partial literature review on the threat of smallpox bioterrorism and response strategies

1
partial literature review onthe threat of
smallpox bioterrorismand response strategies

• David Alderson
• January 2006

2
references

• D.A. Henderson. The Looming Threat of
  Bioterrorism. Science 2891279-1282, 1999.
• C.J. Davis. Nuclear Blindness An Overview of
  the Biological Weapons Programs of the Former
  Soviet Union and Iraq. Emerging Infectious
  Diseases 5509-512, 1999.
• D.A. Henderson. Smallpox Clinical and
  Epidemiologic Features. Emerging Infectious
  Diseases 5537-539, 1999.
• T. OToole. Smallpox An Attack Scenario.
  Emerging Infectious Diseases 5540-546, 1999.
• J. Bardi. Afterrmath of a Hypothetical Smallpox
  Disaster. Emerging Infectious Diseases
  5547-551, 1999.
• M.I. Meltzer, I. Damon, J.W. LeDuc, and J.D.
  Millar. Modeling Potential Responses to Smallpox
  as a Bioterrorist Weapon. Emerging Infectious
  Diseases 7(6) 959-969, Nov-Dec 2001.
• T. OToole, M. Mair, T.V. Inglesby. Shining
  Light on Dark Winter. Clinical Infectious
  Diseases 34972-983, 2002.
• E.H. Kaplan, D.L. Craft, and L.M. Wein.
  Emergency Response to a Smallpox Attack The Case
  for Mass Vaccination. Proc. Nat. Acad. Of Sci.
  USA 99, 10935 (2002).
• M.E. Halloran, I.M. Longini Jr., A. Nizam, and Y.
  Yang. Containing Bioterrorist Smallpox. Science
  298 1428-1432, 15 November 2002
• S.A. Bozzette, R. Boer, V. Bhatnagar, J.L. Brown,
  E.B. Keeler, S.C. Morton, and M.A. Stoto. A
  Model for a Smallpox-Vaccination Policy. The New
  England Journal of Medicine 348(5) January 30,
  2003.
• E.H. Kaplan and L.M. Wein. Letter on Smallpox
  Bioterror Response M.E. Halloran and I.M.
  Longini Jr. Reponse to Letter. Science
  3001503-1504, 6 June 2003.
• 12. Edward H. Kaplan, David L. Craft, and
  Lawrence M. Wein. Analyzing bioterror response
  logistics the case of smallpox. Mathematical
  Biosciences, Volume 185, Issue 1, September 2003,
  Pages 33-72.
• 13. Edward H. Kaplan. "Preventing second
  generation infections in a smallpox bioterror
  attack," Epidemiology, 15264-270, 2004.

3
smallpox an abbreviated history

• 1949 last documented case of smallpox in US
• post-WWII large bioweapons effort by US, SU
• 1969 US unilaterally abandons program
• 1972 US halts systematic vaccination programs
• 1972 Biological and Toxin Weapons Convention
• SU signed, but didnt believe (or comply)
• 1970s SU estimated stockpile 20 tons
• 1990 SU capacity 80-100 tons smallpox/year
• 1978 last global case of smallpox
• 1974-1991 IRAQ operates bioweapons program
• 1991-?? covert IRAQ bioweapons program?

4
smallpox todays threat

• US
• most susceptible population in modern times
• an unfamiliar disease
• Russian Federation
• unknown status of former programs
• location of bioweapons personnel?
• large stockpiles of weapons remain?
• security of smallpox virus?
• IRAQ
• extent of bioweapons program?
• location of bioweapons stockpiles?

5
stages of smallpox infection
asymptomatic non-infectious vaccine sensitive

• vaccine only effective lt 3 days after initial
  infection
• vaccine complications 3/106 (death in 40 of
  such cases)

3 days
incubating
asymptomatic non-infectious vaccine insensitive

• early detection isolation are most important
  for treatment

10-14 days

• aches, fever, rash, pustular
• spread by inhalation
• 1g smallpox can infect 100 people via aerosol

symptomatic infectious vaccine insensitive
symptomatic
3-5 days
symptomatic isolated deceased / immune

• no cure
• mortality rate 30

removed
14-17 days
6
smallpox policy questions

• detection an unfamiliar disease
• isolation who? when? how?
• vaccination who? when? how?
• how best to support a public health
  infrastructure with limited resources?
• coordination between federal and local govt
• managing information/media/mass hysteria

7
vaccination strategies

• traced vaccination (TV) CDC plan c. 2002
• isolate symptomatic cases
• trace and vaccinate their contacts
• vaccinate more broadly if cant contain
• ring vaccination
• mass vaccination in region around outbreak
• limited vaccination
• pre-vaccinate health workers, first responders
• mass vaccination (MV)
• pre-vaccinate entire population

June 2001 US stockpile of smallpox vaccine
15.4 M doses
8
simulated exercises

• First National Symposium on Medical and Public
  Health Response to Bioterrorism
• February 16-17, 1999, in Arlington, Virginia
• 950 public health officials, physicians, and
  other medical personnel, along with government,
  military, and intelligence experts
• T. OToole. Smallpox An Attack Scenario.
  Emerging Infectious Diseases 5540-546, 1999.
• J. Bardi. Afterrmath of a Hypothetical Smallpox
  Disaster. Emerging Infectious Diseases
  5547-551, 1999.
• Dark Winter
• June 22-23, 2001, Andrews Air Force Base
• Live simulation to examine challenges of
  senior-level policy makers in response to a
  hypothetical bioterrorist attack
• T. OToole, M. Mair, T.V. Inglesby. Shining
  Light on Dark Winter. Clinical Infectious
  Diseases 34972-983, 2002.

9
mathematical models

• typically, stochastic disease transmission
• primary uses
• to understand the potential magnitude of attack
  scenarios
• to evaluate the efficacy of prevention and
  response strategies

10
key parameters

• attack size of initial infection, location
• disease progression, transmission rate
• population size, type of mixing
• intervention start day, method
• vaccination resources stockpile, personnel

decision variables

• isolation who? when?
• vaccination who? when?

11
Meltzer et al., EID 2001

• size of initial infection 100, 1000
• average transmission rate 3
• infinite population, homogeneous mixing
• unknown start of intervention 25, 30, 45 days
• unknown quarantine rate 25, 50 per day
• interventions quarantine, vaccination
• metric cumulative infections after 365 days
• metric length of time to halt virus
• conclusions either intervention can work alone
  in theory but may take too long, should combine
  them timely response is perhaps the most crucial
  factor

12
Kaplan, Craft, and Wein. PNAS 2002

• size of initial infection 1000
• average transmission rate 3
• population 10 million, homogeneous mixing
• 5000 vaccination personnel
• interventions TV, MV, CDC interim plan (TV?MV)
• tracing dynamics contact list size, fraction
  named
• policy-dependent vaccination rates
• metric time to implement, number of deaths
• conclusions logistics and limited TV resources
  can constrain the efficacy of TV MV results in
  fewer deaths than TV time to switch from TV to
  MV is too costly so CDC should go with MV up front

13
Halloran et al. Science 2002

• community population 2000, detailed structure
• structure-dependent transmission probabilities
• different levels of residual population immunity
• size of initial infection 1 or 5 unvaccinated
  adults
• interventions pre/post-attack MV, post-attack TV
• pre-attack MV at 30, 50, 80 levels
• post-attack MV 80 over 10 days
• post-attack TV 80, 100
• detailed spread through population
• metrics smallpox cases per 2000, doses per 2000
• conclusions timely MV can be better than TV but
  not as dramatic as in Kaplan pre-existing herd
  immunity helps both MV/TV and makes TV comparable
  to MV

14
Bozzette et al. NEJM 2003

• attack scenarios hoax, laboratory release, human
  vectors, building attack, and low/high impact
  airport
• population size 500,000 4,000,000 (by
  scenario)
• size of initial infection 2-100,000 (by
  scenario)
• start of intervention 26 days
• control strategies contact vacc isolation
  post-attack vacc of health care (HC) workers
  post-attack vacc of HC public prior vacc of HC
  post-attack vacc of public prior vacc of HC
  public
• conclusions highly scenario dependent
• no vacc best for hoax, lab, human vector
• prior vacc best for all only for high-impact
  airport
• prior vacc for HC best for low-impact airport,
  building
• thresholds lower for local governments

15
preliminary conclusions

• relative efficacy of each vaccination strategy
  depends on combinations of model-specific
  parameters
• choice of model features (e.g. vaccination
  logistics) can sometimes dominate the result
• highlighting the sensitivity of model inputs to
  outcomes is perhaps most important feature
• universal model agreement
• the response time is perhaps the most important
  factor in containing an epidemic
• there is a need for a larger vaccination
  stockpile (NB after 9/11 US is stockpiling gt250M
  doses)

The ability to respond rapidly at a national and
local level will depend on a state of readiness