SMALLPOX

1
SMALLPOX
Terrorism, Science, Values, Choice, Public Health
and Public Policy

• Health Systems Face
• UNCERTAINTY

William J. Bicknell, MD, MPH School of Public
Health Boston University
2
The US Issues

• The Risk of Attack?
• If an attack, the magnitude?
• If an attack, can ring containment quarantine
  work?
• Vaccine risks?
• Liability issues?
• Are there responsible alternative options?
• Who should decide what?

3
Issues in Other Countries

• Risk of Attack
• Risk of Secondary Spread
• Risks Benefits of Vaccination
• Vaccine Effectiveness Pre Post Exposure
• Prevalence of Immunocompromised persons
• Medical Care Delivery System Capacity
• National Wealth
• Opportunity Costs Competing Priorities
• Other?

4
Today

• Facts
• Myths and controversies
• What the US is doing
• Where it was just after 911
• Where it is today
• A Decision Analysis Policy Framework for other
  countries

5
Challenges

• Very limited current knowledge experience about
  smallpox
• No one has epidemic control in a non-immune
  population experience
• Relevance of lessons from eradication experience
  (characterized by very different circumstances)
  is likely to be more limited than realized

6
The Risk of Attack

• What was our estimate of 9/11 on 9/10?
• I have never heard any informed person state with
  confidence that smallpox has not been
  disseminated outside the two repositories
• There are reports of vaccination of N.Korean and
  Iraqi troops
• US, UK, Israel, Germany Australia and perhaps
  others are acquiring vaccine.
• Israelis vaccinating first responders
• The US has enough for vaccine for all residents
• US is vaccinating first responders (more later)
• Bottom line - Unknown but non-trivial risk of
  terrorist attack
• Therefore, we need to know something about
  smallpox, lets get some basics

7
Off the Wall?

• Dr. Fenner No errors and A good case,
  reasonable for America and last Friday he said
  he thought the framework for other countries made
  sense.
• Dr. Fauci With regard to the US .excellent and
  hopefully will generate some frank and needed
  discussion. The stepwise approach that you
  recommend makes sense and is quite reasonable.

8
Smallpox Disease

• Highly Infectious
• It is dangerous and in error to say or believe
  otherwise
• Mortality5 to gt 50 - usually 25
• 60 - 80 of survivors disfigured
• Highest in young children
• No specific treatment
• 50 of US and most populations not immune
• 50 may have some residual immunity
• How much immunity ? No one really knows
• An historical note The Aztecs Incas,
  immunologically genetically naïve, lost to
  smallpox not the Spanish Portuguese
• F. Fenner 10/11/02

9
Smallpox Transmission 1

• Incubation - not infectious 10 -12 days
• Last days of incubation you feel lousy with Fever
• Then fever drops and you feel better but not well
  and are infectious
• Usually no visible rash yet - just inside mouth
  and throat
• Classic rash still 2 to 4 days away
• Message - Highly infectious, not very visible or
  obvious and not necessarily very sick
• Remember terrorists are motivated folks and can
  be expected to walk and disseminate even though
  feeling ill

10
Smallpox transmission 2

• Close contacts are best - within 6 feet
• Think of the morning metro or many other places
• How easy is it to transmit?
• Lets consider some historical examples

11
A Chilling Scenario

• One person with smallpox arriving in the country
  traveled by train.he was apparently in the
  initial phase of the disease, as nobody noticed a
  rash on his faceAlmost everyone who traveled
  with him in the compartment from Queensborough to
  Manchester contracted smallpox, the ticket
  collector...and those who traveled with him to
  Stalybridge in another train, something like a
  hundred people being infected from one single
  case.
• Not so different from flying in from Europe,
  traveling downtown by public transport and taking
  a train to the next city
• And terrorists are very motivated, so expect them
  to travel even if feeling quite ill

Wanklyn (1913) cited in Dixon p311
12
More Examples

• Other documented examples
• Yugoslavia 1972 ..denied (having a) rash..no
  evidence of skin lesions 11 secondary cases
• Tripoli 1946 a highly modified
  attack..unrecognized gives rise to fatal
  attacks A smuggler infects wife and child
• Walking by a window and similar examples are
  found in the literature
• Also true this is not always the case - but
  should we count on good luck?
• Worse yet, aerosol by immune disseminators.
• Experts I have spoken with feel, technically,
  this is feasible to expect in a terrorist attack.

13
Possible Attack Rates in Terrorist Contacts
Something between 10 50 may be a reasonable
assumption
Dixon, p310
14
The four day window

• Evidence fromTripoli in 1946 (Dixon 12/48,
  369-370) 21 non-immunes vaccinated within 5 days,
  all acquired smallpox, most mild, none died
• Anecdotal evidence from the eradication years
  that the disease is less severe if vaccination
  within 4 days of contact
• Vaccination within the window may prevent death
  and may prevent some disease
• But the vaccinator has to find and vaccinate the
  infected persons
• Contact tracing not likely to begin until 14 to
  17 days after first exposure. In most situations,
  finding initial contacts within 4 days is
  impossible

15
The Race to Trace

• Contact identification is the most urgent task
  when investigating smallpox cases since
  vaccination of close contacts as soon as possible
  following exposure but preferably within 3-4 days
  may prevent or modify disease. This was the
  successful strategy used for the global
  eradication of smallpox. CDC Interim Plan,
  Guide A, p. A-10
• A race that cannot be won in a terrorist scenario
• An excellent example of DO NOT ALWAYS BELIEVE THE
  EXPERTS

Kaplan, Craft Wein
16
A Recent Mathematical Model(Kaplan -Yale, Craft
- MIT, Wein - Stanford)

• Clearly demonstrates the limits and inadequacies
  of the CDC recommendation for ring containment.
• CDC has not yet adequately acknowledged and needs
  to update and change their website to reflect
  reality.
• Also shows that, for any significant exposure,
  immediate mass vaccination is far superior.
• Ratio of cases and deaths
• Ring/Mass 180/1

I have not checked CDC website in the last 10
days
17
A Recent Mathematical Model - Details(Kaplan
-Yale, Craft - MIT, Wein - Stanford)

• New York City
• 1000 Persons initially infected
• Compares Trace Vaccination (Ring Containment) and
  Immediate Mass Vaccination
• Ring Containment 324,000 cases, 97,000 deaths,
  control slow, epidemic still growing at 100 days
• Mass Vaccination 1,720 cases, 525 deaths,
  control fast, epidemic essentially over in 30 to
  45 days
• Also demonstrates limited value and great
  difficulties with quarantine and isolation of
  susceptibles and the asymptomatic

18
Kaplan Unpublished
19
Ring May Be More Myth than Reality

• Kaplan, Wein Craft - (In Press)
• Central West Africa eradication data
  recalculated.
• Growing levels of population immunity fully
  explain the decline in new cases.
• Bicknell Conversations with Lane, Margolis and
  Bloem
• We went into a village where there was a case
  and assumed everyone was a contact
• Thats local mass vaccination
• Prof. Fenner - Surveillance, finding new cases,
  was critical. Then the response was local mass
  vaccination.
• Conclusion Contact tracing, isolation,
  quarantine and ring vaccination seems to have
  been more the exception than the rule.

20
Plausible US Scenario after 40 days(Play with
the model ask wbicknel_at_bu.edu)

• 5 terrorists each travel to 3 urban areas
• 200 close contacts per city
• 20 of contacts infected (40 cases/site)
• 20 mortality
• 5 of infected contacts travel to other cities
• 1ary contacts infect 9 others, 2ary 5, 3ary 3
• Cities Towns - 1,600 (21 by day 11)
• Smallpox Cases - 114,000
• Smallpox Deaths - 22,000

21
Very Bad/Extreme Case ScenarioFirst 40 days

• 10 terrorists each travel to 5 different urban
  areas
• 500 close contacts per city
• 40 of contacts infected (200 cases/site)
• 30 mortality
• 5 of infected contacts travel to other cities
• 1ary contacts infect 10 others, 2ary 7, 3ary 4
• Cities Towns - 40,000 (100 by day 11, then
  1000s)
• Smallpox Cases - 3,600,000
• Smallpox Deaths - 1,000,000

22
Ring Containment, Isolation Quarantine

• Eradication was accomplished in populations with
  high and growing population immunity, relatively
  low mobility and without malicious intent - A
  MAGNIFICANT ACHIEVMENT.
• Terrorism today is different
• Malicious intent
• Low to absent immunity
• Highly mobile terrorists and a more mobile
  population
• Transmission to 2 or 3 - unrealistically low
  (Meltzer, et al)
• The 4 day window - may not exist and not really
  relevant
• Vaccination within the window not likely
• Widespread isolation quarantine - A near
  hopeless task, chaos and possible national
  shutdown
• In brief - A plan that cannot work in a terrorist
  scenario and saw far less use in the eradication
  years than is commonly believed.

23
Ring Containment - Summary

• Today, to the extent possible, with the first
  case or two, vaccinate probable contacts as soon
  as possible as you prepare for local or wider
  mass vaccination.
• Consider contact tracing, isolation and
  quarantine if
• residual cases in an environment with high
  population immunity
• an isolated exposure, particularly if there is
  high population immunity
• Inadequate for a mobile population, with low to
  absent immunity and a malicious exposure in
  multiple cities
• For controlling secondary spread in other
  countries - not a primary tool

24
The Magnitude of an Attack

• Plan for the worst, hope for the best
• Malicious and well executed
• Multiple terrorists, Multiple cities

25
The Vaccine

• It works and works well
• There is plenty for everyone in the US and will
  be lots more
• It is has more side effects including deaths than
  other vaccines currently in wide use
• Who dies and who has the most severe side
  effects? Children 9 and under (NEJM, p1202,
  11/27/69.
• Accidental inoculation most common kid to kid
• About 80 of the serious complications and deaths
  (1968 data) avoided if children not vaccinated
• Teen and adult deaths extremely rare (CDC, Israel
  US military 1968 data)
• Semi-permeable membrane dressing prevents 95 to
  99 of viral shedding (Dr. Belshe, 5/8/01 at CDC)
• Atopic dermatitis tricky (avoiding children helps
  a lot)
• New and old vaccine probably similar
  complications
• VIG good for many but not all complications

26
New Vaccines

• Acambis -Replicating, not attenuated
• Intended to mimic NYBH
• Expect similar side effects
• License on a fast track
• Japanese LC16m8 - Replicating, attenuated
• Fewer less severe side effects
• Still not OK for immunocompromised
• Earliest, if developed 2005
• Modified Vaccinia Ankara (MVA), Live
  non-replicating
• Intention is OK for everyone
• Earliest 2005
• LC16m8 MVA - Can we be really sure they will be
  effective in humans? How to know?

27
Vaccine Issues - 1

• Immunocompromised are at the highest risk of
  vaccine complications and of death from smallpox
• Pre-exposure vaccination done with forethought
  provides a calm atmosphere where education and
  precautions can be assured
• And if an attack, counseled to self isolate with
  selective vaccination based on well thought out
  criteria
• Post-exposure will be in crisis with ability to
  protect the immunocompromised from complications
  greatly decreased
• Many will want to be vaccinated and not reveal
  their status
• Our ability to identify and protect very limited
  when in crisis
• Deaths from vaccine complications can be expected
  to exceed pre-exposure PLUS more smallpox deaths
  in the immunocompromised

28
Vaccine Issues - 2

• Accidental vaccination of contacts of vaccinees
• Non-immunocompromised
• Immunocompromised
• Extremely rare
• Almost exclusively in household contacts
• Mostly children to children
• Vaccine complications including deaths most
  common and most severe in children
• Solution
• Pre-exposure do not immunize under age 9
• Use semi-permeable membrane dressings (Dr.
  Belshe)
• Post-exposure drop to age 1 (and below if risk of
  exposure is high)

29
Vaccine Issues - 3

• 1968 data - Vaccination deaths in gt15 all (2 of
  14 million) would (should) be screened out today
  (aplastic anemia and leukemia)
• If children lt10 not vaccinated pre-exposure,
  careful screening and use of semi-permeable
  membrane dressing
• Severe complications and deaths should (my
  opinion) be at or below historical rates

30
Bifurcated Needle or Jet Injector?

• Jet is faster
• Jet can be difficult to maintain
• Some evidence of inadvertent disease transmission
• US currently off the table
• CDC is developing a new, safer jet injector
• Dr. Bruce Weniger is the US expert at CDC

31
Dilute Vaccine Lasts 180 Days
From Dr. Belshe ACIP CDC Presentation May 8, 2002
32
US Position - Fall 01 to Mid 02

• Reality - Limited Vaccine, have to prioritize
• Did not say this, rather gave false assurances
  that Ring, etc.would work
• State Health Officers silent
• Substantial federal and state bad judgment
• Believe public must be reassured - WRONG
• Know it wont work but dont want to rock the
  boat - WRONG
• Fear of Loosing federal funds
• Possibly realistic and, to the extent it is true,
  reveals a dangerous weakness in the federal
  process
• And dangerous timidity on the part of state
  public health officials

33
Who should decide in the US?(US cultural bias)

• Attack risk is unknowable
• Personal risk can be illuminated
• Citizens make decisions about everything from
  participating in research protocols to deciding
  between vaginal delivery and C-section,
  angioplasty and open heart surgery on a daily
  basis
• Smallpox vaccination is no more difficult,
  arguably much simpler with far lower risks than
  many other choices
• Let the citizen decide within the framework of
  thoughtful pre-exposure guidelines
• Unfortunately, we have seen that relying on PH
  professionals in the US may not be safe - more
  reason let individuals decide for themselves
• This slide expresses my opinion and is,
  culturally, very specific to the US. Many PH
  professionals disagree.

34
Why Voluntary Pre-Exposure Vaccination in the US?

• Decreases consequences of an attack
• May decrease likelihood of attack
• Provides the best protection for the
  immunocompromised
• Is low cost and relatively easy to do as part of
  ongoing care
• Recognizes the limited surge capacity of US
  hospitals and near impossibility of quarantine
• In case of attack
• Makes containment control much easier, whatever
  the strategy
• Decreases panic and maintains order
• Minimizes interruption of the nations normal
  business
• Is realistic, has face validity and is easily
  understood by the professional and lay public
• By decreasing the likelihood and severity of an
  attack may benefit the rest of the world
• Will protect the most people at the lowest cost

35
Objections that were raised

• Our overall medical care delivery system is
  inequitable. Therefore pre-exposure vaccination
  will unfairly protect those with health insurance
• We cannot solve all social problems before
  protecting against terrorism
• Wait for newer safer vaccines and/or better,
  simpler diagnostic methods
• The country needs protection today. We must plan
  for and use tools we have while developing better
  tools
• We cant vaccinate unless we are prepared to
  vaccinate the rest of the world
• US vaccination, to the extent it decreases the
  likelihood of our being attacked , deceases risk
  to other countries. Many other countries have or
  are acquiring vaccine. This is fundamentally a
  foreign policy and foreign assistance question
• A rational terrorist wont use smallpox as it
  will boomerang
• Lets hope this is correct. However, it is
  irrational to apply our logic to terrorists

36
Inhibit the epidemiologic pump first protect
those most at risk

• First responders, at a minimum, should include
  ALL staff of hospitals, clinics and physicians
  offices ( 5.5 million people)
• The definition of first responder priority for
  vaccination should be determined by each state
• Which health workers?
• Who in the executive branch?
• Fire and police?
• Essential public service providers?
• Media crews?
• The Federal Government decides for itself -
  1,000,000 doses going to the army (NYT Oct 5)

37
First - a Measured Trial

• Resolve liability issues
• Careful guidelines to protect immunocompromised
• Vaccinate 500,000 first responders (Weve already
  vaccinated over 11,000 civilians since 1983, plus
  many military in the US until 90 and Israel
  until 96)
• Use first responder volunteers to donate blood
  for VIG production
• Observe vaccine complications very carefully
• Revise guidelines and approach as indicated
• Repeat with 1 to 2,000,000 first responders
• Observe with care and revise as indicated
• Vaccinate balance of first responders

38
Then - Expand to the general population

• VIG now widely available
• Public education as to risks and benefits of
  vaccination taking care to honestly and carefully
  distinguish between very serious/very rare and
  not so serious and far more common complications
• Informed consent
• Greatly reduce complications and deaths by
  restricting vaccination to
• Persons older than 9 years
• Persons who are not immunocompromised and do not
  have other disqualifying conditions
• Urge vaccinees to
• Announce their intent to family, friends and
  co-workers
• Use appropriate dressing
• Possibly consider avoiding crowds

39
Roles Responsibilities

• CDC
• Safety guidelines for pre- and post-exposure
  vaccination - NOT the societal or individual risk
  decision
• Technical assistance on request
• Guidelines for pre- and post-exposure state
  action
• States
• Determine risk for their state
• Make state-specific plans and recommendations
• Who are first responders?
• Pre-exposure guidance for general public
• Post-exposure planning
• Individuals
• Assess their own risk
• Opt or decline pre-exposure vaccination

40
My Recommendations Conclusions for the US

• CDC (analogous to WHO) guidance for
• Pre-exposure vaccination
• Post-exposure vaccination
• State planning frameworks
• CDC technical assistance (as capacity allows)
• State (analogous to countries) control (nb
  federal reportable diseases)
• Individual choice
• Assessment of risk and benefit in the US should
  rest with those who have the risk - Citizens
• Provides the most protection, at the lowest cost,
  with the least chaos, and recognizes that
  response will and must primarily be a local and
  state responsibility
• Pre-exposure voluntary vaccination protects
  against a specific threat and puts prevention
  first. This is what public health and responsible
  government are all about

41
Likely Results of Pre-Exposure Vaccination

• Based on survey data, 50 to 70 of population
  will opt for vaccination
• Very rare serious complications and deaths
• Decreased risk to the immunocompromised from
  vaccination and smallpox
• Trained vaccinators and supplies in place in case
  of attack
• Possible decreased likelihood of attack
• Containment and control far easier in case of
  attack
• Hospitals and the health care system not
  overwhelmed
• Panic, disorder and the interruption of essential
  services and activities minimized
• Known specific preventive steps taken before a
  terrorist attack
• The public has an example of sound proactive
  public health

42
Public Trust

• Whatever is done, it is vital that actions,
  including discussions, take place in a way that
  builds public trust
• Inappropriate secrecy, silence or recommendations
  that do not make sense erode public trust
• The responses of the federal government and state
  health departments to bioterrorism provide an
  opportunity to build trust and understanding of
  the importance of public health
• Our response to smallpox and bioterrorism, if
  done with humility, openly and non-defensively,
  can be a win for everyone, protecting the
  publics health and strengthening the public
  health system

43
Liability

• This is a big US issue
• A combination of federal, state and private
  actions are well on the way to solving the
  pre-exposure liability problem
• and will vary in other countries
• Other Countries
• A function of law and custom
• Lets hope few are as litigious as the US!

44
Worldwide - What to do?

• Country Specific Risk Response Profile Based
  on
• Risk of Direct Attack
• Risk of Secondary Spread
• Strength of Medical Care PH Delivery System
• HIV/AIDS Prevalence
• Opportunity Costs
• Economic Social Consequences
• Cultural Values
• Wealth

45
Different Strokes for Different folks

• Not flippant - circumstances vary greatly
• Canada and Mexico
• Ireland
• Israel and the Occupied Territories
• Bhutan
• Singapore
• Cambodia
• Australia
• Lesotho
• The Marshall Islands

46
National Policy Options

• 1 - Countries at high risk of attack
• 2 - Countries at high risk of secondary spread
• 3 - Countries at moderate risk of secondary
  spread
• 4 - Countries at lower risk of secondary
  infection
• 5 - Countries with special risks

47
High risk of attack

• Minimum package Voluntary vaccination of
  eligible medical and public health first
  responders. Stockpile vaccine sufficient for the
  entire population and stockpile VIG sufficient to
  manage probable vaccine complications.
• Maximum package Minimum package plus voluntary
  vaccination of all remaining first responders.
  Make the vaccine available on a voluntary basis
  to the general public.

48
High risk of secondary spread

• Minimum package Stockpile vaccine sufficient for
  50 to 100 of the population. Stockpile VIG
  sufficient to manage probable vaccine
  complications.
• Maximum package Minimum package plus vaccinate
  medical and public health first responders.

49
Moderate risk of secondary spread

• Minimum package Stockpile sufficient vaccine and
  VIG to initiate but not complete widespread
  vaccination. Vaccine and VIG stockpile
  sufficient for 10 to 25 of the national
  population.
• Maximum package Minimum package plus vaccinate a
  limited number of medical and public health first
  responders.

50
Lower risk of secondary spread

• Minimum Package Assure rapid availability of
  vaccine and VIG from sources in country or
  abroad.
• Maximum package Stockpile vaccine and VIG
  sufficient for 10 of the population. Vaccinate a
  limited number of medical and public health first
  responders.

51
Special risk countries

• If a country has a severely under-funded health
  system or has a high prevalence of AIDS, as is
  the case in much of eastern and southern Africa,
  then the combination of risks to the
  immunocompromised and the opportunity costs of
  immunizing against smallpox are sufficiently
  great to merit doing no more than assuring the
  rapid availability of vaccine and VIG should
  smallpox occur.

52
A Menu

• Pre-exposure
• Take no action - This can be a correct choice
• Vaccination of first responders
• From very limited to extensive
• With or without semi-permeable dressing
• Vaccination of general public
• None, voluntary, mandatory and dressing?
• Stockpiling of vaccine, needles and VIG
• Assessing regional resources
• Post-exposure
• Confirming the diagnosis
• Accidental or deliberate?
• Travel restrictions from other countries?
• Vaccination - How widespread?

53
Possible WHO Roles

• Assist countries in developing their own
  Risk/Response profile
• Provide assistance with advance planning
• Stockpile sufficient vaccine to initiate a rapid,
  effective response to manage secondary spread in
  lower income countries
• Stockpile bifurcated needles
• Consider establishing an open purchasing contract
  for dressings
• Identify and train members of regional rapid
  response teams
• Identify/Provide laboratory diagnostic support

54
Take Away Messages

• 4 day window more myth than reality
• Ring containment not for terrorism and not much
  else
• The old vaccine, calf lymph or tissue culture is
  what we know works
• Other vaccines not yet ready, may work, but can
  we be certain?
• Countries should plan based on their own values
  and assessment of risks, benefits and opportunity
  costs
• One size WILL NOT fit all.

55
Summary

• Hope - Smallpox will never return
• Smallpox is the worst bioterrorism threat
• The US is on the verge of being well prepared
• Israel is well prepared
• All countries should give this some thought
• High attack risk countries should minimally do
  selective pre-exposure prepare for post attack
  area or national mass vaccination
• Countries (all other) at risk of secondary spread
  need their own plan.
• Responses should vary from nothing to selective
  pre-exposure vaccination with stockpiling for
  all.
• WHO has a major role to play in country-specific
  planning regional preparation

56
Thank You
Email ltwbicknel_at_bu.edugt