History of Biosafety andHistory of Biosafety andU.S. Biodefense Programs

Bioterrorism, Biological Warfare, and DefensesU.S. Biodefense Programs

Bioterrorism, Biological Warfare, and Defenses

Level 3 Biosafety Training CourseMidwest Regional Center of ExcellenceMidwest Regional Center of Excellence

for Biodefense and Emerging Infectious Disease ResearchSept. 24, 2012

Washington University in St. LouisSt Louis MO

Emmett Barkley, Ph.D.President

Proven Practices, LLC

St. Louis, MO

1

Robert J. Hawley, Ph.D., RBP, CBSPSenior Advisor

Midwest Research Institute

A Beginning:

• 1854 London cholera epidemic

• Edwin Chadwick and Jack Snow

• Water pollution and diseaseWater pollution and disease transmission traced to Broad St. water pump

• Ignited “the sanitation revolution”

A Beginning:  Lessons Learned (1)

• Effective intervention does not always need accurate knowledge of disease causation

• Environmental measures may be more effective than changing individual behavior

• Always search for pragmatic solutions

BMJ readers chose “the sanitation revolution” as the top medical milestone since its inaugural publication in 1840.

(1) Mackenbach, J. Sanitation: pragmatism works. BMJ 2007; 334: s17

In with the Germ Theory ‐In with the Germ Theory ‐Out with the Miasma Theory

First Laboratory InfectionsFirst Laboratory Infections

• 1885 Typhoid lab infection, unknown cause1885 Typhoid lab infection, unknown cause

• 1893 Tetanus lab infection by syringe

• 1894 Cholera lab infection by pipette• 1894 Cholera lab infection by pipette

• 1897 Brucella lab infection by syringe

• 1898 Glanders lab infection by syringe

• 1899 Diphtheria lab infection by pipette

Adapted from Kisskalt, 1915; Riesman, 1898; Birt, 1899

In with the Germ Theory ‐In with the Germ Theory Out with the Miasma Theory

• Pasteur established the germ theory in 1862– Demonstrated that fermentation is caused by the growth of 

microorganisms; published paper on lactic fermentation in 1857

• Isolation and culturing of bacteriaR b t K h– Robert Koch: 

• Bacillus anthracis ‐ 1877; • tuberculosis bacilli ‐ 1882; • Vibrio cholera ‐ 1883; 

b d h h• Corynebacterium diphtheriae ‐ 1881‐ 1884; • Salmonella typhi – 1884 (Gaffky); • Yersinia pestis ‐ 1894 (Yersin)

– David Bruce: Brucella melitensis ‐ 1887

Reports and Surveys of Laboratory Associated Infections

Multiple Laboratory Infections

Agent Probable Source

LAI YearSource

Franciscella tularensis

handling rodents 6 1920

Brucella melitensis centrifuge 45 1938Brucella melitensis centrifuge 45 1938

Coxiella burnetii centrifuge use 47 1947

VEE dropped lyophile tubes

24 1959

Marburg virus blood and organ 23 1968

Reports and Surveys of LaboratoryA i d I f iAssociated Infections

Cause of 3921 Laboratory‐associated Infections

Cause Number Percent

A l 522 13%Aerosol  522 13%

Accidentneedle and syringe

703 18%

spills and sprays

sharps injuries

pipetting by mouth

animal bite or scratch

Essentially unknown 2696 69%69%

Adapted from Pike 1976

Fort DetrickC ib i Bi fContributions to Biosafety

1943 – 1969

• Occupational health program– Health and safety of workers highest priority– Treat every infection as a LAI until proven otherwise– Reporting exposures was encouraged

• Risk assessment– Number and severity of LAI– Number and severity of LAI– Infectious dose for humans– Availability of specific therapy or effective vaccine

• Applied research• Applied research– Pioneered risk assessment studies– Developed and validated decontamination protocols– Evaluated microbial hazards and protocols

l d ff f f l f l l– Evaluated efficiency of HEPA filters for capturing viral particles

Estimated Rate of Laboratory‐acquired InfectionsEstimated Rate of Laboratory acquired Infections Among Fort Detrick Personnel

1943 ‐ 1969

Period Personnel at Risk ApproximateContainment

Level

LAI / MillionPerson-hours

WorkedLevel Worked1943-1945 Primarily military P1 351954-1958 Primarily civilian P2 91960 1962 P i il i ili P3 21960-1962 Primarily civilian P3 21960-1969 Primarily civilian P4 1

Lessons from History and Epidemiology of Laboratory Infections

Applied Research in Biosafety

• When an agent that may cause disease is studied in the laboratory it is• When an agent that may cause disease is studied in the laboratory, it is logical to expect sooner or later that some laboratory worker will become infected with the agent.

A l i f tb k i id l b t b ildi ith i• Analysis of outbreaks inside laboratory buildings with no primary or secondary barriers shows no infections outside the buildings in persons not associated with the laboratory.

Cl III BSC t t ith t LAI i h l b d d h d l• Class III BSC systems can operate without LAI in whole‐body and head‐only aerosol studies using repetitive procedures with stable, well trained, and well disciplined workers.

R h i titi d i l h d th h• Research using repetitive procedures is less hazardous than research requiring frequent changes in technique and equipment.

• In the absence of effective vaccination, it is not possible to do basic , presearch using Class I BSCs with a highly infective agent without LAI.

Biosafety OutreachFort Detrick (1943 ‐ 1969)Fort Detrick (1943  1969)

• Created the Biological Safety Conference in 1956Conference in 1956

• Provided guidance to federal agencies in support of the development of biosafety programs and guidelines

• Published papers on biosafetyPublished papers on biosafety practices, risk assessments, and applied research projects

D W d t t• Dr. Wedum was a mentor to whomever asked for his guidance

Arnold G Wedum M D Ph DArnold G. Wedum, M.D., Ph.D.(1903‐1976)

Biosafety PioneersBiosafety PioneersMentors on Whose Shoulders Biosafety Flourished

• Arnold Wedum: Father of Microbiological Safety• Everett Hanel: member of Dr. Wedum's safety group at y g p

Fort Detrick from 1943-1972• Briggs Phillips: aerobiological safety, Ft. Detrick• Manny Barbeito: biocontainment engineering, Ft. Detrick

• Jerry Tulis: First and only degree program in biological safety

• Emmett Barkley: NCI, NIH, HHMI, Proven Practices

• Robert Hawley: USAMRIID, MRI

Biosafety GuidelinesBiosafety Guidelines

Classification of Etiologic Agents on the Basis of HazardClassification of Etiologic Agents on the Basis of Hazard

• Published by the CDC (DHHS) in 1969y ( )• Four classes of hazard (1,2,3,4)• A fifth class (5) of animal agents with USDA restrictions• Scientific judgment of the PI (risk assessment)• Competence of investigators

Ph i l t i t• Physical containment

Biosafety GuidelinesBiosafety Guidelines

Asilomar Conferences, Pacific Grove, CA:Asilomar Conferences, Pacific Grove, CA:1. Jan. 22-24, 1973

– Experiments of concern:Experiments of concern:• SV40-lambda hybrid• Non-defective adenovirus-SV40 hybrids

– Led to publication of: NCI Safety Standards for Research Involving Oncogenic Viruses

• Three classes of potential hazard (Low Moderate High)Three classes of potential hazard (Low, Moderate, High)• PI and individual responsibility• Practices, safety cabinets, facilities

M di l ill• Medical surveillance

Biosafety GuidelinesBiosafety Guidelines

Asilomar Conferences, Pacific Grove, CA:Asilomar Conferences, Pacific Grove, CA:2. February 24-27, 1975

– Experiments of concern: Recombinant DNA MoleculesExperiments of concern: Recombinant DNA Molecules• Organized by Paul Berg; David Baltimore; Sydney 

Brenner; Richard Roblin III; Maxine Singer

• Conference agenda:– Review progress of rDNA research– Consider potential biohazardsConsider potential biohazards– Consider ethical and legal concerns– Draft a conference summary paper with recommendations

Biosafety GuidelinesBiosafety GuidelinesAsilomar Conferences, Pacific Grove, CA:2. February 24-27, 1975

– Led to publication of: NCI Recombinant DNA Research Guidelines• ContainmentContainment

– Physical: P1, P2, P3, P4– Biological: EK1, EK2, EK3

• Experimental Guidelines– Risk assessment– Selecting containment

• Roles and Responsibilities– Principal investigatorsPrincipal investigators– Institutions– Institutional Biohazard Committees

Biosafety GuidelinesBiosafety GuidelinesCDC/NIH Biosafety in Microbiological and y g

Biomedical Laboratories (BMBL)• First edition published in 1984

• Current (5th) edition published in 2009• Advisory recommendations

V l t d f ti• Voluntary code of practice• Goal of upgrading operations• Guide for laboratory construction or y

renovation• Application to laboratories is based upon

risk assessmentrisk assessment.

Biosafety TrainingBiosafety Training

• Safe practices in research involving oncogenic viruses and rDNASafe practices in research involving oncogenic viruses and rDNA molecules (NIH 1972-1979)

• Train-the-trainer course on fundamentals for safe microbiological research (NIH/ASM 1977-1978)research (NIH/ASM 1977-1978)

• Instructors’ Guide for Biosafety Training (NIH, 1983)• American Biological Safety Association

– Offering training since 1984– Offering training since 1984– Training primarily directed at biosafety professionals

• Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases ResearchEmerging Infectious Diseases Research– Among several RCE-based programs to offer training intended for

investigators; first course offered in Feb, 2004– First biosafety fellowship program in the worldy p p g

• NIH National Biosafety and Biocontainment Training Program

Regulatory Oversight of Biosafety Laboratories

• Interstate Shipment of Etiological AgentsDOT 42 CFR P t 72 (1957)– DOT 42 CFR Part 72 (1957)

• Occupational Exposure to Bloodborne Pathogens– OSHA 29 CFR Part 1910.1030 (1991)

Possession Use and Transfer of Select Agents• Possession, Use and Transfer of Select Agents– CDC 43 CFR Part 73 (2005)– APHIS 9 CFR Part 121, and 7 CFR 331 (2005)

• Public Health Security & Bioterrorism Preparedness and Response Act of 2002• Public Health Security & Bioterrorism Preparedness and Response Act of 2002– Regulations for the transfer, possession and use of select agents– Risk assessment (including children and vulnerable populations)– Ensure appropriate training and skill in handling select agentssu e app op a e a g a d s a d g se ec age s– Containment laboratories– Security measures commensurate with the risk such agent or toxin poses to

public health and safety (including the risk of use in domestic or international terrorismterrorism

– Availability of select agents for research, education and other legitimate purposes.

Definitions

BioterrorismBioterrorismThe threat or use of biological agents by individuals or groups motivated by political,

Biological WarfareBiological Warfare

religious, ecological or other ideological objective.*

Biological WarfareBiological WarfareThe intentional use of microorganisms or toxins derived from living organisms to produce death orderived from living organisms to produce death or disease in humans, animals, or plants

21

* W. Seth Carus, 1998. Bioterrorism and Biocrimes. Center for Counterproliferation Research, National Defense University

Biological Warfare History

1346: Caffa - Plague1763: French and Indian War - Smallpox1937-1945: Japan - Unit 7311972: Biological Weapons Convention1978: Ricin (Assassination)1979: Sverdlovsk Anthrax1979: Sverdlovsk - Anthrax

22

Biological Warfare History

23

Larry Wayne Harris

1995 possession of Yersinia pestis

1998 i f B ill th i 1998 possession of Bacillus anthracis

24

International Biological Weapons Programs

KnownIraqRussia

Weapons Programs

Russia

ProbableChinaIranNorth KoreaLibyaSyriaSyriaTaiwan

PossibleCubaEgyptIsrael

25

Source: Committee on Armed Services, House of Representatives. Special Inquiry into the Chemical and Biological Threat. Countering the Chemical and Biological Weapons Threat in the Post-Soviet World. Washington, D.C.: U.S. Government Printing Office; 23 Feb 1993. Report to the Congress.

Sverdlovsk Incident

• April 1979• April 1979> 66 Anthrax fatalities

• 1988Soviets present data:

• 96 cases• 79 gastrointestinal

• May 1992Boris Yeltsin admitsBoris Yeltsin admits due to “military developments”

26

Russian Federation and the FSU

27Stepnogorsk Obolensk

Iraq

Al HakamAl Hakam

28Salman Pak

Offensive BW Program: Iraq

1995 disclosures to UNSCOM

P d d W i d

(United Nations Special Commission)

Produced Weaponized

Botulinum toxin 19,000 Liters 10,000 L

Anthrax spores 8,500 L 6,500 L

Aflatoxin 2 200 L 1 580 LAflatoxin 2,200 L 1,580 L

29

UN Doc S/1995/864, 11 OCT 1995

Afghanistan

30

September 18 – November 2001 Anthrax lettersAnthrax letters

31

Insider Threat

• Insider threat is most common but underrated• Primary threat on most organizations’ list of threats

32

Minimizing the Insider Threat

Laboratory Biosafety:A set of preventive measures designed to reduce the risk of accidental exposure to, or releaseaccidental exposure to, or release of, a biological hazard.

Laboratory Biosecurity:A set of preventive measuresA set of preventive measures

designed to reduce the risk of intentional removal (theft) of a

33

valuable biological material.

Minimizing the Insider Threat

• Common strategy - Implement graded levels of protection based on a risk management methodology.

• Control of certain biological materials is necessary, but g y,how that is achieved must be carefully considered.

Biosecurity and biosafety should be integrated systemsthat avoid compromising necessary infectious disease

research and diagnostics

34

research and diagnostics.

Potential BW Agents*

BacteriaBacillus anthracis (Anthrax)Yersinia pestis (Plague)Coxiella burnetii (Q-Fever)

VirusesSmallpoxRift Valley Fever

ToxinsBotulinumRicin

Coxiella burnetii (Q-Fever)Brucella spp. (Brucellosis)Francisella tularensis (Tularemia)Vibrio cholerae (Cholera)

Crimean - Congo HFVEEMarburg?

SEBT2 MycotoxinsSaxitoxinC. perfringens toxin

*NATO AMedP-6(B)1996; Annex B unclassified*Not to be interpreted as sanctioned “threat list”

35

Low Cost of BW Agents

Costs* of producing mass p gcasualties per square kilometer:

Conventional $2000.00Nuclear 800.00Chemical 600.00Biological 1.00

36* Chemical-Biological Expert Panel, UN, 1969

Advantages of BWIs BW the Ultimate Weapon?Is BW the Ultimate Weapon?

• Easy to obtain• Relatively easy and inexpensive to produce• Readily available delivery modes• Dissemination over large areas • Difficult to detect (odorless, colorless)• Large numbers of casualties possible• Even threat of use would create fear, panic• Perpetrators could escape days before effects seen

37

Disadvantages of BW

Reliance on weather conditions- Air inversion

Wi d l it

ca. 1998

- Wind velocity- Agents inactivated by solar UV radiation

Dangerous for user Dangerous for user Not empirically validated

Simulant studies and computer simulationsca 1968 - Simulant studies and computer simulations- Small scale animal and volunteer studies

ca. 1968

38

Impact of Biological Warfare

H lth S ton a Healthcare System

• Terror in the affected population and in the medical care systemO h l i b ICU• Overwhelming numbers, ICU demands, or special medication needs

• Need for personal protection in• Need for personal protection in medical care, clinical laboratory, autopsy suites

• Problems with handling remains

39

Countering BioterrorismThrough Integration and Teamwork

I t lli

Through Integration and Teamwork

Intelligence• Agent• Delivery System

Medical Countermeasures

• Vaccines / Prophylaxis• Organization• Time

p y• Diagnostics• TherapeuticsBiological

Defense

Physical Countermeasures

Education & TrainingMilit d Ci ili H lth Countermeasures

• Detection• Physical Protection

• Military and Civilian Health Care Providers

• Electronic Communication

40

• Decontamination• Distance Learning

Biodefense Resources

• Internet:

- www.usamriid.army.mil- www.nbc-med.org

Textbook of Military Medicine

g• Toll-free number: 1-888-USA-RIID• Texts

MEDICAL ASPECTS OF

CHEMICAL AND BIOLOGICAL WARFARE

- TMM - 2008

- “Blue Book” (6th ed., Apr 05)- JAMA, 6 Aug 97

• CD ROM

41

Biodefense Resources

Biosafety in Microbiological and Biomedical Laboratories[HHS P bli ti N (CDC) 5th d F b 2007][HHS Publication No.(CDC) - 5th ed., Feb 2007]

Control of Communicable Diseases Manual[American Public Health Association - 18th ed., 2005]

L b t Bi f t M lLaboratory Biosafety Manual[World Health Organization – 3rd ed., 2004]

Biological Safety PRINCIPLES AND PRACTICES[ASM Press 4th ed 2006][ASM Press – 4th ed., 2006]

Biosafety REFERENCE MANUAL[AIHA Publications – 2nd ed., 1995]

42

““BiosafetyBiosafety””, Post, Post--9/119/11

BiosafetyBiosafety

BiosecurityBiosecurity BiosureBiosureBackground ChecksFBI/DOJ ClearanceTwo person rule

tyty

Evolution of Protections for Research Animals, Biomedical Research and Health Care Personnel and Human Subjects

Animal Care and Use Biological Safety Protection of Human Subjects

1940-1959

1950 Animal Care Panel 1942 Fort Detrick BW program

1947 NIH Memorial Laborator

1955 First Biological Safety ConferenceConference

1960-1969

1963 Guide for Laboratory Animal Facilities and Care

1964 NCI Biohazard Safety Program

1960 The Nuremberg Codeg

1965 AAALAC 1966 Biohazard Symbol 1964 Declaration of Helsinki

1966 Animal Welfare Act (PL-89-544)

1969 CDC Classification of Etiological Agents on the

1966 NIH issues policies for the protection of human

Basis of Biohazard subjects; establishes IRBs

1969 Animal Care Panel became AALAS

Evolution of Protections for Research Animals, Biomedical Research and Health Care Personnel and Human Subjectsj

Animal Care and Use Biological Safety Protection of Human Subjects

1970-1979

1974 PRIM&R 1971 Nixon terminates US BW program

1974 National Reseach Act (PL 93-348) mandates IRBs and National Commission for the Protection of Human Subjects

1979 PHS Policy requires institutional committees to oversee animal research

1972 BW Convention 1978 Belmont Report

1975 Asilomar Conference on rDNA MoleculesrDNA Molecules

1976 NIH rDNA Guidelines creates IBC

1980-1989

1985 Amendments to the AWA mandates IACUC

1984 Biosafety in Microbiological and Biomedical Laboratories (BMBL)

1980 Institutional Review Board Guidebook

1985 Health Research 1984 rDNA gene transfer 1984 rDNA gene transfer Extension Act (PL 99-158) sets guidelines for animal care

guidelines guidelines

1989 Amended Declaration of Helsinki

Evolution of Protections for Research Animals, Biomedical Research and Health Care Personnel and Human Subjects

Animal Care and Use Biological Safety Protection of Human Subjects

Research and Health Care Personnel and Human Subjects

1990-2009

1992 IACUC Guidebook-ARENA and OPRR

1991 Bloodborne Pathogens Rule

1993 OHRP IRB Guidebook

1996 Guide for the Care and Use of Laboratory Animals 7th Edition

2002 Public Health Security and Bioterrorism Preparedness and Response Act (PL 107-188)

2009 OHPR Research Community Forums

1997 AAALAC I t ti l 2004 Fi k R t1997 AAALAC International 2004 Fink Report

2002 IACUC Guidebook, 2nd

Edition2006 NSABB

2009 BMBL 5th Edition2009 BMBL 5 Edition

Acknowledgements

• Emmett Barkley, Ph.D.• Robert Hawley, Ph.D., C.B.S.P., R.B.P.

• David R. Franz, DVM, Ph.D.• George W Christopher M D• George W. Christopher, M.D.• Edward M. Eitzen, Jr., M.D.• Ted Cieslak, M.D. U.S. Army Medical Research Institute

• Rob Darling, M.D. • John W. Huggins, Ph.D.• John W. Ezzell, Ph.D.

of Infectious Diseases

John W. Ezzell, Ph.D.• Jerry Jaax, DVM, Ph.D.• Art Anderson, M.D.

Ri h d Di t

47

• Richard Dinterman• Joe Kozlovac