Bioterrorism Preparedness: Smallpox Contingency Planning

1
"Bioterrorism Preparedness Smallpox Contingency
Planning"

• Dr Bonnie Henry
• Associate Medical Officer of Health,
• Emergency Services Unit, Toronto Public Health

2
Public Health Role

• Health effects of emergencies recently
  highlighted
• MOH part of City EOC
• Mandated lead role in events involving biologic
  agents

3
Public Health Role

• Early Detection
• Mass Patient Care
• Mass Immunization/Prophylaxis
• Epidemiologic investigation
• Command and Control

4
Public Health Role

• Mass Fatality Management
• Evacuations/sheltering
• Environmental Surety
• Community Recovery

5
  Toronto Public Health Incident Management System
 
Chair, Board of Health  Medical Officer of Health
Divisional Management Team  
Public Health Incident Manager
Public Information
Liaison
Operations
Planning
Logistics
Administration
Claims/ Compensation  
Mass Vaccination/Post Exposure Prophylaxis  
Situation Assessment
Facilities
Staffing Resource Needs
Human Resources
Hotline Operation
Costing
Reception Centre/Mass Care
Procurement
Resource Deployment
Communications Equipment   Miscellaneous Supplies
Case Management/Contact Tracing
Documentation
Environmental Inspection/ Sampling
Demobilization Recovery
Nutrition/staff accommodation
Epidemiological Investigations
Recovery
6
Bioterrorism Preparedness
7
Bioterrorism is the intentional use of
microorganisms (bacteria, viruses, and fungi) or
toxins to produce death or disease in humans,
animals or plants.
Electron micrograph of anthrax bacteria
Electron micrograph of ebola virus
8

• Category A
• Biologic Threat Agents
• Can be easily disseminated or transmitted
  person-to-person
• Cause high mortality, w/potential for major
  public health impact
• Might cause public panic and social disruption
  and
• Require special action for public health
  preparedness.

9
Biological Agents of Highest Concern

• Category A
• Smallpox variola major
• Anthrax Bacillus anthracis
• Plague Yersinia pestis
• Botulism Clostridium botulinum toxin
• Tularemia Francisella tularensis
• Viral hemorrhagic fevers arenaviruses,
  filoviruses (Ebola, Marburg, Lassa, Junin)

10
Category B Second Highest Priority

• Coxiella burnetti (Q fever)
• Brucella
• Burkholderia mallei (glanders)
• Alphaviruses (Venezuelan encephalomyelitis and
  Eastern and Western equine)
• Rickettsia prowazekii
• Toxins (Ricin, Staph enterotoxin B)
• Chlamydia psittaci
• Food safety threats (e.g.Salmonella, Shigella. E.
  coli O157H7)
• Water safety threats (Vibrio cholerae,
  Cryptosporidium parvum)

• Moderately easy to disseminate
• Cause moderate morbidity and low mortality
• Require specific enhancements of diagnostic
  capacity and enhanced disease surveillance

11
Category C Third Highest Priority

• Pathogens that could be engineered for mass
  destruction because of availability, ease of
  production and dissemination and potential for
  high morbidity and mortality and major health
  impact

• Nipah virus
• Hantavirus
• Tickborne hemorrhagic fever viruses
• Tickborne encephalitis viruses
• Yellow fever
• MDR TB

12
Characteristics of Bioterrorist Agents

• Mainly inhaled - may be ingested or absorbed
• Particles may remain suspended for hours
• May be released silently with no immediate effect
• Person-to-person spread happens for some agents
• Long incubation periods mean "first responders
  may be primary health care providers
• Agents may be lethal or incapacitating
• Vaccines antitoxins exist for some agents

13
Recent Examples of Bioterrorism
1984 Salad bars contaminated with Salmonella to
influence local election in Oregon / 751 people
affected (8 salad bars) 1995 Sarin nerve gas
release by Aum Shinrikyo in Tokyo subway / At
least 9 failed attempts to use biological
weapons 1996 Pastries contaminated with Shigella
by disgruntled lab worker in Dallas
14
Recent Examples of Bioterrorism
Former Soviet Unions extensive biological
weapons program thought to have found their way
to other nations Iraq acknowledged producing and
weaponizing anthrax and botulinum
toxin Currently, at least 17 nations believed to
have biological weapons programs
15
Anthrax Soviet incident

• An accident at a Soviet military compound in
  Sverdlovsk (microbiology facility) in 1979
  resulted in an estimated 66 deaths downwind.

16
Smallpox

• Variola virus
• Declared eradicated by WHO in 1980
• Civilian vaccination stopped 1972, healthcare
  workers stopped in 1977 and CF stopped 1988
• Known stockpiles remain in CDC and Institute for
  Viral Preparations, Moscow
• Virus spread by aerosol
• Incubation period average 12 days (7-19 days)

17
Last Case, Variola major
Rahmina Banu, 2001
Rahmina, 1975
18
Smallpox

• Clinical symptoms abrupt onset of malaise,
  fever, rigors, headache, emesis, backache,
  delirium (15)
• Onset of rash 2-3 days later on face, hands,
  forearms, and legs, then spreading centrally
• Lesions progress from macules to papules to
  pustular vesicles
• Lesions typically in same stage of development
• Patients highly infectious during initial
  respiratory phase and until all eschars are off
• Mortality in unvaccinated about 30

19
SMALLPOX RASH EVOLUTION

• Day 1 Day 2 Day 3

20
SMALLPOX RASH EVOLUTION

• Day 4 Day 5 Day 7

21
SMALLPOX RASH EVOLUTION

• Days 8-9 Days 10-14 Day 20

22
Smallpox
Characteristics differentiating the rashes of
Smallpox and Varicella
23
Smallpox

• Vaccination
• Within 3 days will likely prevent disease
• Within 5 days is life-saving (ameleorates)
• Canada has about 320,000 doses
• ?long term immunity
• Cell culture and oral vaccine in research
• Research on antivirals also ongoing (particularly
  Cidofovir)

24
TYPES OF SMALLPOX
25 of vaccinated cases present as variola minor
25
VARIOLA MINOR
26
DIFFERENTIAL DIAGNOSIS VESICULO PUSTULAR
RASHES

• CHICKEN POX
• ERYTHEMA MULTIFORME - BULLOUS
• COWPOX
• MONKEY POX
• HERPES ZOSTER (Shingles) - DISSEMINATED
• DRUG ERUPTIONS
• HAND FOOT AND MOUTH DISEASE
• ACNE
• IMPETIGO
• INSECT BITES

27
Todays Perspective in CanadaPros vs Cons

• Moderately contagious
• Virus not robust
• No natural reservoir
• Able to vaccinate
• Able to control
• Improved medical care
• Better popn health

• 30 mortality
• Misdiagnosis
• Long incubation
• Low level of Immunity
• Popn mobility
• Immuno-compromised
• Mass panic, hysteria

28
National Smallpox Contingency Plan (v.4)

• Canadas search and contain strategy
  highlights
• Early detection, immediate notification
• Immediate isolation of cases
• Immediate deployment of smallpox responders
• Immediately vaccinate all those directly exposed,
  all known direct contacts, all local personnel
• Intensive contact tracing
• Rapid set up of isolation facilities
• Rapid set-up of local Smallpox assessment centres

• Assumption
• In the absence of smallpox anywhere in Canada
• A risk of disease and death from a vaccine, no
  matter how small, may be unacceptable
• Especially when pre-attack vaccination is
  considered

29
Political Divisions

• Canadas search and contain strategy consists
  primarily of public health measures, which fall
  under provincial/territorial jurisdiction
• Federal role
• Immediate mobilization of vaccine
• Deployment of federalized smallpox response
  teams (SERF)
• Provision of supplies
• 24-hour support line to the public, professional
  and other governments
• International notification and consultation

30
Smallpox Isolation, Toronto (1909)
31
WHOs success with isolation

• WHOs experience in India
• 1960 1973 Smallpox transmission continued
  during this time under a mass vaccination
  strategy.
• In 1973, a search and containment strategy was
  introduced, stressing isolation of cases.
• Smallpox was then eliminated in just two years,
  in 1975.
• We will come back to this.

32
VACCINE ADMINISTRATION
33
VACCINATION THE RESPONSE
34
VACCINE CONTRAINDICATIONS

• History or presence of eczema
• Other acute , chronic or exfoliative skin
  condition
  
• Immunosuppression ( HIV, AIDS, cancer,
  immunodeficiency disorders, chemotherapy,
  radiotherapy, organ transplant, high dose
  corticosteroids
• Pregnancy
• History of anaphylaxis to a vaccine component

35
VACCINATION RATES OF COMPLICATIONS
No. of events per million vaccinations
Source NEJM 346 (17) April 2002 Data from 1968
survey of 10 States
36
Consider Recent Smallpox Response Models

• Kaplan et al. (Proc Natl Acad Sci USA)
• Halloran et al. (Science)
• Mention
• Epstein et al. (Brookings Working Paper)
• Bozzette et al. (N Eng J Med)

37
Technical Discussions Highlight Different
Modeling Approaches

• Kaplan et al. free mixing explicit logistics
• Halloran et al. structured stochastic
  simulation
• Epstein et al. agent-based
• Bozzette et al. simulation with assumed
  response efficacy from historical data

38
Other Factors Matter More

• Scale of model
• Kaplan et al. consider population of 10 million
• Halloran et al. look at community of 2,000
• Epstein et al. consider county of 800
• Bozzette et al. no role for population in model

39
Other Factors Matter More

• Rate of vaccination and logistics
• Traced (ring, targeted) vaccination proceeds with
  the pace of the epidemic need to see
  symptomatic cases to trigger vaccination
• Mass vaccination proceeds at a pace limited only
  by available resources
• number of vaccinators
• time required to vaccinate

40
Important To See If Models Have Different Policy
Implications

• To do so, need to control for inputs as much as
  possible to see if different assumptions on model
  structure lead to different results

41
Kaplan et al. (PNAS)

• Focus on a large city (10,000,000)
• Construct traced vaccination (TV) model
• Contrast with mass vaccination (MV)
• Consider TV/MV switch if TV fails to control
  outbreak after 2 generations of cases
• Consider pre-attack vaccination

42
Kaplan et al. (PNAS)

• Disease transmission/progression 4 disease
  stages (includes infected but vaccine sensitive),
  free mixing in population (worst case),
  imperfect vaccination and (low) vaccine-related
  mortality
• Response logistics consistent tracing with
  disease transmission/progression linked to index
  case (race to trace), TV queues (finite TV
  capacity), MV rate higher than TV rate,
  quarantine capacity requirements
• State transitions governed by both disease
  transmission/progression and response logistics
  epidemic and response are on the same time scale!

43
TV or MV 50 Tracing Accuracy

• MV is optimal (fewer deaths) for any R0 gt 1.3

44
TV or MV 100 Tracing Accuracy

• Still favor MV for any R0 gt 2
• If initial attack gt 20, favor MV for R0 gt 1.3
  (same as 50 tracing accuracy)

45
TV or MV Asymmetries

• Consequences of choosing the wrong policy are not
  symmetric!
• If TV is optimal, choosing MV would lead to few
  incremental deaths
• If MV is optimal, choosing TV could lead to a
  disaster with many incremental deaths
• Would therefore suggest choosing TV only if
  extremely confident (i.e. highly certain) that
  initial attack size and R0 fall on the
  TV-favorable side of the tradeoff curve

46
The Post-Attack Decision
Expected Deaths
Big Attack
d
(TV Big)
b
Traced Vaccination
1- b
d
(TV Small)
Small Attack
Big Attack
d
(MV Big)
b
Mass Vaccination
1- b
d
(MV Small)
Small Attack
47
The Post-Attack Decision Example

• Suppose attack/response yields deaths as
• Choose MV if b gt 7.4 x 10-5

48
Switching Helps, But Delay is Costly

• In base case, switching from TV to MV after two
  generations of cases (28 days) results in 15,570
  cases and 4,680 deaths
• Cost of delay is high 4,120 incremental deaths
  compared to MV
• Given option to switch, still would only start
  with TV if extremely confident that both R0 and
  initial attack size are small

49
Pre-Attack Vaccination

• Reduces degree of susceptibility in the
  population
• Effect is to reduce R0 and initial attack size
• Pre-attack vaccination makes post-attack TV more
  attractive as a result

50
TV with Pre-Attack Vaccination
51
Pre-Attack Vaccination?

• Suppose 100 successful pre-attack vaccination
  expect 10 vaccine-related deaths
• Let a PrSmallpox Attack, d(p) deaths post
  attack from response policy p
• Note think of attack risk over 5-10 year time
  frame
• Solve 10 a d(p) for a consider pre-attack
  vaccination if perceived attack risk exceeds a
• Base case results
• for p TV, a 9 in 100,000
• for p MV, a 1.8 (!!)
• for p TV/MV (CDC policy), a 2 in 1,000

52
Pre-Attack Vaccination?

• Take home message decision to vaccinate
  pre-attack should depend not only on the risk of
  vaccine and attack, but also on the response
  policy
• If one does not have confidence in the response
  policy, one is much more likely to favor
  pre-attack vaccination (i.e. a is very small)
• If one is confident that the response policy
  could contain an attack, desire for pre-attack
  vaccination lessens (i.e. a is larger)

53
Build the Button Now?
Think like a terrorist a gt a (An attack is less
likely if you prepare)
54
Policy Conclusions

• Optimal response policy depends critically on
  beliefs regarding initial attack size and R0
• MV allows many fewer deaths and is much faster
  over a wide range of scenarios
• TV or TV/MV switch are best if highly certain
  that R0 and initial attack size are very small,
  or if pre-attack vaccination greatly reduces R0
• Vaccine complications not an issue in choosing
  post-attack response policy any successful
  policy will vaccinate large percentage of
  population in big attack
• Death-minimizing decision to vaccinate pre-attack
  should depend upon the risk of vaccine and
  attack, and the post-attack response policy
  employed

55
Halloran et al. (Science)

• Uses structured stochastic simulator
• Looks at 2,000 person community of four
  neighborhoods, one high school, one middle
  school, two elementary schools, play groups and
  day care centers
• Introduces 1-5 infected terrorists who mingle in
  population

56
Main Finding

• Absent residual immunity from vaccinations among
  adults 20 years ago, deaths under TV only a
  factor of 2 higher than deaths under MV
• With residual immunity, TV does better
• Attributes difference from Kaplan factor of 200
  TV/MV death ratio to difference between
  structured and free mixing

57
A Different Interpretation...

• If we place the Science inputs (population of
  2,000, single initial infection, R0 3.2, 80
  vaccination coverage, response delays to match
  the detection of smallpox after the 1st, 15th,
  and 25th case) look what happens

Deaths per
1000 Halloran et al (1)
Kaplan et al (2)   80 MV after 1 case
0.9
0.4 15th case 9.4
6.4 25th case 13.7
17.8   80 TV after 1
case 10.9
8.8 15th case 19.6
12.0 25th case
28.2 33.9
58
What Is Going On?

• Newly identified cases required to trigger
  contact tracing
• TV proceeds with the pace of epidemic
• Number of deaths scales with population size
  independent of initial infections
• MV operates on its own timetable
• 10 days in the examples above
• Number of deaths depends on initial infections
  independent of the population size
• Ratio of deaths from TV/MV grows with population
  size

59
Canadian situation

• 12.5 million Canadians with no vaccination to
  smallpox
• Over 64 of Canadas population live in the
  nations 27 census metropolitan areas
• 79.4 of Canadians live in an urban centre of
  gt10,000

• Local populations are connected by migration of
  individuals
• By air alone
• Toronto-Chicago (1,000,000/year)
• Toronto-Vancouver (822,000/year)
• Toronto-Montreal (1,257,000/year)

60
Need to consider Population Density

• Population
• Canada 30,007,094
• Toronto 4,682,897
• Montreal 3,426,350
• Vancouver 1,986,965
• Population density
• Canada 3.3/km2
• Toronto 793/km2
• Montreal 847/km2
• Vancouver 690/km2
• Kitchener 501/km2
• Hamilton 483/km2
• Oshawa 328/km2
• Windsor 301/km2

• Population density determines how fast the
  infection may spread
• (R0 is proportional to population density)
• Population density determines the amount of
  effort for control and eradication

61
Important Caveat

• All of the models are closed that is, no
  immigration or births
• what about importing cases from one area to
  another?
• historically, case importation allowed for
  continued transmission following widespread
  vaccination
• Suppose you are the MOH of Toronto, and smallpox
  is detected in Vancouver
• what is your new assessment of attack probability
  in Toronto?
• do you worry about importing a case from
  Vancouver?
• what do your citizens want?

62
Effect of Search and Containment on Reported
Smallpox Cases, West and Central Africa
1968-1969 (Figure 9 from Foege et al)
Surveillance Containment Initiated
population not vaccinated
Smallpox cases reported/expected ratio

Foege WH, Millar JD, Henderson DA. Bull WHO 1975
52 209-222
63
Decline in Reported Smallpox Cases Matches
Decline in Susceptibility Over Time
64
What About India?

• In India, transmission continued even when 90
  of the population was vaccinated (though often
  via importation)
• When ring vaccination started in India, new cases
  were higher than they had been in decades

from Fenner et al., Smallpox and its Eradication
65
But Accounting For Population...
66
Policy Lessons

• In all of the models (and in West and Central
  Africa, and in India), smallpox deaths decline as
  vaccination coverage increases
• Absent pre-existing immunity (or pre-attack
  vaccination), both PNAS and Science explicitly
  show fewer deaths from post-attack mass
  vaccination

67
Questions for us to Consider

• Current Federal policy starts with
  surveillance-containment
• Should the policy begin with local MV instead
  (with priority to known close contacts)?
• How many persons should be vaccinated now to
  build Canadas button?
• 500? 5,000? 50,000? 500,000?
• answer depends on response policy and scale
• In US 500,000 now 10 million later this year
  voluntary for public next year

68
Questions for us to Consider

• Vaccination within 2-3 days after initial
  exposure to smallpox almost always prevents
  disease
• how confident are we in this claim?
• if claim is wrong, would we do the same anyway?
• Contact tracing plan calls identifying both
  close contacts, and also contacts in restaurant
  grocery store gas station hair stylist
  sporting event movie theatres...
• is it efficient to spend time searching for
  distant contacts at expense of more rapid clinic
  vaccination?

69
Questions for us to Consider

• Is there a case for urban versus rural policies?
• Ring vaccination is much more likely to work in a
  rural environment where people dont travel as
  much, whereas in the urban setting (where 70 of
  Canadians live), tracing will be much tougher.

70
The only thing more difficult than planning for
an emergency is having to explain why you didnt