Transcript NEVER SAY NEVER AGAIN: MITIGATING THE EFFECTS OF

NEVER SAY NEVER AGAIN:
MITIGATING THE EFFECTS OF
INFECTIOUS ZOONOTIC DISEASES IN
THE UK
John R. Stephenson
Recent and current zoonotic
infections affecting the UK
BSE/vCJD
Type A influenzas
Campylobacter
Salmonella
E. coli
Anthrax
HIV ?
Examples of the economic impact
of zoonotic disease
YEAR
1990 - 1998
1994
1997
1999
1999
COUNTRY
UK
India
Hong Kong
Malaysia
USA (NY)
DISEASE
BSE
Plague
avian influenza
Nipah virus
West Nile virus
COST (US$)
38 billion
2 billion
22 million
540 million
~100 million
[Data taken from “Getting Ahead of the Curve” 2002]
Case histories
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BSE/vCJD
Swine influenza
Deliberate release agents
West Nile virus in the USA
Bovine Spongiform Encephalitis
(BSE)
variant Creutzfeldt-Jacob Disease
(vCJD)
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
How do prions form?
Normal form
of the PrP protein
Disease form of the
PrP protein (PrPsc)
Molecular basis PrPsc formation
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.
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
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
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
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
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
Total public spending on TSE
research
40
Total £308.5m
35
30
25
20
15
10
5
0
1986/87 1989/90 1992/93 1995/96 1998/99 2001/02 2004/05
£m
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.
BSE in GB
confirmed cases by year of CONFIRMATION
Feed Ban July 1988
40000
Confirmed cases
35000
30000
Peak Year 1992 >36 000 cases
SBO Ban Sep 1990
Total >180 000 cases
2005: 203 cases (inc. 29 BARB)
To 28/04/2006: 38 cases (inc. 8 BARB)
25000
ACTIVE
20000
PASSIVE
15000
10000
5000
0
1988 1990 1992 1994 1996 1998 2000 2002 2004
Year of CONFIRMATION
No confirmed cases have been reported for the past 3 years
The incidence of vCJD
30
25
20
Deaths from definite
or probable cases
15
10
Total - 175
5
0
1995
1998
2001
2004
2007
2010
No deaths have yet been reported in 2012 and no patients are still alive
Swine influenza
The swine flu pandemic of 2009-2010
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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.
Reassorted genomes
create new virus that
can be passed to
humans and create a
pandemic
Spanish flu is related to pig and bird virus
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.
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
Surveillance during the 'Treatment-only phase'
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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.
Calendar of seasonal influenza vaccine
production
Feb
Mar
WHO
Apr
May
Jun
Jul
Sep
Public sector
EU
Licence
Vaccine potency reagents
HGR yield
Batch release
Ag
Clinical
Seed
Oct
Vacc. available
Clinical
trial
HGR
Aug
trial vaccine
Vaccine production/formulation/QC
Vaccine manufacturer
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
What did we do well?
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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
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
The threat from the deliberate
release of infectious agents
The threat from deliberate release
1 - bacteria
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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
The threat from deliberate release
2 -viruses
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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
Co-ordinated State-of-the-Art Epidemic Modelling Toolbox
for Mitigating Deliberate Releases of Biological Agents
Beowulf Cluster Computer
Co-ordinated State-of-the-Art Epidemic Modelling Toolbox
for Mitigating Deliberate Releases of Biological Agents
5. Data Availability:
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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 nontransmissible bioterrorist
outbreak occurs.
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.
8. 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)
The invasion of the USA by West
Nile virus in 1999.
West Nile Virus Transmission Cycle
Mosquito vector
Incidental infections
West
Nile
virus
West
Nile
virus
Incidental infections
Bird
reservoir
hosts
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.
WNV in the USA -2003
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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
WNV morbidity in USA
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
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human cases of
encephalitis
1999
2001
2003
2005
2007
2009
2011
WNV mortality in the USA
300
250
200
150
deaths
100
Total - 1163
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1999
2001
2003
2005
2007
2009
2011
Current US situation - 2011
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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
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.
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 longlasting; better economic analysis of interventions and the
effect of poor advanced planning is urgently required