspension Tissue suspension Vesicular fluid Fluid Serum EDTA-blood Probang Swab Faecal suspension Total samples tested % of samples tested

11 Diagnostic windows 2 Active surveillance for infected animals (including pre-clinical cases) Transmission 1 Rapid confirmation of clinical signs Clinical lesions 3 Surveillence for FMDV exposed animals antibody response MEASUREMENT FMD virus in blood FMD virus at mucosal sites DAYS Representative in contact cattle data from Alexandersen et al., 2003 and unpublished data from The Pirbright Institute

12 IP2c: pre clinical diagnosis Additional holding associated with the 2 nd case (IP2) All animals closely checked for clinical signs No clinical signs evident 19 of 58 animals rrt PCR positive blood samples Subsequent testing by VI supported these findings Indicates near simultaneous infection of multiple animals First use of real time preclinical diagnosis for FMD in field

13 Active surveillance: use of rrt PCR for preclinical detection Intensively Patrolled Areas (IPA) established within protection zone (PZ) around Egham Visited every other day Clinical examination 14 high risk cattle herds ~ 500 animals Blood samples collected and tested for FMDV by rrt PCR Reduced un necessary slaughter Do we have capacity to do this for a larger outbreak????

14 Sequence data for high resolution tracing Uncertainty about precise source of infection for IPs FMDV is a rapidly evolving RNA virus Previous studies (from UK 2001) have shown that nucleotide changes occur during every farm farm transmission event Nucleotide changes accrue linearly with time and are inherited Could we use full genome sequence data to trace the spread of FMDV during 2007?

15 FMDV 2001 accumulated nt changes Full genome sequences: nucleotide substitutions in comparison to index case Farm 1 22/02/01 Farm 2 23/02/01 Farm 3 24/02/01 Farm 4 25/02/01 27/02/01 28/02/01 26/02/01 Farm 5 01/03/01 time

16 Practical uses of full genome sequences: Farm to farm level resolution (UK 2007) TCS representation of sequences ( ) recovered from farms with putative intermediates ( ) IAH2 MAH IP1b(2) IP1b(1) IP2c IP2b IP5 IP3c IP4b IP6b IP3b IP3b IP8 Expected changes for each IP7 farm to farm transmission link: 4.3 ±2.1 nts for 2001 Cottam et al., (2008) Proc. Roy. Soc. B Discriminates between viruses recovered from 8farms Data was provided rapidly (in real time) to support UK eradication programme Provided evidence for the existence of IP5 (farm with FMD serology positive cattle and sheep) bridges gap between two phases of the outbreak Cottam et al (2008) PLoS Pathogens

17 Summary FMD outbreaks are unpredictable Real time RT PCR used as the front line diagnostic tool for virus detection High specificity (>99%) Preclinical diagnosis Used to support active surveillance in high risk cattle herds Increased demand of testing! Rapid LFD tests evaluated Sequence phylogeny recreates transmission pathways Data generated close to real time can support field epidemiology Predicts missing links that were subsequently found Second phase of outbreaks in September is derived from August cases not reintroduction

18 Wider Impacts Official Enquiries Spratt: Independent Review of the safety of UK facilities handling foot and mouth disease virus ( investigations/pdf/spratt_final.pdf) Anderson: FMD 2007: A Review and Lessons Learned ( HSE: Final report on potential breaches of biosecurity at the Pirbright site 2007 ( Callaghan: A review of the regulatory framework for handling animal pathogens ( es/fmd/pdf/callaghan reviewreport pdf) UK level changes Change to a single regulator for work with biological agents under three different sets of legislation for human pathogens, specified animal pathogens and GMOs New licensing regime for animal pathogens (April 2015): Comprehensive biorisk management system as a prerequisite for work on animal pathogens in high containment ( EU Level Revision of Minimum Standards for FMDV laboratories (2009) to anchor biorisk management in the EU level requirements ( ) Inspection of all FMDV laboratories in Member States ( ). 4 member states have stopped working with infectious FMDV in their reference laboratories

19 BBSRC National Virology Centre: The Plowright Building 2015: Occupied new high containment laboratory Houses all work with live FMD and International Reference Laboratories for FMD, BT, PPR, ASF, AHS, Capripox

20 Acknowledgements: Nick Knowles David Paton Ryan Waters Uwe Mueller Doblies Scott Reid Katja Ebert Nigel Ferris Geoff Hutchings Eleanor Cottam Jemma Wadsworth Juliet Dukes Caroline Wright Zhidong Zhang Yanmin Li Ginette Wilsden Phil Keel Bob Statham Carrie Batten Kate Swabey Pip Hamblin Sarah Cox Kasia Bankowska Andrew Shaw Annette Saunders Julie Stirling John Gloster Eoin Ryan Bryan Charleston Bartek Bankowski Chris Oura Heather James Chris Chisholm Linda Dixon.. and the many colleagues and friends who provided welcome support and encouragement