1. Safety and Security Requirements for Select Agent Research

2. Bioterrorism

3. Definitions
Biological terrorism (BT) – Use of biological agent on a population to deter, hinder, or otherwise slow the productivity of a community.
Biological warfare (BW) - Use of biological agent to harm or kill an adversary’s military forces, population, food, and livestock.
Select agents (SA): designated subset of biological agents or toxins identified as having the potential to be used in weapons of mass destruction (WMD’s)

4. Types of Biological Weapons
Bacterial agents
Viral agents
Biological toxins

5. Advantages of BT Killing efficacy Cost effectiveness Vehicle
Relative ease of production
Interval between dissemination to infection

6. History
Ancient – 20th century
20th century – 1972
1972 – today

7. Does the Siege at Caffa Correlate with the Initiation of Black Death?

8. 20th Century to 1972 World War I Geneva Protocol (1925)
Glanders and anthrax used on horses
Geneva Protocol (1925)
40 violations from of prohibitions of bioweapons used in war
World War II
- Unit 731, Manchuria, China – weapons tests on Chinese

9. 20th Century to 1972 US military bio-weapon program, 1950-72
Ft. Detrick, Maryland
Pine Bluff Arsenal, Arkansas
1966, B. subtilis in NYC subway
- Study dissemination patterns
1969, Serratia in San Francisco
- Study line-source dissemination
Biological Weapons Convention, 1972
Today, 148 signatories
- India, North Korea, Pakistan, Iran among those not signed

10. 1972 - Today 1979, Sverdlovsk, Russia
66 fatalities from anthrax release
For 13 years USSR government tells public it was due to ingestion of contaminated meat.
1992, Boris Yeltsin admits a faulty HEPA exhaust filter as the result of the release from Building 19.
Science, 1994, 266(5188):

11. 1972 - Today 1992, Aum Shinrikyo cult Weaponize anthrax
- 10 botched attempts (1992)
Travel to Zaire to find Ebola
Sarin gas attacks in Japan

12. Where in the World is Safety Bob
and what is the public health significance of this place?

13. The former Shakey’s Pizza where the Bhagwan Shree Rajneesh cult conducted the first known bio agent attack in the US in September 1984, spraying salmonella on the salad bar to in an attempt to prevent citizens from voting in an upcoming election

14. The 2001 Anthrax Letters 23 reported cases of anthrax
New York City (8), New Jersey (7), D.C. (5), Florida (2), and Connecticut (1)
11 inhalation anthrax (5 deaths)
12 cutaneous anthrax
9/11 inhalation anthrax cases are linked to direct exposure to contaminated mail
2 cases had no known exposure (61 y.o. woman in NY, 94 y.o. woman in CT)

15. Anthrax Bacillus anthracis Gram (+) sporulating rod 3 antigens formed
(EF), (LF), (PA)
Presence of (LF) and (PA) = pathogenic
3 distinct clinical syndromes
Cutaneous
Inhalational
Gastrointestinal

16. Inhalational Anthrax Infective Dose = 8,000 - 15,000 spores
Incubation period = 1-6 days
Duration of illness = 3-5 days
Diagnostic Hallmark
Widened mediastinum
Treatment:
Ciprofloxacin: 500mg bid x 4 wk
Doxycycline: 100mg bid x 4 wk

17. Anthrax - Clinical Presentations

18. October 2001: Anthrax Mail Attacks: UTHSC-H Experience

19. Ricin Derivative from castor bean plant, Ricinus communis
Protein cytotoxin that inhibits protein synthesis through its 2 polypeptide chains
Marginal toxicity when compared to other biological toxins
LD50 = 30 μg/kg
Recent history
1978 – Bulgarian dissident
1996 – KC Oncologist intent to use
1997 – WI resident possession
2003 – Al Qaeda plot
2004 – Washington DC letter

20. Ricin, cont’d Major clinical presentations: Inhalation Injection
Rapid onset (4-8 h) – fever, chest tightness, cough, dyspnea, nausea
Respiratory failure (36-72 h) and pulmonary edema
Injection
Same onset as inhalation
Local lymphoidal and muscle necrosis, GI hemorrhaging
Ingestion
Less toxic than above
Onset of symptoms similar time – abdominal pain, vomiting, diarrhea, progressing to GI hemorrhaging, hepatic, splenic, and renal necrosis
Death 3-5 days – cessation of circulatory system

22. Smallpox Variola major virus BW threat from aerosolization
Orthopox virus
BW threat from aerosolization
Acute stages often confused with Varicella (chickenpox)
Differentiation:
Smallpox typically evolves distally
Lesions generally all is same stage
Febrile illness prodromal stage
Eradicated by WHO in 1980
US & UN delay destruction of reserves until 7-02
Delayed longer
Treatment
No known cure
Vaccinia Immune globulin
Cidofovir

23. Smallpox Presentation

24. Given the Threat – What to Do?
Preparedness Needs
Detection - Health Surveillance
Rapid Laboratory Diagnosis
Epidemiological Investigations
Implementation of Public Health Control Measures
Communication network
Research and Development
PPE, respirators
Triage and decontamination methods
Vaccines, prophylaxis

25. Web Resources www.bt.cdc.gov

26. The Select Agent Rule

27. Foundation for Select Agents
Antiterrorism and Effective Death Penalty Act of (PL )
Invoke transport requirements, and prohibited possession as weapons
USA PATRIOT Act (PL )
Effective 10/16/01
Controlled the possession of 49 Select Agents/Toxins for any use: peaceful, research, or intentional
Outlawed use if a “restricted person”

28. Public Health Security and Bioterrorism Preparedness and Response Act of 2002
(PL ) effective 6/12/02
Covers both human and plant/animal select agents; joint program between HHS (CDC) and USDA (APHIS)
9/10/02 - CDC notification of possession or use of SA by facilities required; negative certification also required
12/12/02 – Interim final rule published
02/14/03 – Interim final rule enacted as law
03/18/05 – Final Rule released

29. What is a Select Agent?
List of agents can be found on the CDC and APHIS websites
Includes infectious agents and biological toxins of WMD concern; often termed “dual use”
There are some exemptions for certain strains and amounts of toxin per PI

30. 42 CFR 73 – Select Agent Regulations
73.7 Registration & related security risk assessment
73.9 Responsible Official
73.10 Restricting access to Select Agents
73.11 Security plan
73.12 Biosafety plan
73.14 Incident Response
73.15 Training
73.18 Inspections
73.19 Notification for Theft, Loss, or Release

31. CFR 73.7 - Registration You must be registered prior to beginning work
Registration good for 3 years
Facility must meet CDC/NIH BMBL guidelines in addition to security requirements

32. CFR 73.7 – Related Security Risk Assessment
Registration information required to be submitted so that Attorney General may perform risk assessment of work at institution with Select Agents

33. CFR 73.9 – Responsible Official
Responsible Official (RO) and an Alternate Responsible Official (ARO) must be designated
This individual must have resources available to ensure compliance

34. CFR 73.10 – Restricting Access
Must be an authorized person to have unrestricted, unsupervised access to Select Agents
-training & experience required
-must be approved by Attorney General
Authorization granted for a period of five years

35. Statement of Eligibility
Denied SA possession if ‘Yes’ to any of following:
Jail >1 year
Fugitive from justice
Controlled substance use
Citizen of one of UN recognized terrorist countries
Committed to a mental institution
Dishonorably discharged

36. CFR 73.11 – Security Inventory Control Measures Physical Security
- Looking for at least 3 levels
Cyber Security
Provisions for visitors, housekeeping, and maintenance
Procedures for lost passwords, keys, IDs, personnel leaving, unauthorized personnel

37. CFR Biosafety Plan
Biosafety and containment procedures set forth following BMBL and NIH rDNA Guidelines
i.e. entry protocols; PPE; general and special practices and procedures
Plan must be tested at least annually using drills to evaluate the effectiveness of plan or after any incident

38. CFR 73.14 - Incident Response
Do you have an institutional Emergency Situations Response Plan (ESRP)? Where is it located?
Planning and coordination with outside parties
What are the emergency hazards associated with select agent?
Oral, Contact (dermal), Inhalational hazards
What are the hazards associated with response that could lead to the spread of select agent?
Do you have appropriate site security and control during emergency?
Where do you find information about the specific hazards associated with the select agent?
Biosafety Plan

39. CFR Records
Current, accurate list of individuals approved for access to select agent
Current, accurate inventory of select agent
Name, characteristics, and source data
Quantity acquired and date of acquisition
Quantity destroyed and date of destruction
Quantity transferred, date of transfer, and to whom it was transferred (EA-101)
Records of APHIS/CDC Form 2 (EA-101) transfers
Access to area where select agent is used or stored

40. CFR 73.19 – Notification for Theft, Loss, or Release
Must have a procedure for any of the above events
Must complete report to USDA or CDC using APHIS/CDC Form 3

41. Penalties
42 CFR 1003 imposes strict penalties for violations of 42 CFR Part 73
Imprisonment of up to 5 years
“….. $250,000 in the case of an individual”
“……$500,000 in the case of any other person”
Failure to completely comply also carries significant reputational risk

42. Foreseeable Trends
Increasing regulatory requirements, inspections, scrutiny
Opportunities for research
The FY03 budget for Department of Homeland Security was $37,450,000,000

43. Commentary
Additional bureaucratic controls for select agents are imminent
These rules will not always be based on sound science
Incompatibilities with universities:
Designed as traditionally open environments
Internationally diverse populations
Population eschews being told what to do
Openly shares information
But the work is important –so an infrastructure is needed to support this type of activity

44. Commentary (con’t)
When looking at positions, suggest asking about the support infrastructure in place - specifically:
Who does EH&S report to?
Who is the designated “responsible official”?
Is “select agent” work currently underway?
What facilities exist and are planned?

45. Summary
Biosafety is much more than just research protocol reviews or bloodborne pathogens
Risk assessment process the key to properly classifying and reviewing research with infectious agents or rDNA
Safety department must rely on the expertise of the committee for assistance
Select agent work is highly regulated and scrutinized

46. References http://www.phac-aspc.gc.ca/msds-ftss/index.html#menu?
42 CFR 73 (CDC)
7 CFR 331 and 9 CFR 121 (APHIS)
Biosafety in Microbiological and Biomedical Laboratories, 4th ed. CDC/NIH 1999
Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) April 2002
Health Canada MSDS for Biological Agents