Biowarfare to Biodefense: Operation Whitecoat

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Biowarfare to BiodefenseOperation Whitecoat
USAMRIID History

• Arthur O. Anderson MD
• Office of Human Use and Ethics

CD-22 Exp 25 Jan 1955, USAMU Est 20 Jun 1956,
USAMRIID Est 27 Jan 1969
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U.S. Was Unprepared For BW

• U.S. Concerned About The Possibility That The
  Nazis Were Preparing For BioWarfare As Entry into
  WW II Approaches

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Detrick Field Was An Air National Guard Training
Center
It Became A Bio- Warfare Center as Camp Detrick
April 1943
1931
Scientific Director, Dr. Ira Baldwin, U.Wisc
planned operations 1942-44 LTC William S. Bacon,
CMLC was first Commander of Camp Detrick
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Biosafety invented at Camp Detrick before
bioweapons developed
A.G. Wedum MD - Safety S Division - first
division to be activated in 1943
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Fort Detrick - Fully Engaged
Equipment needed was invented on site by a
brilliant design and fabrication team
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1943-46 Human Experimentation Camp Detrick -
Safety Practices

• Occupational Safety by S Division
• Training Program, Posters, Constant Survey of
  Safety Practices
• Personnel Inspection and First Aid
• In the First Aid room near hot suite change
  rooms, nurses inspected workers leaving hot
  suites for breaks in skin or clinical signs of
  disease as they prepared to shower out.

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1943-46 Human Experimentation Camp Detrick -
Safety Practices

• Immunization
• Vaccination routine called special procedures
  instituted by Biological Protection Branch of S
  Division
• Primary Objective was to protect workers
• Secondary Objectives
• Determine most efficacious immunization methods
• Determine effectiveness of available preparations
• No existing vaccines for some agents
• Only experimental vaccines available for others
• Ltr (S), CO CD to Post Surgeon CD, 22 Jan 44,
  Sub Immunization. SPCYF 400.12. In Hq CD (720.3)
• Sp Rpt 15, Immunological Protection of
  Personnel Against B.W. Agents (Oct 46), p.2

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Special Procedures - SIP
Most 1950s Fort Detrick alumni remember Nurse
Betty Grable, Dr. Paul Kadull the shot shop,
which is what they called the building where all
workers and research subjects received their
vaccines prescribed by Special Procedures.
Both groups got the same IND vaccines but only
the research volunteers were given the choice
with informed consent
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Human Subjects Research at Fort Detrick 1943 -
1946
The station hospital, originally activated in
1943, provided a unique opportunity to study the
inception, course and therapeutics of many rare
diseases in patients whose baseline health data
was known LTC Abram Benenson MC This was
primarily opportunist research that depended
upon occupational incidents among workers in the
various biowarfare facilities
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Nuremberg Trial - 1947

• The Nuremberg war crimes trials convicted 23 Nazi
  doctors for murder
• Mengele (left) escaped
• By 1946 Andrew Ivy released his list of ten
  conditions required for permissible medical
  experiments in healthy subjects which became the
  Nuremberg Code

Liberation of Auschwitz 27 Jan 1945
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Human Vulnerability to BW Aerosols Not Previously
Tested

• In 1952, the Armed Forces Medical Policy Council
  wanted information on human vulnerability and
  countermeasures to biological warfare
• Army SG met with Chief Chemical Officer at the
  same time that Secretaries of Defense Army,
  Army Chief of Staff and Chemical and Medical
  elements were meeting to discuss possible use of
  humans in biowarfare defense research.

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Wilson Memorandum of 1953
The Nuremberg Code principles were incorporated
into the Wilson Memorandum to the Secretaries of
the Army, Navy and Air Force 26 Feb 1953 Use of
these principles for non-clinical research
related to warfare defense was promoted before
experiments were planned and funded Army
Directive CS-385 issued 30 June 1953 added
consent in writing and additional safeguards
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Human Vulnerability to BW Aerosols

• Between April 1953 and 25 January 1955, an ad hoc
  committee that included civilian military
  advisory groups planned a research program aimed
  at responding to the AFMPC requirements of 1952.
• Human Volunteer Studies, CD-22 and Operation
  Whitecoat, were planned along with design and
  construction of the USAMU (later renamed
  USAMRIID).

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Objectives of Multifaceted CD-22 were designed
to determine

• Human vulnerability in realistic BW scenarios.
• Effective prevention and treatment of BW
  casualties.
• Determination of minimal infective doses.
• Effectiveness of vaccines and drugs.
• Serological responses to infections, and.
• Clinical effects of various doses of infectious
  agents.

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The CD-22 program focused on Human responses to
prototypes

• Q fever and Tularemia were regarded by CES of
  AFEB as acceptable prototypical BW agents for
  testing in Humans that satisfied limiting
  characteristics of low lethality, no serious
  chronicity anticipated, effective therapy
  available and there was adequate animal
  experimental data on safety and protective
  efficacy also described in cs-385.

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The US Army Medical Unit at Fort Detrick
USAMU was created to develop the means to
diagnose, treat and prevent diseases caused by
biological warfare agents. Approval of the
cs-385 directive for ethical operation, plans for
organization of the institute, preparation of
protocols and initiation of the first human
studies took place within 3-6 months of its
creation.
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USAMU - USAMRIID
The station hospital was built in 1957. It was
linked via walkways to support laboratories (vir,
bact, clin lab, etc) and USAMU. The 8-ball is at
upper left and the BL-4 suite called black
moriah is at upper right.
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COL W.D. Tigertt USAMU

• October 1954 Colonel Tigertt contacted Dr.
  Theodore R. Flaiz of Seventh Day Adventist
  General Conference about seeking 1A-O SDA
  volunteer subjects.
• General Conference of the SDA Church approved
  recruitment of drafted SDA volunteer subjects
  into Operation Whitecoat program

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Operation Whitecoat Volunteers were SDA
Conscientious Objectors recruited from Medic
Training school at Fort Sam Houston
Operation Whitecoat Volunteers at Forest Glenn
Ballroom 1956
Between 1954 and 1973 2,300 Seventh Day Adventist
participants of Operation Whitecoat served at
Fort Detrick and associated locations.
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Protocol Review during Operation Whitecoat

• The Medical investigator prepared protocol.
• Reviewed for approval at a Protocol Meeting
  attended by Commander, Scientific Advisor, and
  the Research Division Chiefs.
• Approved protocols were forwarded to HQDA
  (SGRD-DR) for further approval by CES of AFEB
  (before 1962) or HSRRB (after 1962 ).
• After final approval, Whitecoat volunteers were
  briefed, attended a project interview, and
  informed consent documents were signed only after
  at least 24 hours.
• AR 70-25 published in 1962 was identical to
  cs-385.

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Review and Approval ProcessUSAMU 1955-73 vs
USAMRIID

• 1955 73 USAMU Protocol Meeting Minutes were one
  page long with only one sentence for the
  committee decision. Issues were not documented.
• 1976 USAMRIID IRB Minutes 5 pages long, 4 of
  which were QA that documented issues.
• Presently USAMRIID IRB Minutes are gt 14 pages
  long with 2 pages of narrative summary, 2.5 pages
  of QA per protocol with decision plus 9 pages of
  expedite approval ratifications, continuing
  review and SAE discussion.

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Protocol Briefing
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Operation Whitecoat served as a model of the
ethical use of human subjects in research. The
three step process of informed consent - by which
research subjects become familiar with the
purpose of a study in order to understand the
risks and potential benefits involved before
agreeing to participate - was successfully
implemented from the programs inception. The
soldiers were not required to participate in any
of the studies, only to be present for briefings
by principal investigators seeking volunteers.
Two more steps occurred before subjects were
asked to consent. About 20 percent of the men
did not participate in any studies during their
tenure at Fort Detrick.
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Vaccines that were tested under approved clinical
protocols included those for Q fever, Tularemia,
Yellow Fever, Eastern Western and Venezuelan
equine encephalitis (EEE, WEE VEE), Hepatitis,
Plague and Rift Valley fever,.
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Aerosol Efficacy Studies in 8 Ball
Q-fever and Tularemia were approved for these
studies because safety criteria were met and cure
was assured.
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Volunteer from the Aerosol Q-fever Study at
Dugway Proving Grounds
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Experimental Risks Minimized by Availability of
Effective Treatment
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In addition to the advances made in vaccine and
drug development, Operation Whitecoat volunteers
contributed to a better understanding of the
signs, symptoms, and clinical diagnostic
parameters in human disease associated with
Q-fever, Tularemia, Sandfly fever, and
staphylococcal enterotoxins.
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Ethical AccomplishmentsOperation Whitecoat

• Effectively Used Nuremberg Code Principles
• Created Effective Informed Consent Process
• Involved Community of the SDA Volunteers
• Local and Extramural Oversight / Monitoring

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Biosafety and Engineering Accomplishments

• Containment Glove Boxes, Laminar flow Hoods,
  Biohazard suit with air supply
• Ambient Air Pressure Controls - Positive Staff
  Areas, Negative Laboratories and Filtered or
  incinerated exhaust
• Education of workers on Safety
• Biosurety procedures, Vaccines, Occupational
  Follow-up
• Laminar flow / light scatter technology, that was
  developed aerosol for particle sizing became the
  basis of the Fluorescence Activated Cell Sorter
  other flow cytometry systems in use today

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Medical AccomplishmentsOperation Whitecoat

• Licensed vaccines were developed, including
  yellow fever, hepatitis, and plague.
• Investigational New Drug (IND) vaccines were
  developed, including those for Venezuelan equine
  encephalitis (VEE), Rift Valley fever, Q fever,
  and tularemia.
• Effective systems for biological hazard
  containment were developed
• Rift Valley Fever Virus vaccine used in 1977
  outbreak in Egypt, effected 200,000 humans (2,000
  deaths) and entire sheep population.

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RVF Vaccine caused Peace to break out in the
middle east

• Therefore, a little known benefit that Operation
  Whitecoat Volunteers provided was to enable peace
  between Egypt and Israel to break out because
  obtaining RVF Vaccine was an important bargaining
  chip to both parties.

• Emissaries from Egypt and Israel requested RVFV
  as Sadat Begin met at Camp David.

N Meyers - Nature 1986 Jan 9 v319(6049) p91
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Research Programs Influenced by News Events and
World Affairs

• Cold War imperatives continued into the 1980s
  and we saw growth in Virology Research under Dr.
  Jerry Eddy with COL Huxsoll as commander.
• The Anthrax outbreak in Sverdlovsk,
  (Ekaterinburg) re-started Anthrax Research here.
• Yellow Rain in Cambodia and Laos signaled the
  need to increase focus on Toxins and Toxinology
  was created from Physical Sciences Division.
• And Aum Shinrikyo warned that Bioterrorism was on
  the horizon just as the Evil Empire was
  crumbling. This prompted expansion of the means
  for Rapid Diagnosis just as PCR miniaturization
  was developing along with other dx technologies.

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Bioterrorism Changing Priorities

• Bioterrorism in the US was no longer theoretical
  after 2001
• DHS, was created for domestic security and
  countermeasures
• RD for Biodefense medical countermeasures under
  DHHS
• Present Bioterrorism response resembles US
  response to threat of BioWarfare during World War
  II

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Moral Dilemma Comply with FDA law vs
Intent to Benefit in BW Emergency

• 1962 Amendments to the FDC Act required proof of
  efficacy of drugs and vaccines for BW created a
  moral dilemma.
• Risk killing subjects in a valid clinical trial,
  versus
• withholding potentially life saving drugs or
  vaccines because they lacked substantial evidence
  of human clinical efficacy.

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Project BioShield

• CDC, HHS DoD may use HHS Project BioShield as
  specified in the following legislation
• Passed H.R. 2122 Project Bioshield Act - July
  16 2003
• Passed S. 15 Project BioShield Act - May 19
  2004
• President Signed Public Law No 108-276 July 21
  2004
• Presented H.R. 4258 Rapid Pathogen
  Identification to Delivery of Cures Act - May 3,
  2004
• These legislative Acts resolve a dilemma and the
  dichotomy that is associated with the need for
  widespread use of FDA-unapproved products in
  civilians for national biodefense or in soldiers
  facing war hazards when it is unethical to do FDA
  mandated human clinical efficacy studies.
• Re-Capitalization of USAMRIID and creation of a
  Business Model became linked intrinsically
  because of increasing diversity of our funding
  sources

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USAMU - USAMRIID Evolution

• Over the past 50 years since the start of
  Operation Whitecoat, the U.S. Army Medical
  Research Institute of Infectious Diseases has
  grown considerably from what it was as the U.S.
  Army Medical Unit, yet It continues to conduct
  basic and applied research on biological threats
  resulting in medical solutions to protect
  military service members.
• The present building was planned by COL Dan
  Crozier, and is named in his honor.

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COL Arthur O. Anderson MCChief, Human Use and
EthicsUS Army Medical Research Institute of
Infectious Diseases Arthur.Anderson2_at_amedd.army.m
il