NEVER SAY NEVER AGAIN: MITIGATING THE EFFECTS OF INFECTIOUS ZOONOTIC DISEASES IN THE UK

1. NEVER SAY NEVER AGAIN:MITIGATING THE EFFECTS OF INFECTIOUS ZOONOTIC DISEASES IN THE UK John R. Stephenson

2. Recent and current zoonotic infections affecting the UK BSE/vCJD Type A influenzas Campylobacter Salmonella E. coli Anthrax HIV ?

3. Examples of the economic impact of zoonotic disease [Data taken from “Getting Ahead of the Curve” 2002]

4. Case histories • BSE/vCJD • Swine influenza • Deliberate release agents • West Nile virus in the USA

5. Bovine Spongiform Encephalitis (BSE)variant Creutzfeldt-Jacob Disease (vCJD)

6. What are TSEs – transmissible spongiform encephalopathies • 100% fatal diseases of mink (TME) sheep & goats (scrapie), cows and exotic ungulates (BSE), man (CJD), cats (FSE) and deer (CWD). • Transmissible • Encephalopathy • Very long incubation • Transmitted by an unconventional agent

7. How do prions form? Normal form of the PrP protein Disease form of the PrP protein (PrPsc)

8. Molecular basis PrPscformation

9. Why are TSEs such a problem for the NHS. • All forms of CJD have a 100% case fatality rate and vCJD targets younger people, mostly in their 20s and 30s. • Potentially all the UK population could have been exposed to material contaminated with BSE and could be carriers. • There is no cure or vaccine • There is no early diagnostic test - no unique gene, protein or immune response • Contaminated surgical instruments and blood transfusions were shown to transmit disease • Prions are resistant to standard decontamination protocols and adhere to surgical steels.

10. Why is PrPsc resistant to inactivation • Nucleic acid sequence integrity is not important and therefore UV and other radiation is ineffectual. • A rigid 3D structural is necessary for infectivity (unlike viruses) and therefore formalin preserves infectivity rather than reduces it. • Similarly slow heating or relatively low temperatures which enhance dehydration may form a protective layer which preserves secondary structure. • Therefore only chaotropic agents and those which break peptide bonds will be able to effectively inactivate prions

11. BSE – The Initial Response • Novel disease identified by the State Veterinary Service in 1985 and samples sent to VLA at Addlestone. • Information was not passed from MAFF to DoH or the Neuropathogenesis Unit (NPU). • An election was called in 1987 with a new group of ministers being appointed. • Formal disease notification was introduced in 1987. • Southwood Working Party set up in 1988 • Consultative Committee on Research set up in 1989 • SEAC (Spongiform Encephalopathy Advisory Committee) set up in 1990 to advise DoH and other government bodies as well as MAFF (Defra) • Research Councils were slow to engage • TSE funders group was not set up until 1995

12. Key policy actions: Preventing the spread of disease. • Leukodepletion of blood • Purchasing plasma from outside the UK • Donor deferral • Screening blood, tissue and organ donations • Quarantine or disposal of instruments used on known cases or at-risk individuals • Introduction of disposable instruments where appropriate – advice from NICE • Provision of clean and non-infectious re-usable surgical instruments • Developing drugs and vaccines for at-risk groups

13. Research resources • TSE Resource Centre at IAH • CJD Resource Centre at NIBSC • CJD tissue banks at NCJDSU and IOP, overseen by the MRC/DH Tissue Management Committee • TSE tissue resource centre at VLA • Surgical instrument store at HPA-Porton • Provision of used endoscopes and endoscope components for research

14. Co-ordination of TSE Research • High Level Committee to Monitor Progress in Research on the Transmissible Spongiform Encephalopathies (TSEs) – chaired by the secretary to the Cabinet • TSE R&D Funders Co-ordination Group – chaired by the DH R&D Director • MRC/DH Research Advisory Group • Subject - specific groups for decontamination, blood safety and tissue surveillance

15. Total public spending on TSE research Total £308.5m

16. Commercial activities • HPA are planning to market thermostable enzymes in conjunction with GENENCOR • Southampton University will market their EDIC technology with Microgen Bioproducts and Best Scientific • TSO3 are evaluating their UV/Ozone technology with HPA • Steris have recently published a method that involves a mixture of chemicals and detergents which they plan to market in 2005 • Firstwater plc plan to market their tonometer barrier after the completion of a clinical trial. • The MRC Prion Unit have found a commercial partner for their mixture of detergents and enzymes. • Several DH-funded research groups have patented their work and are discussing commercial development with industrial partners.

17. BSE in GBconfirmed cases by year of CONFIRMATION Feed Ban July 1988 Peak Year 1992 >36 000 cases Total >180 000 cases 2005: 203 cases (inc. 29 BARB) To 28/04/2006: 38 cases (inc. 8 BARB) SBO Ban Sep 1990 No confirmed cases have been reported for the past 3 years

18. The incidence of vCJD Total - 175 No deaths have yet been reported in 2012 and no patients are still alive

19. Swine influenza

20. The swine flu pandemic of 2009-2010 • In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. • During the first few weeks of surveillance, the virus spread worldwide to 30 countries by early May 2009 through human-to-human transmission, causing the World Health Organization to raise its pandemic alert to level 5. • The epidemic was notably for the high proportion of young people being infected and relatively high numbers of infant deaths • This virus had the potential to develop into the first influenza pandemic of the twenty-first century. • Genetic analysis showed that the virus was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak. • A phylogenetic estimate of the gaps in genetic surveillance indicated a long period of unsampled ancestry before the S-OIV outbreak, suggesting that the reassortment of swine lineages may have occurred years before emergence in humans, and that the multiple genetic ancestry of S-OIV is not indicative of an artificial origin. • These results highlighted the need for systematic surveillance of influenza in swine, and provide evidence that the mixing of new genetic elements in swine can result in the emergence of viruses with pandemic potential in humans.

21. Reassorted genomes create new virus that can be passed to humans and create a pandemic Spanish flu is related to pig and bird virus

22. Surveillance during the 'Containment phase' • In the early stages of the pandemic, during the 'containment' phase, pandemic preparedness systems provided detailed information about the evolving epidemiology, the spectrum of clinical disease, and the transmission characteristics of the disease. • Data were collected on all suspected cases, allowing the age distribution, origin of infection, symptoms etc. to be monitored.  More detailed information was collected on just under 400 early cases, and their close contacts, as part of the First Few Hundred (FF100) Surveillance System. This enabled estimates of transmission characteristics of the novel virus to be calculated.   • To monitor the extent of community transmission during the early stages, a self-sampling scheme through NHS Direct was established.  In this scheme, a selection of NHS Direct callers with an influenza-like illness were sent kits to take a nose/throat sample to be sent back to the lab for testing.

23. Surveillance during the epidemic phase • Clinical surveillance through primary care using networks of sentinel General Practitioners (GPs) and the nurse-led telephone helpline NHS Direct. • Microbiological surveillance was limited to testing of community and hospitalised patients to assess the burden of disease, circulating influenza strains and antiviral resistance. • Disease severity and mortality surveillance including excess mortality estimates using data on all-cause mortality from the Office of National Statistics.   • In addition to the existing influenza surveillance systems, a number of systems specific to this pandemic were implemented. These systems included: • monitoring changes in the characteristics of the virus, especially antiviral resistance and antigenic drift • assessing the severity of disease associated to provided epidemic intelligence to inform public health action and policy decisions

24. Surveillance during the 'Treatment-only phase' • In the second phase of the pandemic, the 'treatment-only phase', additional surveillance systems were implemented to monitor the spread and the severity of the pandemic in the population. • The number of assessments, authorisations and antivirals collected through the National Pandemic Flu Service (NPFS) were monitored. This service allowed people suffering from an influenza-like illness in England to access antiviral drugs without attending their GP.  The self-sampling scheme through NHS Direct was transferred to NPFS. • Using clinical and virological data from GP schemes and NPFS, an attempt was made to provide estimates of the number of new clinical cases of pandemic influenza in England each week.  • To assess the severity of the virus, two systems using data from hospitals were used.  One collected the number of people admitted each week with suspected pandemic influenza and the second provided detailed information on hospitalised patients with confirmed pandemic influenza infection.  Information on cases who died with pandemic influenza was also collected to analyse which groups in the population were most at risk from complications. In addition, all-cause mortality surveillance was expanded to include data on age-specific mortality from the General Registry Office. • When the pandemic vaccine was introduced systems were in place to monitor the uptake of the vaccine and it's effectiveness. 

25. Calendar of seasonal influenza vaccine production Feb Mar Apr May Jun Jul Aug Sep Oct Public sector EU WHO Vacc. available Clinical trial Licence HGR Vaccine potency reagents Batch release HGR yield Ag Clinical trial vaccine Seed Vaccine production/formulation/QC Vaccine manufacturer

26. Development of vaccine virus by reverse genetics New virus HA & NA rescue plasmids Reassortant vaccine virus Cell 6 backbone rescue plasmids high yielding virus PR8

27. What did we do well? • The UK had the best pandemic flu preparedness plan. • International surveillance worked well • The UK rapidly developed a diagnostic PCR • The power of molecular genetics was clearly demonstrated by the rapid characterisation of the new virus and the rapid development of new diagnostic reagents and vaccines • NIBSC rapidly developed new vaccine seeds • The new “ reverse genetics” vaccines worked well • The analysis of the “first few hundred” cases provided valuable information

28. What lessons need to be learned? • Surveillance in pigs should be expanded • The early estimates of mortality rates were too pessimistic as mild cases were not detected due to lack of accurate serological reagents • This resulted in a heavy handed response which adversely affected other public health services • The national diagnostic services were quickly overwhelmed • Too great a reliance on self-reporting and easy access to antivirals • The switch to syndromic surveillance lost valuable information • Too greater reliance on the ONS for mortality data

29. The threat from the deliberate release of infectious agents

30. The threat from deliberate release1 - bacteria • Bacillus anthacis (anthrax) • Clostridium botulinum (botulism) • Yersinia pestis (plague) • Francisella tularensis (tularemia) • Coxiella burnetti (Q fever) • Brucella species (brucellosis) • Burkholderei mallei (glanders) • Staphylococcus enterotoxin B • Multidrug resistant TB

31. The threat from deliberate release2 -viruses • Nipah virus • Hantavirus • Yellow fever • Japanese encephalitis • dengue fever • Variola, major and minor, (smallpox) • VEE, EEE & WEE • tick-borne encephalitis complex viruses • Congo-Crimean haemorrhagic fever • Filoviruses e.g. Marburg and Ebola • Influenza A • Arenaviruses e.g. Lassa fever

32. Co-ordinated State-of-the-Art Epidemic Modelling Toolbox for Mitigating Deliberate Releases of Biological Agents Beowulf Cluster Computer

33. Co-ordinated State-of-the-Art Epidemic Modelling Toolbox for Mitigating Deliberate Releases of Biological Agents • 5. Data Availability: • In the absence of much data for bioterrorist agent releases the work on this project has so far focussed on potential surrogate data from more natural occurrences such as Legionnaires disease outbreaks. • It is highly probable that a future bioterrorist attack will be aerosolised and so this data is a strong candidate for the accuracy and completeness of information that will be gathered by field epidemiologists if an actual non-transmissible bioterrorist outbreak occurs.

34. Co-ordinated State-of-the-Art Epidemic Modelling Toolbox for Mitigating Deliberate Releases of Biological Agents • Progress: • Work currently in progress : • 7. Progress Report/Meeting on the development of the modelling toolbox and on backcalculation tools. • Backcalculation tools for contagious agents reviewed and developed. Pre-calculated scenarios showing potential public health impacts and optimum mitigation strategies for smallpox* • * Continuation of two recently published papers: • Hall et al. (2007), Riley & Ferguson (2006)

35. The invasion of the USA by West Nile virus in 1999.

36. West Nile Virus Transmission Cycle Mosquito vector Incidental infections West Nile virus West Nile virus Incidental infections Bird reservoir hosts

37. Recent outbreaks of West Nile fever in America • In the summer of 1999, 62 cases of viral encephalitis were reported in the New York state. 7 deaths were recorded. • Many dead corvid birds were reported in the area, killed by an unknown illness • Several scare stories involving bioterrorism, escape of a virus from a DOD germ warfare laboratory etc. circulated • The virus was eventually identified as a WNV isolate similar to those then circulating in Israel. • Virus was shown to overwinter in birds and in mosquito eggs • A smaller outbreak was recorded the summer of 2000 and another in 2001 when there were 66 cases and 9 deaths. But 2002 saw a rise in human cases and fatalities. • Insecticide spraying controlled, but did not halt the outbreak.

38. WNV in the USA -2003 • 9,136 human cases in 2003 • 228 deaths • 489 viraemic blood bonors • 2 cases of West Nile Fever transmitted by blood donation • At least one case of placental transmission of West Nile Fever

39. WNV morbidity in USA

40. WNV mortality in the USA Total - 1163

41. Current US situation - 2011 • Total cases – 690 • Neuroinvasive cases – 474 • Non-neuroinvasive cases – 216 • Deaths – 43 • Presumptive viraemic donors – 130 • Only one state reported no WNV activity • Only 4 states reported non-human activity only

42. Conclusions and lessons learned -1 • The animal health and public health communities need to be in regular contact • The “CBRN” policy and research communities also need to be included • Key research capabilities must be identified and maintained – i.e. facilities and expertise • Research needs to be coordinated to prevent gaps and duplication • Research needs to be multidisciplinary and will be increasingly reliant on mathematics, especially with the advent of “next generation sequencing” • The commercial sector needs to be engaged, with the establishment of clear pipelines for the development of new diagnostics, vaccines and therapeutics • Molecular genetics can provide systems for the rapid development, assessment and production of vaccines against new diseases.

43. Conclusions and lessons learned - 2 • Surveillance in key animal species needs to be maintained as new infectious agents arise all the time • Surveillance in humans should included serology with defined reagents • Reliance on syndromic surveillance could over-estimate or under-estimate the size of the epidemic • Limiting detailed microbiological analysis to hospitalised patients gives only limited epidemiological data • The introduction of new infections into naïve populations can have profound and long-lasting effects on human and animal health, even in the most developed countries • The economic impacts can also be profound and long-lasting; better economic analysis of interventions and the effect of poor advanced planning is urgently required