"Bioterrorism Preparedness: Smallpox Contingency Planning" Dr Bonnie Henry Associate Medical Officer...

"Bioterrorism "Bioterrorism Preparedness: Preparedness:

Smallpox Contingency Smallpox Contingency Planning"Planning"

Dr Bonnie Henry

Associate Medical Officer of Health,

Emergency Services Unit, Toronto Public Health

Public Health RolePublic Health Role

• Health effects of emergencies recently highlighted

• MOH part of City EOC

• Mandated lead role in events involving biologic agents


• Early Detection

• Mass Patient Care

• Mass Immunization/Prophylaxis

• Epidemiologic investigation

• Command and Control


• Mass Fatality Management

• Evacuations/sheltering

• Environmental Surety

• Community Recovery

Public Health Incident Manager

Liaison

Public Information

Operations Planning Logistics Administration

Mass Vaccination/Post Exposure Prophylaxis

Hotline Operation

Case Management/Contact Tracing

Environmental Inspection/ Sampling

Situation Assessment

Staffing & Resource Needs

Resource Deployment

Documentation

Demobilization & Recovery

Facilities

Human Resources

Nutrition/staff accommodation

Claims/Compensation

Costing

Procurement Reception Centre/Mass Care

Communications Equipment Miscellaneous Supplies

Chair, Board of Health Medical Officer of Health Divisional Management Team

Epidemiological Investigations

Recovery

Toronto Public Health Incident Management System

Bioterrorism Bioterrorism PreparednessPreparedness

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

Category ACategory A

““Biologic Threat Agents”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.

Biological Agents of Highest Biological Agents of Highest ConcernConcern

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)

Category B: Second Highest Category B: Second Highest PriorityPriority

• Moderately easy to disseminate

• Cause moderate morbidity and low mortality

• Require specific enhancements of diagnostic capacity and enhanced disease surveillance

• 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 O157:H7)• Water safety threats (Vibrio

cholerae, Cryptosporidium parvum)

Category C: Third Category C: Third Highest PriorityHighest 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

Characteristics of Characteristics of Bioterrorist AgentsBioterrorist 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

Recent Examples of Recent Examples of BioterrorismBioterrorism1984: 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

Recent Examples of Recent Examples of BioterrorismBioterrorismFormer Soviet Union’s 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

Anthrax: Soviet Anthrax: Soviet incidentincident

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

SmallpoxSmallpox

• 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)

Last Case, Variola Last Case, Variola major major

Rahmina, 1975 Rahmina Banu, 2001

SmallpoxSmallpox• 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%

SMALLPOX RASH SMALLPOX RASH EVOLUTIONEVOLUTION

Day 1 Day 2 Day 3


Day 4 Day 5 Day 7


Days 8-9 Days 10-14Day 20

SmallpoxSmallpox

Superficial lesions: oval or irregular

Scaring: Mild

Deep lesions: circular and regular

Scarring: severe

Rapid evolutionSlow evolution

Lesions in various stagesLesions all at the same stage

CentripetalCentrifugal

VaricellaVariola

Characteristics differentiating the rashes of Smallpox and Varicella

SmallpoxSmallpox

• 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)

TYPES OF SMALLPOXTYPES OF SMALLPOX

97 7Flat/malignant

100 <3Hemorrhagic

<1 2*Variola minor

30 90Variola major

Case fatality rate (%)

Proportion of cases (%)

Type

* 25% of vaccinated cases present as variola minor

VARIOLA MINORVARIOLA MINOR

DIFFERENTIAL DIAGNOSIS: DIFFERENTIAL DIAGNOSIS: VESICULO – PUSTULARVESICULO – PUSTULAR RASHESRASHES

• CHICKEN POX

• ERYTHEMA MULTIFORME - BULLOUS

• COWPOX

• MONKEY POX

• HERPES ZOSTER (Shingles) - DISSEMINATED

• DRUG ERUPTIONS

• HAND FOOT AND MOUTH DISEASE

• ACNE

• IMPETIGO

• INSECT BITES

Today’s Perspective in Today’s Perspective in Canada:Canada:

Pros vs ConsPros vs Cons• “Moderately”

contagious• Virus not robust• No natural reservoir• Able to vaccinate• Able to control• Improved medical care• Better pop’n health

• 30% mortality• Misdiagnosis• Long incubation• Low level of

“Immunity”• Pop’n mobility• Immuno-compromised• Mass panic, hysteria

National Smallpox National Smallpox Contingency Plan (v.4)Contingency Plan (v.4)

• Canada’s ‘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

Political DivisionsPolitical Divisions

• Canada’s 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

Smallpox Isolation, Smallpox Isolation, Toronto (1909)Toronto (1909)

““WHO’s success with WHO’s success with isolation”isolation”

WHO’s 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….

VACCINE VACCINE ADMINISTRATIONADMINISTRATION

VACCINATION: THE VACCINATION: THE RESPONSERESPONSE

VACCINE VACCINE CONTRAINDICATIONSCONTRAINDICATIONS

• 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

VACCINATION: RATES OF VACCINATION: RATES OF COMPLICATIONS COMPLICATIONS

39266Other

32Progressive vaccinia

212Postvaccinial encephalitis

339Eczema vaccinatum

10165Erythema multiforme

9242Generalized vaccinia

42529Inadvertent inoculation

Revaccination*Primary vaccination*Complication

* No. of events per million vaccinationsSource: NEJM 346 (17) April 2002; Data from 1968 survey of 10 States

Consider Recent Consider Recent Smallpox Response Smallpox Response

ModelsModels• 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)]

Technical Discussions Technical Discussions Highlight Different Highlight Different

Modeling ApproachesModeling 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]

Other Factors Matter Other Factors Matter MoreMore

• 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]

Other Factors Matter Other Factors Matter MoreMore

• 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

Important To See If Important To See If Models Have Different Models Have Different

Policy ImplicationsPolicy 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

Kaplan Kaplan et alet al. (. (PNASPNAS))

• 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

Kaplan Kaplan et alet al. (. (PNASPNAS))• 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!

TV or MV: 50% Tracing TV or MV: 50% Tracing AccuracyAccuracy

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

0.8

1

1.2

1.4

0 5 10 15 20 25

Initial attack size (I(0))

Ba

sic

rep

rod

uct

ive

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Ro )

MV optimal

TV optimal

A

TV or MV: 100% Tracing TV or MV: 100% Tracing AccuracyAccuracy

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

0.5

1

1.5

2

2.5

0 10 20 30 40 50 60


Ba

sic

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rod

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Ro )

MV optimal

TV optimal

B

TV or MV: AsymmetriesTV 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

The Post-Attack The Post-Attack DecisionDecision

Expected Deaths

Big Attackd (TV | Big)

Traced Vaccination

1- d (TV | Small)

Small Attack

Big Attackd (MV | Big)

Mass Vaccination

1- d (MV | Small)

Small Attack

The Post-Attack The Post-Attack Decision: ExampleDecision: Example

• Suppose attack/response yields deaths as:

• Choose MV if x 10-5

Big Attack Small Attack

Choose TV 110,000 2.3

Choose MV 560 10.4

Switching Helps, But Delay Switching Helps, But Delay is Costlyis 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

Pre-Attack VaccinationPre-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

0.5

1

1.5

2

2.5

0 10 20 30 40 50 60


Ba

sic

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rod

uc

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ra

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Ro)

MV optimal

TV optimal

B

TV with Pre-Attack TV with Pre-Attack VaccinationVaccination

TV Deaths with Pre-Attack Vaccination

0

20000

40000

60000

80000

100000

120000

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

Fraction Pre-Vaccinated

TV

Dea

ths

Pre-Attack Vaccination?Pre-Attack Vaccination?• Suppose 100% successful pre-attack vaccination –

expect 10 vaccine-related deaths• Let = Pr{Smallpox Attack}, d() = deaths post attack

from response policy – Note: think of attack risk over 5-10 year time frame

• Solve 10 = d() for ; consider pre-attack vaccination if perceived attack risk exceeds

• Base case results:– for = TV, = 9 in 100,000– for = MV, = 1.8% (!!)– for = TV/MV (CDC policy), = 2 in 1,000

Pre-Attack Vaccination?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. is very small)

• If one is confident that the response policy could contain an attack, desire for pre-attack vaccination lessens (i.e. is larger)

Build the Button Now?Build the Button Now?Expected Deaths

Attacknf + d (MV, no delay)

Build Button Now

nf

No Attack

Attacknf + d (MV, delay)

Wait For Attack

0

No Attack

Think like a terrorist:

An attack is less likely if you prepare)

Policy ConclusionsPolicy 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

Halloran Halloran et alet al. . ((ScienceScience))

• 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

Main FindingMain 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

A Different A Different Interpretation...Interpretation...

Deaths per 1000 Halloran et al (1) Kaplan et al (2) 80% MV after:1 case 0.9 0.415th case 9.4 6.425th case 13.7 17.8 80% TV after:1 case 10.9 8.815th case 19.6 12.025th case 28.2 33.9

•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:

What Is Going On?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

Canadian situationCanadian situation

• 12.5 million Canadians with no vaccination to smallpox

• Over 64% of Canada’s population live in the nation’s 27 census metropolitan areas

• 79.4% of Canadians live in an urban centre of >10,000

• 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)

Need to consider Need to consider Population DensityPopulation Density

• 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

• Population:• Canada: 30,007,094

Toronto: 4,682,897Montreal: 3,426,350Vancouver: 1,986,965

• Population density:• Canada: 3.3/km2

Toronto 793/km2Montreal 847/km2

Vancouver 690/km2Kitchener 501/km2Hamilton 483/km2Oshawa 328/km2Windsor 301/km2

Important CaveatImportant 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?

Effect of Search and Containment on Reported Effect of Search and Containment on Reported Smallpox Cases, West and Central AfricaSmallpox Cases, West and Central Africa

1968-1969 (Figure 9 from Foege 1968-1969 (Figure 9 from Foege et alet al))

Foege WH, Millar JD, Henderson DA. Bull WHO 1975; 52: 209-222

Surveillance & Containment Initiated

% population not vaccinated

Smallpox casesreported/expected ratio

;

Decline in Reported Smallpox Decline in Reported Smallpox Cases Matches Decline in Cases Matches Decline in Susceptibility Over TimeSusceptibility Over Time

Reported Cases and % Unvaccinated from Foege et al

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1000

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May Ju

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Jan

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Month

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% U

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Actual Cases

% Unvaccinated

What About India?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

But Accounting For But Accounting For Population...Population...

Smallpox Incidence in India (Cases per Million)

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1920 1930 1940 1950 1960 1970 1980Sm

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Policy LessonsPolicy 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

Questions for us to Questions for us to ConsiderConsider

• 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 Canada’s 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


• “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?


• Is there a case for urban versus rural policies?– Ring vaccination is much more likely to work

in a rural environment where people don’t travel as much, whereas in the urban setting (where 70% of Canadians live), tracing will be much tougher.

““The only thing more The only thing more difficult than planning difficult than planning for an emergency is for an emergency is

having to explain why having to explain why you didn’t”you didn’t”

"Bioterrorism Preparedness: Smallpox Contingency Planning" Dr Bonnie Henry Associate Medical Officer...

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