Biowarfare to Biodefense: Operation 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

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

LTC William S. Bacon, CMLC was first Commander of Camp Detrick Detrick Field Was An Air National Guard Training Center It Became A Bio- Warfare Center as Camp Detrick 1931 April 1943 Scientific Director, Dr. Ira Baldwin, [U.Wisc] planned operations 1942-44 LTC William S. Bacon, CMLC was first Commander of Camp Detrick

Biosafety invented at Camp Detrick before bioweapons developed A.G. Wedum MD - Safety “S” Division - first division to be activated in 1943

Fort Detrick - Fully Engaged These notes are copied from TMM “History of the US Offensive Biological Warfare Program”: 1953: Fort Detrick receives a major laboratory and facility upgrade to support the expanded biological weapons research and development efforts. 1954: In order to continue the expanding research by the Army in infectious diseases and develop vaccines, an ad hoc committee was formed by the Army Medical Corps to investigate biological warfare defense to consider the following objectives that needed to be addressed: 1. vulnerability of the human being to biological agents, 2. prevention of and treatment of biological warfare casualties, 3. determination of minimum effective dose, 4. effectiveness of prophylactic and therapeutic measures, 5. serologic responses to infections, 6. effects of various doses of inoculum. The infectious agent causing Q fever, Coxiella burnetti, was selected by the ad hoc committee as the organism that would serve as the "prototypical" agent for studying biological warfare defense in human volunteer subjects. The proposed project was examined exceedingly carefully with regard to legal, ethical and moral issues. Archived documents indicated that these military and civilian scientists carefully considered the elements of the Nuremberg Code in selection of test agents and in designing experiments so as to comply with its principles. 1955: The Army's Operation CD-22 (also referred to as Operation Whitecoat) seeks to determine the extent to which humans are susceptible to infection from aerosol dispersal of a biological weapons agent. The test does not use simulants, but rather the actual pathogen that causes Q fever, Coxiella burnetti. Initial experiments involve guinea pigs and monkeys, although humans are later incorporated. January 1955: Fort Detrick's vaccine research program expands with contract work at Ohio State University. 1956: As part of the effort to expand the biological weapons program's defensive component, the US Army Medical Unit begins operations under the control of the Army Surgeon General. The unit then takes over the management Project Whitecoat. May 1958: The Joint Chiefs of Staff concludes that budget constraints are limiting the pace of progress in US offensive biological and chemical warfare programs. December 1958: The Defense Science Board sponsors a biological and chemical warfare symposium at the Rand Corporation to examine the military and political impact of biological warfare. The final report recommends the increase of overall chemical and biological weapons research, the development of use doctrines for both categories of weapons, and an attempt to garner greater public support for both programs. Equipment needed was invented on site by a brilliant design and fabrication team

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.

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

Special Procedures - SIP Most 1950’s 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

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

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

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. From a Letter to Chief Surgeon AFFB from commandant AMEDD Center and School dated 9 September 1954: Matter concerns Biological Warfare. The Joint Chiefs of Staff still do not know whether BW is an effective weapons system against man. They have issued a directive to the Weapons Evaluation Group to come up with and answer in FY 1955 and have informed DA that the whole BW program will be evaluated next July. It has been agreed for several years that no authoritative answer is possible without direct human experimentation, but the first such experiment has yet to be undertaken. The Chemical Corps has appealed to the Surgeon General to help them plan and conduct human volunteer evaluations of BW. General Armstrong has agreed to do what he can in the short time available and has asked us at the School to “carry the ball”. I have induced the Armed Forces Epidemiological Board to assist us and they have organized a joint medical team, distributed between here and Camp Detrick, with all being available for field trials at Dugway Proving Ground, Utah. A Steering Committee, consisting of a senior medical officer and a senior civilian medical scientist, each from Camp Detrick and the School, do the planning, run the tests, and evaluate the results. We hope to find the bulk of our volunteer subjects among the Seventh Day Adventists, but we are still awaiting clearance to approach the church officials and the potential volunteers. An authorization and SOP to use volunteer human subjects has already been issued by the Secretary of Defense. The medical officers have been selected with great care, because of factors of safety for the human subjects, risks to the community where trials are held, possibility of bad publicity if the work is not expertly handled, the requirements for a high degree of skills on the parts of all concerned, and the short time to obtain results. The senior epidemiologist of the team, is a key figure in all the planning and conduct of the trials. He must assure subject safety and community safety, and deal with the national, state and local health authorities, including wildlife conservation authorities. The tremendous economic importance of this evaluation, and the tactical and strategic importance to the Armed Forces in the development of plans, is obvious. From AFEB History: Early in 1954, Major General George E. Armstrong, The Surgeon General, U.S. Army, reversed a long-standing policy of the Army Medical Service and agreed, in principle, to a joint Army Medical Service-Chemical Corps study of the problems inherent in biological warfare. Brigadier General John E. Wood, Commandant, Army Medical Service Graduate School, Washington, DC, served as The Surgeon General's representative in the negotiations that followed and continued to serve under Major General Silas B. Hayes, who replaced General Armstrong. Shortly afterward, General Wood requested that the AFEB review this proposal and make recommendations to The Surgeon General. A special meeting of the AFEB was convened in the summer of 1954 to approve the project.

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

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).

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.

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]. Project CD-22 The first research program involving the newly activated CES was entitled CD-22. This project involved a study of Q fever in animals and humans in the laboratory and the field. Q fever is a mild to severe febrile disease resulting from infection with Rickettsia burnetii. Q fever responds rapidly to treatment with broad-spectrum antibiotics (eg, chloramphenicol, tetracycline), particularly when treatment is instituted early after the onset of symptoms. The prognosis for complete recovery from an infection with this organism is excellent. The first requirement for the initiation of the project was the preparation of an adequate amount of egg slurry infected with R. burnetii to be used in both the animal and human studies. This material was prepared by the Army Biological Laboratories, Camp Detrick; and it was characterized and safety tested by both the Biological Laboratories and the Walter Reed Medical Unit. Some difficulty was encountered in meeting purity standards for the infected slurry, and the first lots were considered of insufficient purity to be administered to humans. However, after considerable discussion and some recrimination, it was agreed in November 1954 that an entirely new lot would be prepared. By January 1955, a large amount of infected egg slurry was prepared that was determined to be of sufficient purity for exposure of volunteers. Beginning in January 1955, phase I of the project was initiated. Phase I consisted of a series of studies to determine the infective dose of this material in laboratory animals when administered by the aerosol route. After a careful evaluation of the results of these studies, the CES recommended to The Surgeon General and the Chief Chemical Officer that the project enter phase II, the exposure of human subjects. The first Whitecoat volunteers were exposed on 25 January 1955 with the use of the 1 million-liter sphere (commonly known as the "eight ball") at Fort Detrick. This research device (operated by the Army Biological Labs) was designed to allow simultaneous exposure of humans and laboratory animals to carefully controlled numbers of organisms by the aerosol route. Laboratory animals were exposed and aerosol impinger samples were taken at the time of human exposure. Over the next 2 months, the optimum dosage to be employed in field trials in humans was determined, as was the effectiveness of a Q fever vaccine in protecting humans when exposed under laboratory conditions. After completion of this phase of the study, preparation for phases III and IV was initiated; phase III was planned as a field study of exposure of animals, and phase IV was the exposure of humans to a typical biological warfare aerosol under field conditions. These studies were to be conducted at Dugway Proving Grounds, Utah. Beginning in March 1955, trials were conducted to examine the field dosage levels at various downwind distances of infected material from a line source disseminated by aerosol generators; the objective was to determine the sampling and exposure distance to be used in phase IV.

The US Army Medical Unit at Fort Detrick The US Army Medical Unit (USAMU) was created between 1953 and 1956 to develop the means to diagnose, treat and prevent diseases caused by biological warfare agents. From AFEB TMM: Senior officers of the Army Medical Service recognized the significant contributions that research in biological warfare could contribute to the development of knowledge regarding the pathogenesis, diagnosis, prevention, and treatment of infectious diseases not generally encountered in the United States. Potential biological agents could present serious problems, if military forces were required to operate in global areas where such diseases were naturally prevalent. With this expanded interest, plans were initiated to establish an independent self-supporting unit at Fort Detrick to replace the Walter Reed Unit. On 20 June 1956, the U.S. Army Medical Unit (USAMU), Fort Detrick (08-9901.07) was activated under the command of Colonel Tigertt. This unit was directed to function jointly with the Division of Special Operations of the WRAIR. Funds were provided to the Medical Service by the Chief Chemical Officer. Necessary laboratory office and support facilities occupied at the time by Biological Laboratory personnel were to be vacated, renovated, and assigned to the new medical unit. In addition, another laboratory building located at the Forest Glen Annex just outside of Washington was to be made avail able to the medical unit by WRAIR. This latter facility was designed for studies requiring special equipment for handling highly infectious microorganisms. Unfortunately, the occupants of those facilities were slow to vacate the premises and renovations were delayed. Some buildings specified for medical unit use were not available until late in 1957 and others not until 1958. Colonel Tigertt likened the year as "reminiscent of time spent in a wartime staging area." Gradually, as professional, administrative, technical, and support personnel were assigned, a number of new projects were initiated despite a shortage of laboratory space. In addition to the space assigned to the medical unit at Fort Detrick, laboratory space was made available for the use of USAMU personnel, on a temporary basis, by the Army Biological Laboratories, the Armed Forces Institute of Pathology in Washington, WRAIR, and Dugway Proving Grounds. The medical treatment facility operated by USAMU consisted of two wards, each capable of handling about 20 patients. One of these was for the care of minor illnesses and injuries in Fort Detrick military personnel and their dependents, and the other was for the care of occupational infectious illnesses occurring in biological laboratory and medical unit personnel and for the housing of Whitecoat personnel participating in volunteer studies. A fully equipped diagnostic laboratory was available. This facility operated throughout 1957 despite limited equipment. It had no operating room at that time, and all patients requiring surgery were transferred either to Walter Reed General Hospital, Washington, DC, or to Frederick Memorial Hospital, Frederick, Maryland. The hospital staff was headed by the chief of the medical service, USAMU, who had the immediate assistance of the entire USAMU professional staff. The staff also included four nurses and a cadre of trained medical corpsmen. On 1 August 1957, the treatment facility was designated Ward 200 of Walter Reed General Hospital. During the latter half of 1957 and early 1958, a complete operating room, a central supply room, and updated diagnostic radiographic equipment were added. Arrangements were in effect with Walter Reed General Hospital to supply a complete surgical team and necessary special equipment when required. 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.

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.

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 From AFEB TMM: In October 1954,1 month after approval of the joint Surgeon General-Chief Chemical Officer, biological warfare research program, Colonel Tigertt contacted Dr. Theodore R. Flaiz, Secretary of the Medical Department, General Conference of the Seventh-Day Adventist Church, to ascertain the views of that church organization as related to the use of volunteers in medical research. Later that month, a committee of the Seventh-Day Adventist Church met with Colonel Tigertt. He presented a thorough review of the proposed use of volunteers in the studies of the defense against biological warfare. He explained how the program would be conducted, the safety control measures, the scientific supervision of military and civilian personnel to be employed, the potential dangers, and the benefits to be gained. After due consideration, The General Conference of the Seventh-Day Adventist Church approved the program and so informed General Hayes. In January 1955, the Secretary of the Army approved a program for "the conduct of research investigations utilizing volunteers in defense against biological warfare." Thus was born what proved to be one of the largest and most successful military medical volunteer research programs in the history of the Army. This program, known as Project Whitecoat, involved approximately 2,000 young Seventh-Day Adventist soldiers and was in continuous operation from 1955 until the military draft was discontinued in 1973

Operation Whitecoat Volunteers were SDA “Conscientious Objectors” recruited from Medic Training school at Fort Sam Houston From History Channel transcript: These Seventh Day Adventist research volunteers took a leap beyond where any human being had ever gone before. Testing man’s limits against the vision of science, these courageous individuals faced the danger of the dark unknown. These pioneers were the first to prove man could survive biological warfare. Taking the risk was only the beginning, surviving the test was the key to the personal heroism of Operation Whitecoat Volunteers who served as Human Guinea Pigs in tests of human vulnerability to biological warfare and the feasibility of using medical countermeasures to mitigate it. Dr. Jonathan Moreno Any new endeavor in medical science, whether it’s a drug, to be tested, a device to used, or space, in which we’re going to be projecting humanity. Anytime we’re going to do something new with the human body, there’s going to be a first time. Someone will have to be first. It takes a unique individual to volunteer to take part in an experiment. Some Go first for altruistic reasons, testing some new device or drug that could benefit mankind. Some volunteers have contracted an illness and hope that trying a cutting edge drug or new therapy in a clinical trial may cure them. Experimentation has always been about testing the limits of what man thinks is possible… all within the confines of the scientific model. But early research on humans did not often adhere to the standard rigors of scientific investigation. 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.

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.

Review and Approval Process USAMU 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 Q&A that documented issues. Presently – USAMRIID IRB Minutes are > 14 pages long with 2 pages of narrative summary, 2.5 pages of Q&A per protocol with decision plus 9 pages of expedite approval ratifications, continuing review and SAE discussion.

Protocol Briefing A medical investigator prepared a protocol that was reviewed for approval at a “Protocol Meeting” attended by the Commander, Scientific Advisor, and Research Division Chiefs. Often there was a second review by CES of AFEB or HSRRB (after 1972). The approved protocol was forwarded to HQDA (SGRD-DR) for further review and final approval. Potential volunteer subjects were: briefed on the approved protocol (shown above), attended a project interview, and signed informed consent documents after an obligatory wait of at least 24 hours to 4 weeks depending on the presumed risk of the study. By allowing sufficient time and opportunity for the risks, conduct and potential benefits of the study to be understood, this three-stage informed consent process assured that participation was truly voluntary.

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 program’s 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.

Several vaccines were developed as a result of Operation Whitecoat Several vaccines were developed as a result of Operation Whitecoat. Many of those vaccines are used today by industry and laboratory workers, including USAMRIID personnel who receive special immunizations to work in Biosafety Level 3 containment laboratories. Licensed vaccines (approved by the Food and Drug Administration) include those for Yellow Fever, Hepatitis, and Plague. Investigational New Drug (IND) vaccines, used under approved clinical protocols for research immunization of laboratory personnel, include those for Venezuelan equine encephalitis (VEE), Rift Valley fever, Q fever, and Tularemia. 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,.

Aerosol Efficacy Studies in 8 Ball Project CD-22 From AFEB TMM: The first research program CD-22. This project involved a study of Q fever in animals and humans in the laboratory and the field. Q fever is a mild to severe febrile disease resulting from infection with Rickettsia burnetii. Q fever responds rapidly to treatment with broad-spectrum antibiotics (eg, chloramphenicol, tetracycline), particularly when treatment is instituted early after the onset of symptoms. The prognosis for complete recovery from an infection with this organism is excellent. The first requirement for the initiation of the project was the preparation of an adequate amount of egg slurry infected with R. burnetii to be used in both the animal and human studies. This material was prepared by the Army Biological Laboratories, Camp Detrick; and it was characterized and safety tested by both the Biological Laboratories and the Walter Reed Medical Unit. The initial lot was not of sufficient purity but by January 1955, a large amount of infected egg slurry was prepared that was determined to be of sufficient purity for exposure of volunteers. Beginning in January 1955, phase I of the project was initiated. Phase I consisted of a series of studies to determine the infective dose of this material in laboratory animals when administered by the aerosol route. After a careful evaluation of the results of these studies, the CES recommended to The Surgeon General and the Chief Chemical Officer that the project enter phase II, the exposure of human subjects. The first Whitecoat volunteers were exposed on 25 January 1955 with the use of the 1 million-liter sphere (commonly known as the "eight ball") at Fort Detrick. This research device (operated by the Army Biological Laboratories) was designed to allow simultaneous exposure of humans and laboratory animals to carefully controlled numbers of organisms by the aerosol route. Laboratory animals were exposed and aerosol impinger samples were taken at the time of human exposure. Over the next 2 months, the optimum dosage to be employed in field trials in humans was determined, as was the effectiveness of a Q fever vaccine in protecting humans when exposed under laboratory conditions. After completion of this phase of the study, preparation for phases III and IV was initiated; phase III was planned as a field study of exposure of animals, and phase IV was the exposure of humans to a typical biological warfare aerosol under field conditions. These studies were to be conducted at Dugway Proving Grounds, Utah. Beginning in March 1955, trials were conducted to examine the field dosage levels at various downwind distances of infected material from a line source disseminated by aerosol generators; the objective was to determine the sampling and exposure distance to be used in phase IV. Phase IV of this project consisted of one trial in which actual field exposure of human subjects, guinea pigs, and monkeys was conducted; additional sampling with millipore filters and impingers was accomplished. This study used 30 Whitecoat volunteers in groups of 3 (1 immunized and 2 nonimmunized) at 10 different stations. In addition, 75 rhesus monkeys and 300 guinea pigs were exposed to the aerosol. The volunteers were located 3,200 feet downwind from the aerosol generators. This final study was conducted just before dawn on 13 July 1955 under direct supervision of the Walter Reed Unit with members of the CES present. Generation of the infected aerosol and collection of samples for laboratory studies was under the direction of personnel from the Army Biological Laboratories and Dugway Proving Grounds. Q-fever and Tularemia were approved for these studies because safety criteria were met and cure was assured.

Volunteer from the Aerosol Q-fever Study at Dugway Proving Grounds Video is of Merlin Neff speaking about his experience in the CD-22 Q-fever aerosol study at Dugway Proving Grounds was is excerpted from the ABC News WNT spot aired on 21 December 2001

Experimental Risks Minimized by Availability of Effective Treatment Video is of Dr. Peter Bartelloni (former USAMU Physician Scientist) speaking about safety precautions in his Q-fever or Tularemia studies with Operation Whitecoat volunteers. From ABC News WNT 21 December 2001.

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.

Ethical Accomplishments: Operation Whitecoat Effectively Used Nuremberg Code Principles Created Effective Informed Consent Process Involved “Community” of the SDA Volunteers Local and Extramural Oversight / Monitoring

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

Medical Accomplishments: Operation 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.

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. A major, but little known, benefit of Project Whitecoat: A major benefit of Project Whitecoat of peace in the middle east which may not have been possible had the studies not occurred. In 1968 and 1969 many Operation Whitecoat volunteers participated in the development of Rift Valley Fever Virus vaccine. There were several RVF Vaccine studies among the list of Operation Whitecoat research protocols, and a few of the lots of this vaccine had been tested for human safety and immunogenicity in Whitecoat volunteers. This vaccine, NDBR 103 RVFV, was used routinely to immunize all at risk personnel who worked with Rift Valley Fever Viruses in research laboratories at USAMRIID, the CDC and the Plum Island Animal Disease Laboratory. Rift Valley Fever is a viral disease that "emerged" in the middle 60's in the Rift Valley in Africa. Rift valley fever virus is a Bunyavirus and is spread by mosquitoes. It is economically significant in that it infects sheep and cattle primarily, but man is also susceptible. It usually kills animals within 6 days of liver necrosis. This virus also attacks the brain and has effects on blood coagulation so survivors of the liver disease may also have encephalitis or hemorrhagic disease. Mortality in man is less than 1% but approaches 80% in sheep and goats, the principal meet animals in the middle east. Whitecoat volunteers participated in human safety and immunogenicity testing. In 1977 there was a major outbreak of Rift Valley fever in Egypt. Some people say that up to 200,000 human cases of Rift Valley Fever occurred in a 3 week period of time, and virtually all the sheep had become ill or died. Because of the size and scope of this epidemic some people initially speculated that this was a result of biological warfare. The Israelis were concerned about spread to their country. The virus never appeared above the Sahara desert until 1977. The net result was that both countries found that the only RVFV vaccine that had been tested for safety in humans under an IND from the FDA was our vaccine. The vaccine developed in South Africa was a veterinary vaccine that had never been tested for safety in humans. The vaccine that Whitecoats participated in testing was currently being used at USAMRIID and CDC laboratories to protect at-risk personnel, but there were additional lots under this IND that had not been safety tested in human subjects. As the Human Use Committee Chairman in 1977, I personally convened meetings to review protocols for the testing of individual lots of this vaccine. Even as our IRB was meeting, emissaries from Eqypt and Israel came to USAMRIID requesting our vaccine as Anwar Sadat and Menachim Begin were meeting at Camp David with President Jimmy Carter. Therefore, a little known benefit you provided by participating in that 1968 study was the development of a vaccine that caused peace to “break out” between Egypt and Israel. This helped Jimmy Carter to broker a peace accord because he had the capacity to promise these countries our vaccine in addition to other forms of assistance. A sustainable outcome of this accord was continued international scientific and medical cooperation between Egypt and Israel. We also provided vaccine for the UN peace keeping force in the Sinai. From Art Anderson’s speech for the 1998 Operation Whitecoat Reunion at the Frederick SDA church. Emissaries from Egypt and Israel requested RVFV as Sadat & Begin met at Camp David. N Meyers - Nature 1986 Jan 9; v319(6049): p91

Research Programs Influenced by News Events and World Affairs “Cold War” imperatives continued into the 1980’s 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.

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

Moral Dilemma: Comply with FDA law vs Intent to Benefit in BW Emergency 1962 Amendments to the FD&C 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.

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

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.

COL Arthur O. Anderson MC Chief, Human Use and Ethics US Army Medical Research Institute of Infectious Diseases Arthur.Anderson2@amedd.army.mil