The Histories of the Commissions - Contents
Commission on Epidemiological Survey
Foreword
The Commission on Epidemiological Survey (CES) was conceived as part of the mission of the original Armed Forces Epidemiological Board (AFEB). Various infectious diseases were considered as threats to any military force. Toward this end, the United States and adjacent countries were divided into sections to evaluate any threat and define the epidemiological significance of various entities within a geographic unit.
For example, coccidioidomycosis seemed to be localized primarily in the western desert areas of the United States. It came under serious consideration and evaluation by Dr. Charles Smith who gave wise advice based on surveillance studies regarding the need to remain alert.
The CES was formulated in 1954 when it became apparent that the threat of use of biological agents as weapons (biological warfare) was a reality and merited constant vigilance involving new studies of pathogenesis and development of effective means of early detection and control. Defense was the key issue and on this basis the new CES became an integral part of the AFEB. The CES was given oversight responsibility for the newly developed Biological Warfare program at Fort Detrick in Frederick, Maryland. The U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) unit was a later development at Frederick, with which the CES maintained a close and effective relationship.
Dr. Richard Shope was the first CES Director. He was succeeded by Dr. Theodore E. Woodward. Colonel William Tigertt, MC, Colonel Abram S. Benenson, MC, and Colonel Dan Crozier, MC, were the group of responsible military professionals who, with their capable staff and CES members and the full backing of Walter Reed Army Institute of Research (WRAIR), developed a program that placed our country in an effective and ready posture.
I am grateful to Dr. Crozier for preparing this factual and interpretive history of the CES. It is a fitting tribute to our nation`s foresight to accurately predict the rapidly changing future and, at the same time, discharge our responsibilities in an open and forthright manner.
- Theodore E. Woodward, M.D.
History of the Commission on Epidemiological Survey
Dan Crozier, M.D.
THE FIRST COMMISSION ON EPIDEMIOLOGICAL SURVEY (CES)-1941 TO1945
The Commission on Epidemiological Survey (CES) was one of the eight commissions of the original Board for Investigation of Influenza and other Epidemic Diseases established by the Secretary of the Army in 1941. Its first director was Stanhope Bayne-Jones, M.D., originally of Yale University School of Medicine, New Haven, Connecticut. The first president of the Board was Francis G. Blake, M.D., distinguished Professor of Medicine at Yale. On 12 February1941, Dr. Blake corresponded with Dr. Bayne-Jones, informing him of the establishment of the Board and its commissions. Dr. Blake, as Board President, asked Dr. Bayne-Jones to accept the position of Director of the CES. He provided a brief summary of a proposed agenda for the CES and requested that Dr. Bayne-Jones develop a program for the four investigative teams that would function under the CES and provide a list of potential members. Dr. Bayne Jones immediately accepted the appointment and on 21 February transmitted a proposed list of personnel to Dr. Blake and expressed his thoughts regarding the investigative program of the CES. This comprehensive proposal is reproduced in its entirety below because it formed the basis of the CES`s program for the next3 years.
Dear Doctor Blake:
Since receipt of your letter of February 12, I have communicated by telephone and telegraph with the men recommended below as Directors of investigative teams in the designated areas. They are eligible and willing to serve and I understand that this is true also of the persons recommended by them for appointment. There are a few reservations to be considered and releases to be obtained. Therefore, in answer to your letter of the 12th, I submit the following recommendations concerning the initial personnel and outline of programs of the Commission on Epidemiological Survey.
I. Personnel:
1st Corps Area, HQ, Boston, Mass.
Professional staff: J. Howard Mueller, Director, John F. Enders, Emanuel B. Schoenbach.
Technicians: Vincent B. Shields, Pauline A. Miller, William McBrearty.
4th Corps Area, HQ (for Commission), Durham, N.C.
Professional staff: David T. Smith, Director, Wiley D. Forbus, D. F. Milan.
Technicians: Names of 3 to be submitted later.
9th Corps Area, HQ San Francisco, CA.
Professional staff: Edwin W. Schultz, Director, Edward B. Shaw, Charles E. Smith.
Technicians: Names of 3 to be submitted later.
Puerto Rico, Department of, H.Q. San Juan, Puerto Rico
J. Roderiquez Pastor, Manuel A. Perez, Amerigo Pomales Lebron.
Technicians: Names of 3 to be submitted later.
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II. Program: The purpose of the Commission on Epidemiological Survey is to assist in the control of epidemic infectious diseases in the Army by the accumulation of data concerning the prevalence of pathogenic organisms in the personnel of selected stations by repeated sampling over a considerable period. Surveys will be designed to acquire information on pre-epidemic and epidemic periods. The stations and camps at which surveys will be made will bein the 1st Corps area, 4th Corps area, 9th Corps area and the Department of Puerto Rico. The investigative teams will carry out work in laboratories of institutions at their headquarters and at available stationary and mobile laboratories at military stations to which the teams may be sent for temporary duty when deemed advisable by the Surgeon General. The headquarters laboratories will be:
1st Corps Area, Department of Bacteriology and Immunology, Harvard Medical School, Boston, MA.
4th Corps Area, Department of Bacteriology and Pathology, Duke University, School of Medicine, Durham, NC.
9th Corps Area, Department of Bacteriology and Experimental Pathology, Stanford University School of Medicine, Stanford University, CA.
School of Tropical Medicine, San Juan, Puerto Rico.
The most important military epidemics to be considered are:
a. Respiratory transmission group: Pneumonias, meningococcus.
meningitis, scarlet fever, influenza, diphtheria, colds, measles, mumps and chickenpox(?).
b. Enteric transmission group: Typhoid and paratyphoid fever, dysenteries, simple diarrheas and some types of infectious jaundice.
c. Insect transmission group: Rickettsial infections: Typhus, Rocky Mountain spotted fever; protozoal infections, malaria, chiefly; virus infections, yellow fever, chiefly.
As it is not possible to determine the prevalence of the pathogenic organisms and viruses causing a number of these diseases as each investigative team will be confronted with different problems in the separate areas, and as the teams will not be able to cover the whole field, portions of the study will be selected for concentrated investigation by each team or by combinations of the teams.
The investigative teams of this Commission will be primarily concerned with surveys of prevalence of pathogenic bacteria, but will also study the prevalence of other organisms in certain areas and under conditions to be defined as desirable. These surveys will be coordinated with other surveys, particularly in reference to the prevalence and types of viruses. Furthermore, in order to avoid the wasted efforts consequent upon wholesale bacteriological surveys, the work should be restricted to the amount which can be done accurately. Whenever possible, tests of susceptibilities will be included. The Directors of the teams will agree upon standard methods having as much uniformity as possible and upon uniform methods of keeping records. There must be also a uniform system of prompt reports.
Details of methods to be used, and other matters of technique and procedure have been considered during the past ten days but are not in order at present to be outlined in this report.
I should like to recommend that as soon as the regional Directors have been appointed, authorization be given for their meeting with me on temporary duty status at New Haven to consider plans and decide upon procedures.
It is not possible, at this time, to submit a list of laboratory equipment, supplies and animals that may be required. An estimate will be made after a meeting of the regional directors, but this will, of necessity, be subject to change from time to time.
Sincerely yours,
S. Bayne-Jones
sb-j:mh
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Everyone who knew Dr. Stanhope Bayne-Jones, known as B. J., respected him. B. J. accomplished almost everything: chairmanship of a department of bacteriology, dean, chancellor, writer, army general, epidemiologist, and administrator. He was a wise man with unflinching integrity. During World War 11, he served as Deputy Director of Preventive Medicine under General Simmons and Director of the USA Typhus Fever Commission. In addition to these responsibilities, he and General Simmons conceived that a board consisting of lay scientists could serve the U.S. Army effectively. This Board was the forerunner of the AFEB. B. J. served as the first administrator for the new Board and also as its president. During his life, he participated actively and effectively in all activities of the Board and its Commissions. A simple example provides insight into his personal qualities. During the heat of World War 11,B. J. once went after midnight to the Washington National Airport to receive special hyperimmune pertussis serum for an infant son of a junior officer. When most would have sent an aide, B. J. went.
The most outstanding tribute to B. J. is his productive life and his insistence that a professional person should accept responsibility for any role of benefit to society and to complete the assignment. B. J. was a coordinator of research, a "Godfather," who understood so well the need to maintain and record a sequential record of important events.
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At a meeting of the AFEB in the office of The Surgeon General in Washington on 27 February 1941, the proposed investigative program of the CES was approved essentially as presented. On 18 March 1941, after consulting with Drs. A. R. Dochez, Kenneth F. Maxcy, and Blake, Dr. Bayne-Jones presented a budget of $60,000 ($15,000 for each of the four teams) for1 year. Dr. Maxcy thought that this was an unexpectedly large amount and that the teams could start their programs with somewhat less but did not object to the proposal. He also stated, "It is not entirely clear as to where the functions of this commission terminate and those of the Commissions of Hemolytic Streptococcus infections, Meningococcus Meningitis, Pneumococcus Pneumonia and Influenza begin."
ADMINISTRATION, ORGANIZATION, AND PERSONNEL
The CES program was to be conducted under a contract with Yale University with the four investigative teams to be based at Harvard, Duke, and Stanford Universities and the Department of Puerto Rico School of Tropical Medicine acting as subcontractor.
In the early planning stages of the AFEB, it was decided that commissions would be established as necessary and that each commission would have a director and "such additional consultant personnel, as necessary, for the purposes of the Commission."
The original membership of the CES was as follows:
Director: Dr. Stanhope Bayne-Jones
Consultants:
Dr. J. Howard Mueller
Harvard Medical School, Boston, Massachusetts
Dr. Edward B. Shaw
University of California Medical School,
San Francisco, California
Dr. John F. Enders
Harvard Medical School, Boston, Massachusetts
Dr. Charles E. Smith
Stanford University School of Medicine,
San Francisco, California
Dr. Emanuel B. Schoenbach
Harvard Medical School, Boston, Massachusetts
Dr. P. Morales-Otero
School of Tropical Medicine, University of
Puerto Rico, San Juan, Puerto Rico
Dr. David T. Smith
Duke University School of Medicine, Durham,
North Carolina
Dr. J. Roderiguez Pastor
San Juan, Puerto Rico
Dr. Wiley D. Forbus
Duke University School of Medicine, Durham,
North Carolina
Dr. Manuel A. Perez
San Juan, Puerto Rico
Dr. D. F. Milam
Duke University School of Medicine, Durham,
North Carolina
Dr. Amerigo Pomales Lebron
San Juan, Puerto Rico
Dr. Edwin W. Schultz
Stanford University School of Medicine,
San Francisco, California
Considerable delay was encountered working out the contractual details. The final contract with Yale University was not approved until 1 November 1941. This contract was for $34,745 for the remaining 8 months, until 30 June 1942. The investigative program, however, had been underway since early summer. Just how this was handled financially is not clear from the old records, but presumably the
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programs at Harvard, Duke, and Stanford Universities were initiated and conducted on a voluntary basis with locally available funds with some assistance from the AFEB.
Although coccidioidal infections were not included in the original agenda of the CES, Dr. Edwin W. Schultz, director of the 9th Corps area group and Dr. Charles E. Smith, a member of that group, wrote to Dr. Bayne-Jones with a recommendation that it be included in their investigative program. In a letter of 21 May 1941, they stated that the Army`s major bases for aviation instruction located in the southern San Joaquin valley in California were in a region of maximal incidence of coccidioidal infection. They added that 80% of the school children tested near the Air Corps Basic Training Center at Taft Air Base reacted positively to coccidioidin. It was stressed that coccidioidomycosis would be a significant cause of morbidity in these aviation training centers.
Dr. Bayne-Jones strongly supported this proposal, and shortly thereafter it was included in the 9th Corps area program. It proved to be one of the most productive of the early programs conducted under the CES.
Dr. Bayne-Jones entered active duty as a Lieutenant Colonel, Medical Corps, in February 1942. He wrote to Dr. Blake that he was concerned about the advisability of his holding the position of Director of the CES while serving as a commissioned officer in the Office of The Surgeon General. Dr. Blake requested an opinion from The Surgeon General and prevailed on Dr. Bayne-Jones to continue to serve at least temporarily. On 4 May 1942, however, he submitted his resignation, which was accepted. He was replaced by Dr. Blake who served in this capacity until the CES became inactive in December 1945.
BACTERIOLOGICAL SURVEY: MENINGOCOCCAL, STREPTOCOCCAL, ANDOTHERS
The 1st Service Command study was under the direction of Drs. J. Howard Mueller and John F. Enders. Frequent bacteriologic surveys were conducted at Fort Devins and Camp Edwards to determine the prevalence of (3-hemolyticstreptococci, H. influenzae, meningococci, and diphtheria bacillii. It was hoped to use changes in the prevalence of these organisms to predict the onset of epidemics and possibly develop methods for their control. During the first 2 years of this study, objective and critical comments were made by members of the AFEB. Dr. Blake stated his view that "This work should not go on unless it could be reorganized with possibly an investigator commissioned under the Board to take charge of the direction of the experiment." The study, however, was continued. From the spring of 1942until March 1943, routine meningococcal surveys revealed that carriers of types II, II alpha, and non typable (X) stains predominated, with type I carriers remaining essentially constant at about 3.5%. In December 1942, the rate of type I carriers doubled, and in January 1943, tripled. At the same time, the number of clinical cases increased significantly at Camp Edwards. Culture isolates from these patients revealed type I meningococcus, except in one case that probably was a type II alpha. It was concluded from these studies that typing should bean essential part of any survey of meningococcal carriers.
In May 1943, Brigadier General Frederick F. Russel, MC, USA(Ret), reported to Dr. Mueller a sharp outbreak of streptococcal disease at an Army school in Massachusett. It was stated that in the previous 3 weeks there had been "several" cases of scarlet fever, a considerable number of streptococcal sore throats with a number of peritonsillar abscesses, and a high rate of respiratory disease in general. In view of the experience in the U.S. Navy with scarlet fever, and after additional consultation with Dr. T. Duckett Jones, it was decided to administer a 3-day course of sulfadiazine or sulfapyridine, 3 g/day. The next day, chemoprophylaxis began for all students, instructors, kitchen employees, and other personnel after initial cultures were performed. Follow-up cultures were performed in all persons on the day after completion of the treatment. In the period after administration of the sulfonamides, the sick rate dropped sharply, but no significant change was noted in the carrier rate. In the 3-week period preceding the administration of the drug, seven cases of scarlet fever occurred. After drug prophylaxis, no new cases were noted except one that appeared on the day after chemoprophylaxis.
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Coccidioidomycosis
The 9th Service Command study of coccidioidomycosis was directed by Dr. Charles E. Smith of Stanford University School of Medicine. The study was designed specifically to develop a program to minimize the danger of disseminated coccidioidomycosis and at the same time benefit from the expo sure of a large number of troops stationed in the area to evaluate the epidemiology of this fungus infection. Epidemiological evaluation of an early outbreak during maneuvers in Kern County, California, led to significant changes in desert training methods.
The importance of the cocciodiomycosis study extended beyond the significant contributions to the knowledge of diagnosis, treatment, epidemiology, and prevention of this disease. This group directly focused the attention of military authorities on the importance of this disease, particularly as it related to the location of military personnel in a desert environment. Of equal importance was the continuity that was provided in the overall supervision of the program. Area surgeons, laboratory personnel, ward officers, and commanding officers were subject to frequent change. Hence, it was the Stanford group that coordinated the educational, diagnostic, and follow-up programs that were vitally important in controlling the spread of coccidioidomycosis in military personnel.
Survey of Respiratory Pathogens
The 4th Service Command group based at Duke University conducted a survey of respiratory pathogens in troops at Fort Bragg, North Carolina. This was under the supervision of Dr. David T. Smith, assisted by Mr. W. A. Mickle, Jr.
During the period of 1 July 1942 to 1 November 1942, no significant increase occurred in the prevalence of any particular pathogen that could be related to increased incidence of respiratory disease. With the establishment of the Commission on Acute Respiratory Diseases (CARD), this study was transferred to that Commission.
Budgets and Expenditures
The total budget for the CES for 1942 to 1943 was $44,000, with $14,000 allotted to the 1st Service Command study, $10,000 to the 9th Service Command project, and $20,000 for "epidemiological work in other areas and reserve." This last budgetary item, which had been reduced to $16,000, funded the 4th Service Command study. The remainder was transferred to the Commission on Meningococcal Meningitis ($2,000) and to the Commission of Neurotropic Virus Diseases ($10,500). The 1943 and 1944 report stated, "The availability of this fund has been of great value in assisting in the work of other commissions which during the course of the year were found to need additional funds for special projects."
In the annual report of the CES for 1944, the following appears: "In July Major Wilbur G. Downs, MC, AUS, formally of the Rockefeller Institute, New York City, was appointed to the Commission under the allotment of Officers for the Army Epidemiological Board and assigned as Army Medical Liaison Officer with the Naval Medical Research Unit no. 2. As in previous years, this commission has stood ready to assist other commissions and to conduct special investigations for The Surgeon General, as needed."
Proposals for the work of the CES for July 1943 to July 1944consisted of the continuation of the bacteriologic surveys of troops in the 1st Service Command under Dr. Mueller, now assisted by Dr. Ann Kuttner, and the coccidioidomycosis study in the 9th Service Command. The budget for $44,000 was approve.
The carrier studies in the 1st Service Command were terminated at the end of the 1944 and 1945 study year. The investigators pointed out that the streptococcal, influenza, and diphtheria rates had remained "pre-epidemic," and no significant amount of illness caused by these organisms had been noted among the troop populations studied. The prevalence of meningococcal carriers, particularly
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type I, however, showed a pattern paralleling the epidemic curve during the observation period. The coccidioidomycosis study continued to provide valuable data. This group provided skin test antigen to many organizations outside of the War Department, not only in the United States, but to foreign countries. They provided ongoing laboratory diagnostic support for various medical facilities. It became apparent that a number of infections occurred in laboratory personnel from performing animal inoculation at military hospitals. The group recommended that, when laboratory personnel detected a suspicious pathogenic culture, animal inoculation be deferred and the specimen be transmitted to the Stanford University Laboratory for confirmation. This procedure worked well. Significant progress was also made in evaluating various methods of dust control. A representative of the Preventive Medicine Division of the Office of The Army Surgeon General commented at the annual meeting of the AFEB in the fall of 1945 that this 9th Service Command study was the focus of the Army investigative program of coccidioidomycosis.
Influenza Vaccine
Although a 4th Service Command study on influenza vaccine was supported financially by the CES, the results were reported by the Commission on Influenza. The evaluation was carried out at Duke University Hospital from 1 February 1945 to 14 February 1946 under the direction of Dr. Joseph W. Beard.
Studies in Puerto Rico
The 4th Service Command investigative team, which was to have been located in Puerto Rico, with Dr. P. Morales-Otero as Director, never became operational. The allotted funds were diverted to other commissions. It appears, however, that some coordination occurred between the group in Puerto Rico and the CES. In April 1944, a paper entitled, "The Streptococcus Problem in the Tropics. A Throat Culture Survey of Troops stationed in Puerto Rico" by Drs. G. J. Dammin, A. Pomales Lebron, and P. Morales-Otero was approved by The Surgeon General of the Army for publication. A footnote was added to the manuscript by Dr. Bayne-Jones acknowledging association of the authors with the CES. In June 1945, another manuscript entitled, "A Throat Culture Survey of Troops stationed in Puerto Rico" by Drs. A. Pomales Lebron, G. J. Dammin, C. Pons, and P Morales-Otero was cleared for publication by The Surgeon General of the Army. Correspondence related to this clearance stated that the work being reported was accomplished as a project of the CES. In the annual report of the AFEB for 1943, it was stated: "The Commission has stimulated studies of hemolytic Streptococcal infection in Puerto Rico and has stood ready to aid other commissions."
Termination of First Commission on Epidemiological Survey
Shortly after World War II, the investigative program of the CES underwent a close reevaluation. By the late fall of 1945, it was determined that the program envisioned for that commission could be absorbed into other existing commissions and that the CES was no longer essential. All activities were terminated, funding was discontinued, army-owned equipment in the hands of contractors was disposed of, and the CES became inactive.
THE SECOND COMMISSION ON EPIDEMIOLOGICAL SURVEY (CES)-1954 TO 1973
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
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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. After a thorough evaluation and discussion, the AFEB concluded that the Army Medical Service should participate in this proposed joint study.
At the regular meeting of the AFEB in September 1954, this plan was approved and membership of the advisory group, as recommended, was approved. Members of this group were Dr. Richard E. Shope (Chairman) The Rockefeller Institute, New York; Dr. Joseph E. Smadel, Army Medical Service Graduate School, Washington, DC; Dr. Theodore E. Woodward, University of Maryland School of Medicine, Baltimore, Maryland; Dr. John H. Dingle, School of Medicine, Western Reserve University, Cleveland, Ohio; Dr. W Barry Wood, The Johns Hopkins Hospital, Baltimore, MD. Dr. Colin MacLeod (exofficio) New York University College of Medicine, New York; and Colonel William D. Tigertt, MC, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington, DC, who had been named earlier as the project officer.
The stated aims of this group were to assist The Surgeon General and the Chief Chemical Officer in developing a program as quoted below:
a. To obtain a realistic evaluation of biological warfare as a weapon in its present state of development.
b. To define the defensive problems in biological warfare with sufficient clarity and authority to serve as the basis for development of a program of defense against biological warfare.
At the time of this meeting, the subject of biological warfare was extremely controversial. This was true among certain members of the scientific world as well as lay groups. It was suggested that the title, "Commission on Epidemiological Survey," would be a suitable designation for this new advisory group because the title was considered to be vague and noncommittal. This recommendation led to reactivation of the CES.
The CES was unique within the structure of the AFEB in that its responsibility extended into the in-house research program as well as that conducted under contract with nongovernmental institutions. As the Surgeon General`s charge to this commission was studied, it was concluded that the research programs should concentrate on three broad categories.
1. The pathogenesis of infectious diseases considered to be important in the medical defense against biological warfare, including susceptibility of man to appropriate potential agents.
2. Prophylaxis and treatment of such diseases.
3. Methods for the early recognition of infection in an exposed population and rapid identification of specific organisms or groups of organisms.
Shortly after the September meeting, Drs. Shope, Smadel, and Tigertt spent several days at Camp Detrick, Frederick, Maryland, with the personnel of the Biological Laboratory reviewing the problems inherent in the defense against biological warfare. They concluded that Rickettsia burnetii, the causative agent of Queenstown or Q fever, would be the most acceptable organism to employ in studies proposed to evaluate the potential dangers of a biological attack against a U.S. military and civilian population. These studies were to be conducted as a joint endeavor between the CES , as an agent of The Surgeon General of the Army, and the Medical Subcommittee of the Army Chemical Corps Advisory Council. The objective of these studies was to conduct an open air field test of a virulent organism in volunteers. After long and careful evaluation of the entire program, this approach was approved by the CES and presented to the AFEB. After approval by the AFEB and with concurrence of The Surgeon General, the project known as CD-22was initiated.
The operating agencies, at this point in the program, were the Army Biological Laboratories, a Chemical Corps research unit at Camp Detrick, and the Special Operations Division, Army Medical Service Graduate School in Washington. The research program was centered at Camp Detrick as a joint
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operation. The senior representative of the Army Medical Service was Lieutenant Colonel Tigertt, commanding officer of Medical Unit (9901.07) Walter Reed Army Medical Center. This unit was established as a part of WRAIR specifically to conduct the joint Medical Service-Chemical Corps Project. Medical Service Operations at Camp Detrick were the responsibility of Colonel Abram S. Benenson, MC, and laboratory procedures were supervised by Colonel William S. Gochenour, VC.
As the program progressed, each step was evaluated and approved by the CES and the AFEB. During this phase of the project, the Army Medical Service acted as a contractor for the chemical corps because funding was received from the latter branch of the Army.
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.
Project CD-22
The first research program involving the newly activated CES was entitledCD-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, chloramphenieol, 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 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.
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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.
Numerous test trials used noninfected egg slurry to standardize the aerosol-generating equipment, evaluate aerosol response, evaluate various meteorologic conditions, and determine the numerous parameters to be considered in the final studies. Three trials were then conducted with the use of infective whole-egg slurry. These trials involved collection of organisms in all glass impingers and the exposure of guinea pigs at various distance downwind from the source. Fluorescent particles also were aerosolized and collected to provide additional information for determining dosage levels and the path of the aerosol.
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 used30 Whitecoat volunteers in groups of 3 (1 immunized and 2 nonimmunized) at 10different 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 July1955 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.
The details of this study are still classified, but it was shown beyond any doubt that susceptible humans could be infected under field conditions by exposure to an artificially generated aerosol containing infectious organisms.
After completion of the Q fever field trials, additional experimental work was conducted at Camp Detrick on the effectiveness of Q fever vaccine and the use of oxytetracycline (Terramycin) for post exposure prophylaxis and treatment. Exposure was accomplished by the aerosol route with the use of several different dosage levels and at different time periods after completion of the vaccination series. The Formalin-inactivated vaccine was highly effective in protecting against clinical illness, although an occasional individual did become ill. Terramycin was highly effective in treatment of Q fever under all conditions of infection. Individuals given Terramycin prophylactically after aerosol exposure at different dosages were completely protected if the drug was started late in the incubation period (1 or 2 days before anticipated appearance of clinical disease). If a 6-day course of Terramycin was begun 24 hours after exposure, most individuals developed clinical illness after an incubation period approximately twice as long as anticipated for an unprotected person. All volunteers responded well to readministration of the Terramycin.
When one dose of Q fever vaccine was administered after aerosol exposure, some protection was detected against low dosage exposure but very little protection against higher dosages. All persons who developed clinical illness responded well to Terramycin therapy.
Those volunteers who were reexposed to Q fever Rickettsia by the aerosol route, after having recovered from clinical illness caused by this organism showed no evidence of infection. No evidence was noted of person-to-person transmission between those with clinical illness and the unprotected personnel who provided day-to-day medical care.
In 1956, three additional members were appointed to the CES. They were Ivan L. Bennett, Jr., M.D., Associate Professor of Medicine, Biological Division, The Johns Hopkins Hospital, Baltimore, Mary-
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land; Geoffrey Edsall, M.D., Director, Communicable Disease Division, WRAIR, Washington, DC; and Colonel Tigertt, MC, Assistant Commandant, WRAIR, Washington, DC.
U.S. ARMY MEDICAL UNIT-FORT DETRICK
During Project CD-22, laboratory facilities available to the Walter Reed Unit at Fort Detrick were almost nonexistant. All aerosol exposures were accomplished by personnel of the Army Biological Laboratories, with the human exposures being conducted under the direct control of the Walter Reed group. After the successful completion of Project CD-22, interest in the medical defense against biological weapons increased significantly among senior officers of the Army Medical Service. These officers 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 June1956, 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. On1 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.
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Dr. Ivan Bennett graduated with a degree in medicine from Emory University in 1946 and was a product of the Grady Memorial, Duke, and Johns Hopkins Hospitals, where he trained in medicine and pathology. He was assistant professor of medicine at Yale from 1952 to 1954 under Paul Beeson, his associate and close friend. he then progressed through the ranks at Hopkins from associate professor to professor of medicine and held the Baxter Chair in Pathology there from 1958 to 1966. This was followed by his appointment as acting director of the office of science and technology, executive office of the president from 1966 to 1969. He then became a senior officer at the New York University Medical Center, where he served with distinction as vice president for health affairs, dean, director of the medical center, provost, and acting president.
Few American physicians have contributed so much and so wisely to the public interest as Ivan. He had natural blessings of high intelligence, keen wit, and an impelling desire to tackle difficult problems. The AFEB and its CES profited from his keen sense of uncovering potential threats and devising means to counter them. Throughout his later years, he contributed wisely at all levels of professionalism, including the World Health Organization, on matters pertaining to defense against biological warfare.
The United States Cooperative Medical Science Program Benefitted from his wise and inspired leadership over 18 years. Ivan had good taste and a unique talent for choosing the right people for the proper job. He promoted the welfare of good scholars and found gratification in their career development. His record of public service is endless. He died in Tokyo, Japan, on July 22, 1990, while he was attending the 25th anniversary meeting of the U.S. Japan Program.
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Dr. Geoff Edsall graduated from Harvard Medical School in 1934 and served his house officer ship at the Massachusetts General Hospital from 1934 to 1936. Research fellowships followed at Harvard, and he served as an instructor in bacteriology and immunology at the Harvard Schools of Medicine and Public Health. Dr. Edsall was assistant director of the Division of Biologic Laboratories of the Massachusetts Department of Public Health and its director until 1949. For several years, he was Professor of Micr6biology and head of the Department of Microbiology at the Boston University School of Medicine, which was followed by his appointment as Director of the Division of Immunology at WRAIR in 1951.
Geoff served the AFEB in may ways, particularly as the director of the Commission on Immunization from 1952 to 1963. The membership of this Commission was graced with some of the leaders in American medicine in biology and immunology. Under Geoff`s direction, the Commission accomplished a vast amount of work and collaborated with the activities of other Commissions. The 3-day meetings of this Commission held at WRAIR were actually reviews of contemporary work in immunology and vaccine development. Geoff also served as a member of the CES, where his advice was put to good use. His research interests were broadly distributed throughout the immunological field and his special contributions related to the purification of toxoids, particularly tetanus and diphtheria.
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BRIGADIER GENERAL WILLIAM D. TIGERTT, MC (RET.), M.D.
During Bill Tigertt`s distinguished military career, he was closely affiliated with the AFEB and several of its Commissions. With the advantage of a remarkable experience in laboratory medicine and an accurate bibliographic memory, Bill applied this broad capability in pursuit of those many difficult infectious disease problems that confronted him. He gained broad experience in tropical disease problems in New Guinea and the Phillipines as director of the 26th Army Laboratory and the 406th General Laboratory, Tokoyo, where malaria, other parasitic diseases, and enteric infections were rampant. Later, as commanding officer of the USAMU at Fort Detrick (later USAMR11D), many answers to problems of pathogenesis, pathophysiology, and control of important viral and rickettsial diseases were clarified under his guidance.
Bill Tigertt was the principal force behind the new thrust to find a better prophylactic and chemotherapeutic way to control malaria, a dilemma caused by the plasmodia resistance problem.
He collaborated closely with the CES and was a member of the Commissions on Malaria, Viral Diseases, and Parasitic Diseases. He always consulted directly with the AFEB on matters vital to the military services.
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In late 1958, construction of a specially designed building to house a 1,000 KVP medical radiographic unit was completed and the unit installed. This facility was designed to study the effect of varying doses of radiation on the course of infection in laboratory animals.
Responsibility of CES
After the successful completion of the joint Medical Service-Chemical Corps Project CD-22, activation and expansion of the USAMU at Fort Detrick, availability of a suitable medical treatment facility at Fort Detrick, and the readily available pool of volunteers, the Army Medical Service and the CES became increasingly involved in medical defense against biological warfare. In April 1958, The Surgeon General issued the statement on the following page outlining his current thinking on this subject.
In 1959, The Surgeon General issued a Statement of Policy on control of infectious disease. This statement included the following excerpts:
4. Education:
a. The education of medical personnel in the identification, control and treatment of infectious disease is a function of the Personnel and Training Division since such training is a part of the overall training of Army Medical Service personnel. The provisions of such training should be divided into that of extensive training of trainers, the establishment of a capability of expansion of training in case of mobilization and the accumulation of a readily available library of training aids kept constantly up to date.
b. The extensive training of trainers could be accomplished, in various ways.
1. By the assignment of career internists, pediatricians, laboratory officers, veterinarians and Army Nurse Corps officers to the Medical Unit, Fort Detrick.
2. By the assignment of career medical officers to foreign areas where infectious disease is frequently encountered.
3. By the development of a course in the diagnosis and control of communicable disease at WRAIR, this course to be short, recurring and on a temporary duty basis.
7. Research and development:
The research and development program for the prevention and treatment of infections should be expedited. Such research should include, but not be limited to, expansion of identification efforts and development of more efficient reporting methods and procedures. It is particularly important that new methods of automatic reporting be developed. It is desired that the present agreement with the Chief Chemical Officer ultimately be changed so that the Army Medical Service be assigned mission responsibility for research and development in medical prevention and treatment of disease resulting from biological warfare.
These developments were the result, in part, of increasing recognition of the potential impact of the medical problems that would be faced in the event of biological warfare and the importance of naturally occurring infectious diseases for the Armed Forces, particularly in certain overseas areas. After this, two significant personnel developments occurred. The first was the successful effort by Colonel Tigertt in getting career officers assigned to the medical unit and in obtaining the assignment of young noncareer officers interested in infectious disease research. This effort was immeasurably aided by recommendations from members of the AFEB and particularly from members of the CES.
The second was recognition of the assistance available from the CES. The medical unit had not only the benefit of the general guidance provided by the CES, but also the immediate availability, when necessary, of the knowledge of some of the most highly qualified men in the United States in the field of infectious disease. When a problem arose, it was possible to have a phone consultation in a matter of minutes or convene a panel of experts within a few hours. Just the fact that these nationally and internationally recognized authorities were available for guidance and consultation was a significant factor in developing and executing the research program of the medical unit.
By mid-1958, the medical unit facilities at Fort Detrick and the Hazardous Laboratory at Forest Glen were equipped and operational, and the staff was in place. The CES was now actively involved in both the in-house and contract research programs.
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The Surgeon General`s Statement Regarding Medical Defense Against Biological Warfare The Surgeon General is concerned with his responsibilities in the control of infectious diseases in situations wherein appreciable portions of a military population can be expected to become ill from exposure anticipated in future types of operation, regardless of whether an agent was naturally or artificially disseminated. He is currently reviewing his capabilities and obviously this involves consideration of his research program in the infectious disease field. Those areas related to his preexisting research program and to the current research program specifically related to defense against biological warfare are to be reviewed and the advice of the Commission on Epidemiological Survey as to the adequacy of the program will be sought. When formulated, portions of the program will be assigned to specific AMEDS laboratories, or to the contract effort as appropriate. Quarterly reports will be required on all in-service research programs which are determined to be pertinent to the defensive aspects of biological warfare. The Surgeon General desires that the Commission on Epidemiological Survey act, as do other commissions, in stimulating and guiding a contract research program. The AMEDS Research and Development Program will support this effort with funds from AMEDS and Chemical Corps sources as appropriate. In addition, The Surgeon General desires that the Commission on Epidemiological Survey assume an active role in review of the In-service Research Program related to medical defense against biological warfare. In this regard, they will advise The Surgeon General on the soundness of the entire research program related to medical defense against biological warfare. With the possible exception of certain sensitive, classified matters, these activities should be carried on as are other AFEB affairs. The differences that this altered situation will make as regards the activities of the Commission on Epidemiological Survey are as follows: 1. It will become more like other Commissions of the Armed Forces Epidemiological Board in that it will stimulate and be responsible for research in areas of its competence under the aegis and with the approval of the Board. 2. In addition, it will assume responsibilities beyond those of other commissions in that it will advise The Surgeon General on in-service research directly applicable to the defensive aspects of biological warfare. 3. It will aid in the planning and will advise on projects under its cognizance, both in-service and contract, and will follow their progress closely. 4. It will advise on experimental protocols in volunteer studies and recommend their individual approval or disapproval. 5. It will expect periodic reports through The Surgeon General of in-service work under its cognizance. 6. It will, when requested by The Surgeon General, initiate experimental work in sensitive areas. 7. It will periodically review the defensive biological warfare research program and will make recommendations for areas that it feels are inadequately covered. |
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During that year, Dr. Dingle, School of Medicine, Western Reserve University, Cleveland, Ohio, was appointed to a full membership on the CES and Dr. Smadel declined reappointment. Dr. Woodward was designated Deputy Director. One formal meeting was held. In addition, a number of informal conferences were held at Fort Detrick and in Baltimore and Washington. These meetings resulted in a detailed appraisal of the problems inherent in medical defense against biological warfare, permitting a definition of those areas where research was required and the assignment of relative priorities. This appraisal served as the basis for a presentation by Colonel Tigertt to the Special Panel on Biological Warfare of the President`s Scientific Advisory Committee on 10November 1958. This presentation was a wide review of the subject.
Colonel Tigertt stated that The Surgeon General had a demonstrated competence to handle naturally occurring outbreaks of disease of military importance but did not have the capability to handle the very large-scale outbreaks of illness that theoretically might result from a successful biological warfare attack. He also brought to the attention of this group that The Surgeon General was not directly charged with the execution of are search program that would provide such capability. This latter responsibility had been assigned to the Chief Chemical Officer, but in 1954, at the request of the Chief Chemical Officer, The Surgeon General, in effect, became a contractor to the Chemical Corps to engage in a limited research program on certain phases of medical defense.
This presentation discussed the development and use of vaccines of importance in biological warfare and the employment of chemoprophylaxis and the training of physicians and other medical service personnel in the management of exotic disease of biological warfare. The rapid and accurate reporting of disease outbreaks during wartime were discussed along with the requirement for development of more rapid methods of diagnosis and organism identification.
Colonel Tigertt summarized the problems of medical defense against biological warfare as follows:
We believe we know in considerable detail the type of medical research program which must be undertaken, if a known satisfactory posture for defense against biological warfare is to be attained. This program is hazardous, time consuming, and must inevitably involve the deliberate risk of human life. It has one real bonus value, however, if properly conducted. The results obtained will be applicable to the control of disease whether or not biological warfare ever becomes a reality.
The Research Program
The research program in 1957 and 1958 was centered chiefly on tularemia, which constituted a significant portion of the program, Venezuelan equine encephalomyelitis (VEE), typhoid fever, Rift Valley fever, anthrax, plague, and Q fever.
It was determined that the respiratory-induced form of tularemia could be adequately controlled by the administration of tetracycline as well as streptomycin. Studies conducted by Dr. S. Saslow at Ohio State University, under a contract with the CES, showed that the infectious dose for humans was of the order of a few organisms when exposure was by the aerosol route. At these low doses, the incubation period averaged about 5 days. The Foshay-type vaccine that had been used at Fort Detrick for the protection of laboratory personnel was determined to be not effective. Extensive studies were conducted on a living vaccine strain obtained from Russian sources by Dr. K. F. Meyer during a trip to that country.
Dr. Henry Eiglesbach of the Army Biological Laboratories confirmed that the vaccine had two bacterial colony types, blue and gray, and that only the blue strain was immunogenic. The vaccine that he prepared from the blue strain was studied extensively at the Biological Laboratories and the medical unit and under contract at the University of Maryland Medical School and at Ohio State University. Aerosol exposure was made possible in the contract studies by the use of portable aerosol-generating equipment developed and operated by Biological Laboratory personnel. In addition, these studies determined that the Larson vaccine was of little value in protecting against aerosol exposure.
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Rift Valley fever was studied at the Hazardous Disease Laboratory at the Forest Glen Annex of WRAIR under the direction of Dr. Raymond Randall, DVM. His studies were oriented toward development of an effective vaccine. The vaccines used previously in this country and in Africa had produced limited protection. A Formalin-inactivated vaccine produced from a pantropic strain of virus grown in monkey kidney tissue culture was found to produce significant neutralizing antibody in laboratory animals and in humans.
Studies of VEE also were oriented toward development of an effective vaccine. Inactivated vaccines were of little or no value in protecting against laboratory infections. Studies were in progress to obtain a living attenuated vaccine from the Trinidad strain by serial passage in guinea pig heart cell tissue culture.
Under contract with the University of Maryland Medical School, typhoid fever was studied in volunteers from the Maryland House of Corrections at Jessup, Maryland. These studies were conducted at the University of Maryland Hospital and involved 12 volunteers divided into 3 groups. Infection was produced by ingestion of large numbers of Salmonella typhosa propagated on artificial media. All 12volunteers developed disease. The average incubation period was 5 days, and therapy with chloramphenicol resulted in lysis of fever over a period of several days. Studies by Dr. Sheldon Greisman showed that, during the early febrile period, hyperreactivity to norepinephrine was noted with the use of microscopy of the nailbed fold. This was believed to be caused by endotoxin sensitization.
In response to The Surgeon General`s guidelines for the research program of the USAMU, Fort Detrick, and the CES, work on the early and rapid diagnosis of disease and the identification of disease-producing organisms were intensified. A contract with Dr. Paul Fremont-Smith, Harvard Medical School, involved the development of a technique for the rapid growth, identification, and antibiotic sensitivity testing of clinically important bacteria. Bacteria grown on thinagar films on glass slides were studied for colonial morphology cellular pattern and tinctorial characteristics. The application of fluorescent antibody techniques to this procedure also were studied.
During this same period, Dr. Martha K. Ward, U.S. Public Health Service, assigned to the USAMU, Fort Detrick was working on methods for the rapid identification of Franciellatularensis. Her work involved the development of a selective culture media that would allow the isolation of this organism directly on plates and eliminate the time and hazard inherent in animal inoculation procedures; methods for obtaining more rapid growth on solid media; and the development of a more satisfactory liquid medium for use in blood culture work and perhaps as an enrichment medium to be used in conjunction with fluorescent antibody technique.
During this period, studies were initiated on plague and anthrax. These two diseases had been under investigation in the Army Biological Laboratories, and some work had been done on development of vaccines. With the availability of the renovated laboratories on hazardous materials at Forest Glen and the medical unit, additional vaccine studies became practical.
Dr. Woodward succeeded Dr. Shope as director of the CES in July 1959. At the same time, Dr. Leighton E. Cluff, The Johns Hopkins Hospital, and Dr. Fred R. McCrumb, University of Maryland Medical School, were appointed to the CES as associate members.
Biological Warfare and the Armed Forces
At the spring meeting of the CES in 1960, Brigadier General Joseph McNinch, commanding general of the U.S. Army Medical Research and Development Command, reviewed the importance being placed, at that time, on medical defense against biological warfare. This feeling extended to the highest levels of the Department of Defense and even to the White House. He stated that The Surgeons General of the Army, Navy, Air Force, and Public Health Service had active research programs in this field. He added that the CES was responsible to The Surgeon General of the Army for advice on planning and guidance pertaining to the scientific program, both in-house and under contract. He emphasized that the CES carried responsibility to review the need, design, and scientific excellence of volunteer studies with power to approve or disapprove a project.
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General McNinch noted that funding was derived from the Chemical Corps and that an increase of almost 100% was projected for the following fiscal year. A portion of these additional funds would be expended on a contract with a pharmaceutical firm to develop methods for the large-scale production of vaccines as they were developed in the biological warfare medical defense program.
At the March 1960 CES meeting, it was recommended that two subcommittees be appointed. The first subcommittee was to formulate plans and policy regarding anthrax. The subcommittee staff were Dr. MacLeod, chairman, Dr. John Y Bennett, member, Colonel Tigertt, member, and Dr. Harold Glassman, advisary member(Deputy Scientific Director of the Army Biological Laboratories, Fort Detrick).The second subcommittee was to study problems relative to reorganization and reorientation of the CES and its role with regard to biological warfare. The staff of this subcommittee were Dr. Shope, chairman, Dr. MacLeod, member, and Dr. Woodward, member.
This latter committee was asked to formulate plans after discussion with General McNinch, The Army Surgeon General, Dr. Bayne-Jones, and others. One of the principal areas to be reviewed was the relationship of the CES and the AFEB with the Medical Advisary Committee to the Chief Chemical Officer and other agencies and committees of the Department of Defense.
In July 1961, Colonel Tigertt was transferred for a 1-year assignment to the Medical School in Shiraz, Iran, and was replaced by Colonel Dan Crozier, MC, as commander of the USAMU, Fort Detrick. The composition of the CES, at that time, was as follows:
Dr. Theodore E. Woodward, Director
Dr. Ivan L. Bennett, Jr., member
Dr. John H. Dingle, member
Dr. Geoffrey Edsall, member
Dr. Colin M. MacLeod, member
Dr. Richard E. Shope, member
Colonel William D. Tigertt, member
Dr. W. Barry Wood, member
Dr. Leighton E. Cluff, associate member
Colonel Dan Crozier, associate member
Dr. Fred R. McCrumb, associate member
When Colonel Crozier took over command of the medical unit, the research program, under the guidance of the CES, was well-organized and highly productive. The laboratories, located in temporary or semi permanent buildings, were adequate, although limited, and the staff were complete and highly qualified. Each of the research divisions was headed by a career officer as were many of the supporting sections. Many of the other staff members were young, enthusiastic physicians and allied scientists in the biological fields who had asked for the assignment or who had been recommended by medical school and university deans familiar with the research program, particularly members of the CES and other AFEB commissions.
Review of Biological Warfare Research Program
At the 7 September 1961 meeting of the CES, a review of the research program, both in-house and contract, was presented. Studies of tularemia, VEE, anthrax, staphylococcal enterotoxin, plague, typhoid fever, and Rift Valley fever constituted a major portion of the program. These diseases and their causative organisms were studied not only to obtain information relative to the particular disease and its specific organism, but also they served as models to study infectious processes in general, including pathogenesis, diagnosis, and prophylaxis and treatment in laboratory animals and humans.
Typhoid Fever
Extensive studies of typhoid fever were conducted under contract with the University of Maryland under the direction of Dr. Woodward. A 15-bed medical ward for the study of this disease in volunteers was opened at the Maryland House of Correction in 1961. The ward was established at a cost of approximately $10,000, and the cost per day per patient was approximately $8.00. Studies were conducted to evaluate the role of typhoid vaccine in modifying or preventing the disease in humans and to investigate the part played by endotoxin in the pathogenesis of typhoid fever. These studies
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Dr. Richard E. Shope accomplished much during his relatively short life (64 years). After qualifying in medicine at the University of Iowa in 1924, he trained in pharmacology, with special work on the chemotherapy of tuberculosis. He joined the Rockefeller Institute at Princeton (ultimately the Rockefeller Foundation). An avid outdoorsman with an interest in animals dating from his youth, his research shifted to hog cholera and virology.
A key observation with Dr. Paul Lewis showed that a mixture of Haemophilus influenzae suis and swine flu virus produced typical influenza and severe pneumonia in swine. This clarified the complementary role of virus and bacteria in producing diseases and led to his contribution that swine flu virus might cycle through lung worms, with ova passed on in the feces, then to earthworms, and back to the hog from the earthworm. This novel and controversial notion helped explain the cyclic nature of influenza. His most brilliant contribution was the demonstration that the two viruses that affected wild cottontail rabbits produced either a fibroma or papilloma. These viruses carry his name and have had important implications with respect to the pathogenesis of cancer.
Dick Shope had a very distinguished war record and worked under Dr. Thomas Rivers with the U.S. Navy Medical Research Unit on Guam. After World War II, he was the first director of the CES from its reorganization until 1959. Tireless as a productive scientist, he had the facility to objectively monitor the broad scientific program on biological warfare defense at Fort Detrick (later USAMRIID), which was one of the roles of the CES. Under his direction, many new concepts of pathogenesis and control were elucidated. He had the facility to make it enjoyable for members of the CES and others to work with him, and his sense of humor was infectious.
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Dr. Theodore Woodward was raised in Westminster, Maryland; he graduated from Franklin and Marshall College in 1934 and the University of Maryland School of Medicine in 1938. He entered the Army in 1941, interrupting his internship and residency in medicine. During the war, he served at Fort Meade, Maryland, for a short time, and with the U.S. Army Corps of Engineers in Jamaica, B.W.I. This was followed by research training at the Army Medical School in Washington, D.C., where he attended a course in tropical medicine. He was temporarily assigned to a field laboratory with the initial landing forces in northern Africa. His work, primarily on the typhus fevers, involved research at the various Pasteur Institutes in northern Africa, and he was a member of the U.S.A. Typhus Fever Commission. He served in Naples, Cairo, the Aden Protetorate, the European theater (in England and Normandy and elsewhere in France), and the Pacific theater (in northern New Guinea and the Philippine Islands).
After World War II, Dr. Woodward practiced medicine privately in Baltimore for several years. In 1948, he joined Joseph E. Smadel in studyingthe clinical efficacy of chloromycetin in the treatment of scrub typhus and the typhoid fevers in Kuala Lumpur, Malaya (now Malaysia). After this valuable experience, he joined the faculty of the University of Maryland School of Medicine, where he organized the Division of Infectious Diseases. From 1954 to 1981 he chaired the Department of Medicine there.
He was a member of the CES from 1952 to 1973 and served as its Director from 1959 to 1973. He was a member of the Commission on Rickettsial Diseases from 1955 to 1973, and an associate member of the Commission on Immunization from 1950 to 1973. He served as President of the AFEB from 1976 to1978 and from 1980 to 1992.
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confirmed earlier studies that suggested that infection can be produced regularly when 10 million to 1 billion viable organisms were ingested. It also was found that occasionally as few as 100,000 organisms could produce clinical typhoid fever. Neither the severity of the resulting disease nor the length of the incubation period could be correlated with the size of the inoculum.
A number of different immunizing materials were studied in humans, including purified antigens obtained from the National Institutes of Health (NIH) and WRAIR, and the commercially available vaccine commonly administered to humans, particularly military personnel. When challenged with 1billion organisms orally, the breakthrough rate was very high.
Studies also were conducted to evaluate critically the physiological alterations occurring during human typhoid fever that could be attributed to the activity of Salmonella typhosa endotoxin.
Studies under this contract also were conducted at the Hazardous Operations laboratory at the Forest Glen Annex on plague and Rift Valley fever. The Formalin-inactivated Rift Valley fever vaccine prepared by Dr. Randall was shown to be highly effective in the protection of laboratory personnel working with this virus in the United States and in Africa.
Limited studies were initiated on two anthropod-borne virus diseases commonly found in parts of Africa: Chikungunya fever and O`nyong-nyong fever.
Tularemia
The studies on tularemia during this period were concerned primarily with the aerogenic administration of the vaccine strain to humans and to the study of aged aerosols of infectious material.
The feasibility of the administration of living vaccines to animals and humans by this route had been shown for the protection of fowl against Newcastle disease and children against measles. After extensive studies of the administration of living tularemia vaccine to mice, guinea pigs, and monkeys, a protocol for administration of the vaccine by this route to humans was presented to the CES. The proposal was approved, and the studies were conducted by the medical unit at Fort Detrick with the assistance of the Aerobiology Division of the Army Biological Laboratories.
Volunteers experienced no effects from inhalation of the organism-containing aerosol. In individuals with negative serologic reactions before exposure, the response was variable below 1,300 cells presented but above that level aerogenic exposure was uniformly effective. Individuals with a positive agglutination test experienced a serologic booster response only when exposed to larger numbers (up to 10,000) of organisms.
The second series of studies of tularemia dealt with viability-infectivity relationships of aged aerosols. These studies were conducted at USAMU, the University of Maryland, and Ohio State University and included exposure of both laboratory animals and humans to the vaccine strain and the virulent SCHU-S4 strain. The age of the dynamic aerosols was only a few seconds; that of the aged aerosols, 12 to 30 minutes. Exposure of unprotected volunteers to dynamic or fresh aerosols containing the virulent strain resulted in a very high infection rate to doses as low as 20 organisms. Exposure to a 30-minute aerosol resulted in only a 50% infection rate at 170 to 260 organisms.
Venezuelan Equine Encephalomyelitis
Studies on VEE were continued during this period. Studies of this disease in mice, guinea pigs, and monkeys were extended to burros. This virus causes severe epizootics in equines and occurs commonly in parts of the Caribbean region and in South and Central America, with mortality rates as high as 80%.
Uniformly high mortality rates occurred in burros inoculated with either the Trinidad or Columbian strain. The attenuated strain of the Trinidad virus produced in the virology division of the medical unit at Fort Detrick provided solid protection in burros against challenge with the virulant strains. This vaccine also protected burros when challenged with virulent strains of both Eastern and Western equine encephalitis. The single passage of attenuated virus inburros did not restore virulence of the virus for mice.
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Dr. Dan Crozier was closely affiliated with the AFEB, particularly with the CES, for more than a decade. He served effectively as Deputy Director of this Commission. At his retirement in 1973, I, who was then the Chairman of the CES, said, "You, Dan, have been meticulous in every detail, wise in decision making when it related to important medical science problems, hardworking, and selfess in your performance of the job [he served simultaneously as the commander of the U.S. Army Medical Unit at Fort Detrick], forthright and dogged in spelling things out when the lines were thin, and perfectly refreshing and generous in your consideration of others."
Dan Crozier developed a fine medical research unit at Fort Detrick, whose members, including himself, made scientific contributions of lasting value. A laboratory there, now known as USAMRIID, is an important national resource for the study of the pathogenesis and control of highly virulent agents, and is of inestimable importance to our country. Colonel Crozier died in 1994.
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Studies on administration of the attenuated vaccine strain of VEE to animals by the aerosol route were extended. No untoward effects were noted, and satisfactory immunity was attained as determined by the development of hemagglutination-inhibiting antibody and challenge with virulent strains. After extensive studies in mice, guinea pigs, and monkeys, it was believed that immunization of humans by this method was feasible and safe. A protocol to this end was being prepared for presentation to the CES.
Anthrax
Studies of anthrax were receiving increased attention during this period. Early in 1961, Colonel Tigertt wrote, "This disease has appeared on every biological warfare agents list since Pasteur. The basic problem lies in the absence of any significant medical experience with the respiratory disease in man. In rare instances, fatal disease results in man following inhalation of an unknown quantity of anthrax spores."
The CES conducted a review of this disease with personnel from the Army Biological Laboratories and the Chief Chemical Officers Medical Advisory Committee participating as invited guests. At the completion of this review, the CES agreed on the following points:
1. Man can be infected through the respiratory route under unknown circumstances.
2. Man can resist exposure to anthrax in large doses under ordinary circumstances.
3. The circumstances that lead to human respiratory infection are unknown.
4. The regularity with which artificial respiratory infection could be induced in man cannot be estimated.
5. A very logical approach to the solution of this problem is through studies on pathogenesis of anthrax infections.
The research program in the medical unit was centered primarily on pathogenesis and studies of laboratory animals, including monkeys, when infected by the aerosol route and studies of the toxin or toxins and the protective antigen produced by the organism.
Staphylococcal Enterotoxin
Studies of staphylococcal enterotoxin with the use of a partially purified product were directed toward defining an acceptable assay procedure, developing suitable experimental models, and investigating the mechanism of the syndromes produced. Various animal species were employed, and the effective and lethal doses by various routes of administration were determined for the rabbit, pig, dog, sheep, monkey, and chimpanzee. It was found that the aerosol and intravenous effective doses in the monkey were similar.
MEDICAL DEPARTMENT-CHEMICAL CORPS COOPERATION
On 7 September 1960, a joint meeting of members of the CES and the Medical Subcommittee of the Army Chemical Corps Advisory Council met at the University of Maryland Hospital in Baltimore. Representing the CES were Drs. Woodward, Shope, Macleod, and Colonel William D. Tigertt. Representing the Chemical Corps Advisory Council were Drs. Charles L. Wisseman, A. McGehee Harvey, William A. Feirer, Riley Housewright, and Harold Glassman.
This meeting evolved from the increasing awareness of various agencies of the government of the importance of the development of defensive measures against biological warfare. The idea of the joint meeting arose at the spring meeting of the CES, at which time it was suggested that the efforts of all groups interested in biological warfare be coordinated. After a series of preliminary meetings, the joint September meeting was organized.
At this meeting, it was agreed that closer liaison should exist between these two committees and that a mechanism for accomplishing this on a continuing basis should be established. It was decided
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that selected members from each group, designated by the chairman, would be invited to each scheduled meeting of the other group, and that joint meeting would be called when requested by either chairman. It also was suggested that a recommendation be made to The Surgeon General and the Chief Chemical Officer that a recommendation be submitted to the Secretary of the Army that a representative of each of these committees be appointed to the Advisory Committee of the Secretary of the Army or the Biological Warfare Panel of the Army Science Committee. It also was suggested that interested members of these latter committees be invited to meetings of the CES and the Chemical Corps Advisory Council when considered appropriate.
COLONEL TIGERTT`S SUMMATION
In June 1961, just before his departure from USAMU, Colonel Tigertt wrote an excellent summary of the mission of the medical unit and its relation to the CES. He stated:
First, and generally accepted without comment, are its relations to any study under the heading of biological warfare which includes the deliberate exposure of volunteers. This includes passing on the justification for the program, an examination of the background data in man and animals, and concurrence in all phases of the study.
A second area of responsibility of the CES was to recommend a course of action to be taken in the study of any particular organism or the various responses to infection that might be obtained during the study of a particular organism. Colonel Tigertt also suggested that the CES and the AFEB, including its other commissions, were in an excellent position to recommend whether a particular study, which was desirable for the defense against biological warfare, could be conducted most efficiently under the auspices of one of the other commissions, in one of the other in-house laboratories, by a civilian contractor, or by some combination of these facilities.
Colonel Tigertt also included a list of potential biological warfare agents that should be considered in the research program:
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Bacterial Diseases |
Rickettsial Diseases |
Virus Diseases |
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Fungus Infections | ||
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Toxins |
Colonel Tigertt also brought to the attention of the CES special areas of research that should be considered in establishing the biological warfare medical defense research program These included:
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. The metabolic response to infection.
. Super voltage radiograph as a diagnostic tool.
. Development of rapid diagnostic methods.
. Aerosol transmission of diseases generally not considered to be transmitted by this route.
. Aerosol immunization.
. Biopsy as a rapid diagnostic tool.
. Use of combined vaccines.
. Stockpiling of vaccines.
. Stockpiling of diagnostic antigens and antisera.
. Large-scale production methods for vaccines.
. Studies of radiation and infection.
In August 1962, at the request of the USAMU commander, a special meeting of a small ad hoc committee of the CES was held at Fort Detrick. Drs. Woodward, Shope, and Smadel met with USAMU division chiefs and senior investigators to discuss, in general terms, the content and direction of the research program. No attempt was made to review details of individual projects but rather to discuss areas in which division chiefs desired comments. It was felt by both committee members and USAMU personnel that the meeting was of benefit and that similar small groups, consisting of various members of the CES, should meet once or twice a year. Most members of the USAMU staff felt that to have these knowledgeable researchers review their programs and discuss their concepts, approaches, and directions, whether they agreed with them or not, were worthwhile and desirable.
PLAGUE
The September 1962 meeting of the CES was devoted primarily to a review of plague. In addition to the members of the CES and USAMU staffs, a number of invited guests attended. These included Dr. Marcel Baltazard, Director of the Pasteur Institute, Teheran, Iran; Dr. Meyer, Director Emeritus of the George William Hooper Foundation, San Francisco, California; Dr. R. Pollitzer, Division of Epidemiology and Health Statistical Service, World Health Organization; Dr. Werner Janssen, U.S. Army Biological Laboratories, Fort Detrick, Maryland; Dr. William Lawton, U.S. Army Biological Laboratories, Fort Detrick.
A review of the research program of plague was presented. Dr. Lawton discussed plague antigens, stressing that V and W antigens can be separated, and that the V fraction rather than the W fraction is protective for mice. Major John Marshall, USAMU, working at the Hazardous Laboratory at Forest Glen, reported on plague vaccine trials in mice, in which a number of killed and attenuated vaccines was studied. Considerable variation in the protection offered by the different vaccines was noted as was the protection provided against different challenge strains. Dr. Randall, also working at the Forest Glen Laboratory, reported on the detection of plague antibodies by micro methods, employing a modified HI tannic acid test that used red blood cells sensitized with purified capsular antigen of the plague bacillus, fraction I. He described a test that used Bentonite particles that might have application for rapid testing under field conditions.
Dr. Meyer, generally considered to be the leading authority on plague at that time, presented the results of systematic observations of immunization procedures carried out at the Hooper Foundation over several years. He stressed the need for booster immunization after the initial basic series.
Dr. Meyer discussed, at some length, some of the historical features of plague, describing pertinent epidemiological, pathological, and clinical manifestation of this age-old disease. He stated that plague had been widely studied throughout many areas of the world for many years but that much was yet to be learned.
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Dr. Baltazard described his studies of the ecology of plague that had been conducted in Iran and India over many years He discussed a theory of the epidemiology of plague that had been presented by the staff of the Pasteur Institute of Iran in 1960. This theory stated that any species exterminated by a disease cannot be the reservoir of the disease and that the true reservoir of the disease must be sought among those animals whose natural resistance shows them to be best adapted to the disease. Thus, highly susceptible rodents, such as the rat, were not the reservoir of infection; the true reservoir was the highly resistant rodents that survived the epizootic while the susceptible species died.
In addition to the review of plague, the following papers were presented:
. Infectivity of Aged Aerosols of Pasteurella Tularensis, William D. Sawyer, Major, MC, USAMU;
. Studies on Tularemia Vaccine, Fred R. McCrumb, M.D., University of Maryland;
. Volunteer Studies of Typhoid Fever, Richard B. Hornick, M.D., University of Maryland;
. The Role of Endotoxin in Typhoid Fever and Tularemia in Man, Sheldon E. Greisman, M.D., University of Maryland;
. Review of the Attenuated Strain of Venezuelan Encephalomyelitis Virus, Robert E. McKinney, Major, MSC, USAMU;
. Studies of Anthrax Toxin, Martha K. Ward, Captain, USPHS, USAMU; and
. Lysine Deficiency and Host Resistance to Anthrax, Irving Gray, Colonel, MSC, USAMU.
SUGGESTED USAMU STUDIES
At the regular CES meeting in 1963, it was suggested that members make recommendations on subjects to be studied either at USAMU, other in-house laboratories including the Navy and Air Force, or under contract with other governmental or civilian institutions. After some prodding from the Director, a number of replies was received. The wide range of suggestions illustrated the diverse range of interest of CES members. Their suggestions included the following:
. Immunological aspects of the spotted fever group;
. Immunological studies of scrub typhus;
. Live vaccines for Chikungunya and O`nyong-nyong fever;
. Combined antigens;
. Combined infections;
. Irradiation and infection;
. Irradiation and immunity;
. Microculture techniques (possibly combined with electronic scanning);
. Cross-immunity within group A arboviruses;
. Stress and infection;
. Psychological aspects of infection;
. Treatment of viral infections;
. Aerogenic immunization;
. The incubation period-enzyme studies;
. New approaches to rapid diagnosis of infectious disease;
. Commercial diagnostic antigen and antisera production;
. Immunological or vaccine studies of any organism of potential biological warfare importance;
. Leukocytes-relation to immunity and sensitivity;
. Teratogenic effects of living vaccines;
. Host susceptibility to infection as a function of age;
. Role of thymus and thymus products in infection;
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Role of physical environment on susceptibility to infection;
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Study of chronicity of viral infections either from disease or immunization;
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Adventitious agents (eg, lymphoma leucosis, pleuropneumonia-like organisms, and Simian viruses):
(a) Methods of inactivation,
(b) Clearing cultures,
(c) New and simpler methods for detection, and
(d) Effects of inactivated agent in vaccines or antigens;
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Role of fibrin and fibrinolysis in host defense;
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Role of phagocytes in aerosol-transmitted disease;
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Role of growth hormone in infection;
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Possible use of purified ovine prolactin in therapy of infection;
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Possible use of testosterone and its various analogues in therapy of infection;
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Search for biochemical chemical chemotatic "humor" from host tissue or the invading organism that serves to attract leukocytes to site of invasion;
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Staphylococcal enterotoxin:
(a) Effect on cellular permeability and fluid dynamics, and
(b) Metabolism-distribution as related to animal sensitivity;
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The application of neural sciences (including learning ability and acuity) to understanding of virus action;
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Blood pigment changes in anthrax;
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Phagocytic enzyme activity as related to host resistance;
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Bacterial structure and virulence;
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Differentiation of the effect of fever versus infection on host metabolism; and
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Fluorescence polarization to determine specificity of antigen-fluorescent antibody binding.
Some of the proposals were already under study, although some were not within the responsibility of the CES. All suggestions were considered carefully, and a number were included in future research plans both in-house and in the contract program.
NATIONAL DRUG COMPANY CONTRACT
As a part of the expanded research program in the defense against biological warfare and the proposed increase in the biological warfare defense budget, the commanding general, USAMU, and Development Command had suggested in 1960 that a joint project with an American pharmaceutical company be initiated to develop methods for the large-scale production of vaccines developed in the biological warfare medical defense program. This project came to fruition in 1962 with the ground breaking for a new laboratory building to be constructed by the National Drug Company in Swift water, Pennsylvania. This laboratory building was designed with all the necessary safety devices to work with highly infectious organisms. It contained four completely independent units where different organisms could be handled with no danger of cross-contamination. The contract also included a requirement to develop, design, and construct automated equipment for the large-scale production of vaccines in eggs and for freeze-drying large production runs of vaccines.
PERSONNEL
At the meeting of the CES at Walter Reed Army Medical Center in August 1963,personnel changes with significant impact on the composition and direction of the CES were evident. Dr. Smadel, a pio-
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neer member of the commission and one of the top scientists in the nation, died on 21 July 1963. In memorial, Dr. Smadel was described as" a painstaking investigator, an inspired leader, a dedicated friend of the Commission and of the Armed Forces Epidemiological Board." An excerpt of atribute paid Dr. Smadel on 9 December 1963 before the AFEB reads:
The members of this board knew Joseph E. Smadel as one of its ablest scientifically active contributors extending over two decades. He organized and directed the programs of two commissions: Immunization and Rickettsial Diseases, and stabilized the Commission on Epidemiological Survey during its formulation and expansion. Achievements of these commissions have made mankind healthier and richer and each proudly bears an indelible Smadel mark.
The resignations of Drs. Shope and MacLeod were accepted with great regret. Dr. Shope, a charter member and initial director, inspired and guided a distinguished scientific program. The CES, under his direction, developed a broader understanding of the basic mechanisms of certain infectious diseases and effective means of their control. Dr. Shope took administrative difficulties in stride. He felt that he could not continue to serve as an active member of the CES and fulfill his ever increasing obligation to the scientific program of the Rockefeller Institute. He agreed, however, to be available for advice and help. Dr. MacLeod was forced to resign because of heavy responsibilities as director of the President`s Scientific Panel. Through many years, he responded to appeals for advice that made seemingly impossible problems simpler and workable. Unfailing in his ready assent to serve, he did soon short notice without regard to personal inconvenience. Dr. MacLeod`s contribution of mature judgment and broad vision were sorely needed by the CES during more than a decade of service. The commission, at that time, was composed as follows:
Members
Ivan L. Bennett, Jr., M.D.
Dan Crozier, M.D.
Thomas Francis, Jr., M.D.
James G. Hirsh, M.D.
Vernon Knight, M.D.
W. Barry Wood, Jr., M.D.
Theodore, E. Woodward, M.D., Director.
Associate Members
Leighton E. Cluff, M.D.
Fred R. McCrumb, Jr., M.D.
William D. Tigertt, M.D.
Charles L. Wisseman, Jr., M.D.
Special guests attending the 1963 meeting included Dr. I. H. Lepow, Western Reserve School of Medicine and Chairman of the Commission on Immunization; Dr. Kenneth Goodner, Professor and Head, Department of Microbiology, Jefferson Medical College; and Dr. J. E. Johnson, Johns Hopkins School of Medicine.
The scientific program included:
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Recent Progress in Anthrax Studies, Martha K. Ward, Captain, USPHS, USAMRIID;
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Effect of Lycine Deficiency on the Leukocyte Response, Irving Gray, Colonel, MSC, USAMRIID;
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The Effect of Acute Experimentally Induced Tularemia in Humans on the Metabolism of Nitrogen Electrolytes and Minerals and on Adrenocortical Function, William R. Beisel, Liuetenant Colonel, MC, USAMRIID;
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Fluorescent Antibody Technique, Robert F. Jaeger, BA, USAMRIID;
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Endotoxin in Typhoid Fever and Tularemia in Man, Sheldon Greisman, M.D., University of Maryland;
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Current Status of Clinical Typhoid Fever Studies, Richard B. Hornick, M.D., University of Maryland;
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Effect of Virus Infection on Host Cell Protein Synthesis, Jerry R. Mohrig, MSC, USAMRIID;
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Status of Venezuelan Equine Encephalomyelitis Vaccine, Thomas J. Smith, Major, MC, USAMRIID;
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Broad Spectrum Chemoprophylaxis of Typhoid Fever and Tularemia, Richard B. Hornick, M.D., University of Maryland;
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Blood-Free Culture Medium for Pasteurella Tularensis, Hugh B. Tresselt, Ph.D., USAMRIID;
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Electromicroscopy as a Diagnostic Tool, Anne Buzzell, Ph.D., USAMRIID;
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Rift Valley Fever Vaccine, Raymond Randall, D.V. M., WRAIR; and
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Report on Plague Antigens, John D. Marshall, Ph.D., USAMRIID.
At the fall meeting in September 1964, Drs. Cluff and Tigertt were made full members of the CES. Drs. Greisman and Hornick were appointed associate members.
RICKETTSIAL AND VIRAL VACCINE STUDIES
In 1965, a cooperative study of AFEB commissions was set up to include the CES, the Rickettsial Commission, and the Commission on Immunization. An ad hoc committee was appointed with Dr. Wisseman as chairman. The committee`s first effort was acting as a consultant group for the evaluation of the infectivity and immunogenicity of phase I and phase II Q fever organisms, conducted at the University of Maryland School of Medicine. The volunteers were from the Maryland House of Corrections. The phase II material was prepared at WRAIR, and the aerosol exposures were conducted at the U.S. Army Biological Laboratories at Fort Detrick. The volunteers were hospitalized at the University of Maryland Research Ward at the Maryland House of Corrections. Individuals receiving phase I vaccine were all protected against aerosol challenge. Individuals receiving the phase II vaccine were protected or not protected depending on dilution of the vaccine. Oral ingestion of challenge material produced no illness.
Additional studies reported 1 year later showed that the protection provided by the phase I vaccine was optimal only for about 1 year and that revaccination produced an unacceptable number of sterile abscesses at the revaccination site. Attempts to reduce the amount of vaccine used for the basic immunization series resulted in a significant decrease in protection. Preliminary studies of a phase II living attenuated strain of Q fever vaccine and a living attenuated strain obtained from Russia were reported. In additional studies of the oral administration of virulent Q fever organisms, it was found that an increase from 103 or 105 organisms to 3 x 107produced a high percentage of infections.
This committee also provided consultant services for the evaluation of Rocky Mountain spotted fever vaccine conducted under the University of Maryland contract. The protection afforded by two vaccines, one prepared by a commercial company and the other by the Rocky Mountain Laboratory, were studied. Neither provided any significant amount of protection when the vaccinated volunteers were challenged with either 10 or 1 guinea pig infectious doses (GPIPID50) of viable pathogenic rickettsia. Incubation periods for the vaccinees were slightly longer than those of the controls.
COMBINED AND SEQUENTIAL IMMUNIZATION
Another area of interest of the ad hoc committee was an evaluation of the studies conducted at USAMU and The Johns Hopkins School of Hygiene and Public Health on the use of combinations of antigens and sequential immunization with group A and B arboviruses. These studies, which were conducted over several years, were designed to determine whether various combinations of vaccines could be administered simultaneously or sequentially without losing antigenicity or producing untoward reactions. It was also reasoned that such administration of three or four vaccines against closely related viruses might confer some immunity against other viruses of the same group.
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In general, group A arboviruses VEE, western equine encephalomyelitis (WEE),and eastern equine encephalomyelitis (EEE) could be administered in various schema without undue interference with immunogenicity or reactogenicity but without significant cross- or extended immunity.
For the group B arboviruses, Dr. Winston H. Price of The Johns Hopkins School of Hygiene and Public Health, working under an Army contract, reported that the sequential administration of attenuated strains of yellow fever, Langot strain of the Russian spring-summer group, dengue II, and Japanese encephalitis virus to spider monkeys gave protection against all known strains of group Barbor viruses.
Other combined vaccines administered to animals were attenuated tularemia vaccine and nonviable anthrax protective antigen. This combined administration afforded homologeous protection without enhancement or interference by either strain.
Living tularemia vaccine and the living VEE vaccine also were administered as combined antigens without significant deviations from the results attained when the antigens were administered separately.
METABOLIC RESPONSE TO INFECTION
The metabolic response to infection was of considerable interest to the staff of USAMU from its early days, but not until 1962, with the arrival of Colonel William R. Beisel, MC did that interest expand into a major program. In addition to employing this approach to understand and describe the host response to an infectious agent and of the pathogenesis of certain infectious diseases better, this program searched for new methods and new concepts to permit recognition and etiologic identification of infectious illness during the incubation period.
These studies were enhanced by the studies in volunteers of metabolic changes occurring after the administration of live vaccines and challenge studies with a number of different organisms. If a study in humans was being planned by the medical division for the evaluation of a particular vaccine, a metabolic study would be added. This would require very careful fever determinations, urine and feces collections, and some additional examinations of blood specimens. The metabolic response of the immunized compared with the unimmunized subject to virulent challenge could be studied. Studies of tularemia, Q fever, and sandfly fever were conducted as was the response to bacterial endotoxin and physically induced hyperthermia. Individuals immunized against VEE and challenged with avirulent strain also were studied.
At the 1964 annual meeting of the CES, Dr. Beisel made the first detailed report on the metabolic studies conducted at USAMU. He stated that volunteers infected with the agents of tularemia, Q fever, and sandfly fever showed negative nitrogen balance soon after the onset of active infection.
Anorexia and loss of nitrogen in the urine and stool were largely responsible for such changes in tularemia. Artificial pyrexia induced in humans by the intravenous injection of Salmonella typhosa endotoxin provoked negative phases during the hyperthermic stages because of poor food intake, urinary losses, and losses caused by excessive sweating.
In sandfly fever, negative nitrogen balance was attributed to poor intake and urinary nitrogen excretion. Subjects ill with Q fever lost excessive urinary nitrogen when febrile. Rickettsemia and positive cultures of the pleural fluid occurred over 3 weeks in one subject even while under tetracycline therapy; despite the absence of fever, excess nitrogen loss occurred. Hence, fever did not play the only role in such changes.
The interest of the commission in this area increased significantly in the following years and the research program of the medical unit was expanded. In 1967, the fall meeting of the CES, which was held 7 and 8September at WRAIR, was devoted exclusively to this subject. In addition to CES mem-
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CHARLES L. WISSEMAN, JR., M.D.
At Southwestern Medical School, Dr. Charles L. Wisseman was a top scholar, and throughout his life, he conducted himself as a scholarly and productive scientist. After World War 11, he worked with Joe Smadel at WRAIR. At the bench and in the fields of Malaya, Borneo, Pakistan, and Africa, he effectively pursued the mysteries of typhus, encephalitis, leptospirosis, and other diseases of military importance.
Foremost as a rickettsiologist and skilled as a microbiologist, Charlie chaired the Department of Microbiology at the University of Maryland for manyy ears. Tireless in his work ethic, Charlie chaired the Commission on Rickettsial Diseases for many years until 1973, when the Commission system of the AFEB eased. Thereafter, he has consulted with many governmental and international agencies, including the World Health Organization.
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bers, the staff of USAMU, and representatives of the U.S. Army, Navy, and Air Force, a number of invited guests attended. These included
Dr. Hilton B. Levy
National Institutes of Health
Dr. Adam J. Rapalski
National Research Council
Dr. Elisha Atkins
Yale University
Dr. Harnish Monro
Massachusetts Institute of Technology
Dr. Paul M. Newberne
Massachusetts Institute of Technology
Dr. Sidney H. Ingbar
Thorndike Memorial Laboratory
Dr. Robert L. Squibb
Rutgers University
Dr. Herbert L. DuPont
University of Maryland
Dr. Vernon R. Young
Massachusetts Institute of Technology
Dr. Harold N. Glassman
U.S. Army Biological Laboratories, Fort Detrick
Dr. Elliot M. Levine
Albert Einstein College
Dr. Joseph E. Johnson
University of Florida
Dr. John M. Woodward
University of Tennessee
Dr. Bernard duBuy
University of Maryland
Dr. Paul C. Zamecnik
Harvard University
Dr. Frank A. Carozza, Jr.
University of Maryland
Dr. Peter F. Benventre
University of Cincinnati
Dr. Walter W. Kernmener
National Air and Space Administration
Dr. Morton I. Rappoport
University of Maryland
Dr. Samuel Bessman
University of Maryland
Dr. Irving Gray
Georgetown University
Dr. Beisel stated in his introductory presentation that this meeting of the CES would provide a critical review of this portion of the USAMU research program, which was then in its 5th year. The meeting brought together, for the first time, a large number of individuals whose research interests were directed toward studies of the host response to infection; other invited guests were asked to participate because of their knowledge in closely related fields. Dr. Beisel concluded with the statement that it was his hope and that of the USAMU staff that the program would provide a platform for open discussion and exchange of ideas and concepts. In this way, new leads and suggestions would guide future investigations. The program was divided into six sections:
Section I-Amino acid and enzyme alterations in the host.
Moderator: Dr. Theodore E. Woodward
Discussant: Dr. Samuel Bessman
Section II-Cellular nucleic acid changes during infection.
Moderator: Dr. W. Barry Wood, Jr.
Discussant: Dr. Hilton Levy
Section III-Immunological aspects.
Moderator: Dr. Wood
Discussant: Dr. James G. Hirsch
Section IV-Infection and generalized host responses.
Moderator: Dr. Leighton E. Cluff
Discussant: Dr. Sidney Ingbar
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Section V-Infection and generalized host responses: Whole body responses.
Moderator: Dr. Cluff
Discussant: Dr. C. Wisseman
Section VI-Bacterial toxins.
Moderator: Dr. J. Vernon Knight
Discussant: Dr. Eli Atkins.
Thirty-one formal papers and discussions were presented during this 2-day symposium. The research presented was conducted at the USAMU at Fort Detrick, other Department of Defense laboratories, universities and institutions under contract to the CES, and a number of other research laboratories with programs closely allied to the research presented at this meeting.
Dr. MacLeod was called on to summarize the proceedings. He stated that many good and new observations had been made during the meeting. Dr. MacLeod was particularly pleased at the progress made by the USAMU in developing the comprehensive approach to the study of the metabolic alterations that take place during infection and congratulated Dr. Beisel and the medical unit research staff for their excellent presentations.
In his summary of the enormous amount of information presented, Dr. MacLeod classified the metabolic changes occurring during infection as follows:
First, as to whether the observed changes are direct responses of cells in tissues to the infectious agents. As examples of this, consider the destruction of cells because microbes are growing within them; damage to the cells by the toxic products of the microbes; or damage suffered by phagocytic cells in the course of the scavenger process. These would be direct effects.
The second set of changes would include those that are associated with the stress reactions, ie, changes that effect the hypothalamic, pituitary, and endocrine systems and lead to alterations that are distinct from those due to direct interaction of the microbe in the host tissue.
The third set would be those deriving from the microbe itself, ie, new enzymes appearing as a consequence of organism multiplication during virus infection, or the products of infectious agents such as extracellular protein or perhaps capsular polysaccharides or related products.
The fourth set of changes, of course, are those associated with the immunological response, the production of immunoglobulins for example.
Fifth, there are those effects described particularly by Dr. Gray that are associated with fever itself.
A sixth group might be the products that are not clearly associated with any one of the others, such as the emergence of C-reactive protein (which was not discussed in the meeting) or possibly the increased glycoproteins.
A seventh category would be a mixture of all of these which is probably what is usually going on in the course of an infectious disease.
In closing, Dr. MacLeod stated that the comprehensive nature of the presentations and discussions should provide anyone interested in this research with information on which new and perhaps different or better approaches aimed at solving some of the mysteries of the host response to infection might be developed.
This meeting stimulated the staff of USAMU into expansion of the metabolism and infection program and resulted in the recruitment of specifically selected staff members. New data from ongoing research fulfilled some of Dr. Macleod`s closing observations. In fact, the metabolic, endocrine, febrile, and immunological consequences of acute febrile illness (now termed acute phase response) were shown to be stimulated by hormone-like mediators. These are now termed cytokines and include the interleukins (interleukin-1 to interleukin-8), the interferons, colony-stimulating factors, and tumor necrosis factor (cackectin). These substances are released by certain body cells when activated by micro-
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organisms or their toxins. The metabolic responses to infection observed at USAMU by Drs. Beisel, Robert W. Wannemacher, Robert S. Pakarek, and Michael C. Powanda were attributed in 1969 to a factor that they termed leucocytic endogenous mediator (LEM). This substance is now known asinterleukin-1 and is identical to endogenous pyrogin (the fever-producing factor studied by Dr. Wood) and to lymphocytic activating factor (LAF), which activates the immune system.
RADIATION AND INFECTION
During the early 1960s, interest in the effects of ionizing radiation on infection and the immune response gained considerable momentum. The Commission on Radiation and Infection (CRI) had been added to the AFEB and plans for representation at meetings of this commission and the CES were formulated. Dr. Victor P. Bond, the Director of the CRI and Dr. Richard D. Stoner, Deputy Director, regularly attended meetings of the CES, and representatives of the CES were invited to meetings of the CRI. In addition, several joint ad hoc meetings were held both at the medical unit in Frederick and the Brookhaven National Laboratory in Upton, New York.
During this period, the CRI undertook a survey of the world literature on radiation and infection, and in 1965, the Medical Research Center, Brookhaven National Laboratory, produced an annotated bibliography containing over 800 abstracts concerning the effects of radiation on infection and the immune response. This endeavor added immeasurably to the research programs in this field.
At the annual meeting of the CES in September 1965, Lieutenant Colonel Nelson R. Blemly, MC, Chief of Radiology Division, USAMU reported on the effect of ionizing radiation on the immune response of mice to VEE. Whole-body radiation was accomplished with the 1 MEV unit at USAMU. The mice were exposed to 500 R of whole-body radiation. Challenge was with the attenuated vaccine strain of virus or the fully virulent Trinidad strain. During normal conditions, the attenuated strain produces no illness in mice and protects fully against later challenge with a virulent strain. Administration of the virulent strain to unprotected mice is 100% fatal. The well-being of the mice did not appear to be altered by the stress of the whole-body irradiation.
When the mice were immunized with a standard dose of the vaccine strain, radiation, either before or after immunization, had no effect on the outcome of challenge with the virulent strain. When the immunizing dose was decreased, the protection afforded the irradiated animals was significantly decreased. It was hypothesized that, in the irradiated animals, replication of the attenuated virus was decreased to the point that protection was not established or that antibody production sites were damaged to a degree that interfered with antibody production.
At the meeting of the AFEB in May 1968, action was taken to combine the CES and the CRI. Members of the CRI were transferred to the CES, and the first meeting of the combined commissions was held on 5 September 1968 at WRAIR. Membership of the newly constituted committee was as follows:
Members
Victor P Bond, M.D.
Leighton E. Cluff, M.D.
Zanvil A. Cohn, M.D.
Dan Crozier, M.D.
John H. Dingle, M.D.
Sanford S. Elberg, Ph.D.
Thomas Francis, Jr., M.D.
Jacob Furth, M.D.
James G. Hirsch, M.D.
J. Vernon Knight, M.D.
Colin M. MacLeod, M.D.
David E. Rogers, M.D.
Myron S. Silverman, Ph.D.
Richard D. Stoner, Ph.D.
Morris Tager, M.D.
William D. Tigertt, M.D.
W. Barry Wood, Jr., M.D.
Theodore E. Woodward, M.D., Director
Associate Members
Austin M. Brues, M.D.
Sheldon E. Greisman, M.D.
Richard B. Hornick, M.D.
Fred R. McCrumb, M.D.
C. Phillip Miller, M.D.
Charles L. Wisseman, Jr., M.D.
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Dr. Bond, Director of the CRI, presented his final report to the new commission. He summarized the mission of the CRI as follows:
1. To review and keep abreast of research and other work and activities that pertain to the effects of ionizing radiation on resistance to infection.
2. To identify deficiencies or voids in our knowledge in this field, particularly as related to problems of potential importance in military operations.
3. To attempt to stimulate and encourage investigative work in this field with particular reference to matters of current or potential military pertinence, recognizing that the information developed would be as pertinent to the understanding of infectious processes as to the effects of ionizing radiation.
4. To apprise the military of newer developments that pertain to the effects of radiation on the resistance to infection of exposed subjects.
5. To review on a continuing basis, immunization and other prophylactic procedures that may be employed by the military in the light of possible atomic and biological warfare.
6. To press, continuously for a more complete realization of the hazards of radiation in nuclear warfare.
Dr. Bond also discussed certain problem areas in the investigation of radiation and infection that should be considered for future research. Final reports of three research projects conducted under contract with the CRI were submitted.
The major portion of that meeting dealt with a classified review of the defense against biological warfare. Papers were presented by Colonel Crozier, Dr. Housewright, Mr. E. K. Wolfe, Dr. Benjamin Warschowsky, Captain Lloyd F. Miller, U.S. Navy, Lieutenant Colonel Dale R. Lindall, U.S. Air Force, Lieutenant Colonel Robert W. McKinney, Captain Charles F. Craig, and Colonel Beisel, USAMRIID. Copies of these presentations can be obtained from the U.S. Army Medical Research and Development Command by those cleared for access to classified information.
At the second meeting of the CES-CRI on 4 and 5 September 1969, Drs. Balish, Myron S. Silverman, and Alvin Volkman reported on their work on the effects of radiation on infection and immunity. The reports included not only studies on laboratory animals, but also studies carried out on three humans accidentally irradiated with doses ranging from 100 to 550 R, and 27 patients that had received whole-or partial-body radiation for therapeutic purposes.
At the 1970 meeting, Dr. Volkman, working under contract on problems of cell-mediated immunity, reported that recovery of hypersensitivity after radiation injury in animals is mediated by macrophages and not lymphocytes.
At the September 1969 meeting of the CES, Dr. Gustave J. Dammin, president of the AFEB, announced that a new category of commission members, advisory members, had been established. These advisory members would consist of commission members who had served over long periods and who felt that they could no longer devote the time and energy required to be a fully active commission member. Advisory members would not be expected to attend meetings on a regular basis but would make themselves available for special consultation and would attend meetings when specifically requested by the Director. Three members of the CES requested placement in this category. They were Drs. Dingle, Wood, and Thomas Francis, Jr. Unfortunately, Dr. Francis died in October that same year, and Dr. Wood died just a year and a half later, in March 1971.
The annual meeting of the CES for 1970 was held at WRAIR on 24 and 25September. The following CES members attended:
Colonel Dan Crozier, Deputy Director
Dr. James G. Hirsch
Dr. J. V. Knight
Dr. Colin M. MacLeod
Dr. Myron S. Silverman
Dr. Morris Tager
Dr. Theodore E. Woodward, Director
Dr. Sheldon E. Greisman
Dr. Richard B. Hornick
Dr. Charles L. Wisseman
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Also present were Dr. Dammin and Colonel Prior representing the AFEB, representatives from the U.S. Army, Navy, and Air Force, contractor personnel, staff members from USAMRIID, and a number of guests, including Dr. Allen L. Forbes from the Office of the Chief of Research and Development of the Department of the Army and Dr. Tov Omland, Director of the Norwegian Defence Microbiology Laboratory, Oslo.
Papers were presented by the following individuals under their affiliation:
USAMRIID
Kenneth A. Woeber
Robert S. Pekarek
Robert W. Wannemacher, Jr.
Robert H. Fiser, Jr.
Michael C. Powanda
William L. Steinhart
Gordon L. Bilbrey
Anne Buzzell
Peter G. Canonico
Neil H. Levitt
Joseph Kaplan
William H. Habig
John D.Marshall
David M. Robinson
Peter J. Bartelloni
William R. Beisel
William J.Caspery
Joseph F. Metzger
Joseph C. Denniston
Trudeau Institute, Saranac Lake, New York
Alvin Volkman
George B. Mackaness
University of Maryland
Sheldon E. Greisman
Celeste L. Woodward
Richard B.Hornick
Herbert L. DuPont
Stanley Music
Joseph Libonati
Richard Wenzel
M. J. Snyder
Theodore E. Woodward
STAPHYLOCOCCAL ENTEROTOXIN
Staphylococcal enterotoxin was of considerable interest tot he CES from the late 1950s. Cooperative studies between USAMU (later USAMRIID)and the Chemical Corps Biological Laboratories at Fort Detrick were carried out in the preparation, purification, and analysis of material appropriate for laboratory studies. Most research endeavors were carried on with staphylococcalenterotoxin B (SEB). Considerable difficulty was encountered in producing adequate amounts of so-called purified material.
Dr. Virginia G. McGann (USAMRIID) stated in 1969 that, after several years of intensive effort, the purified lot then being studied (lot14-30) had at least two enterotoxin B moieties and trace amounts of enterotoxin A, α-hemolysin, β-hemolysin, and polysaccharide. Dr. McGann added that physiological studies must be interpreted in light of these findings because of the high biological activity of many of these trace components and the similarity of some of the effects reported for SEB and such components as α-hemolysin.
The first reports to the CES on this subject were presented at the annual meeting on 9 September 1965. Two of these were presented in open session: Serologic Studies on Staphylococcal Enterotoxin B by Dr. McGann and The Mechanisms of Pyrogenicity of Staphylococcal Enterotoxin B by Captain Frank A. Carozza, MC (USAMRIID). The following day, in executive session, USAMRIID researchers presented a classified program consisting of the following papers:
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Pyrogenic Effect of Staphylococcal Enterotoxin B, Captain Carozza;
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Clearance and Localization Kinetics of Radioactive Labeled Staphylococcal Enterotoxin B:
Part I. Captain Morton I. Rappoport, MC
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Part II. Captain Leland F. Hodoval, VC
Part III. Captain Earl L. Morris, VC
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Effects of Staphylococcal Enterotoxin B on the Coagulation Mechanism and Leukocyte Response in Beagle Dogs-A Preliminary Study, Captain Charles F. Gilbert, MC
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Serologic Methods of Detection of Staphylococcal B Antibody, Captain Martha K. Ward, USPHS; and
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Detection and Measurement of Immunological Responses to Staphylococcal Enter toxin B, Dr. McGann.
These papers were later declassified and are now available in the open literature.
Papers on SEB were presented in 1966 by Captain Carozza and Dr. McGann and in 1967 by Captain S. J. Norman, MC (USAMRIID). Additional studies were presented to the CES at each annual meeting through 1972.
In 1964 and 1965, preliminary human studies of SEB were conducted in senior staff members of the medical unit at Fort Detrick. The results of these studies combined with a very large amount of animal data, including that conducted in chimpanzees, formed the basis for the first presentation of a proposal to the CES for a human study. This proposal was not approved by the CES, and additional information was requested. Shortly afterward, all requested data were provided, and the proposal was resubmitted to the members by mail. This proposal was unanimously approved, and the first study was conducted the same year in Whitecoat volunteers. During the following 14 months, 14 separate human studies were conducted. Most of these were separate parts of the originally approved protocol, but some were individually approved by the CES. These projects were highly productive, but no additional human studies were conducted after 1966.
STATEMENT OF MISSION
At the 1969 meeting, Dr. Dammin, President of the AFEB, stated that each commission should have a written statement of mission and that such statements should be constantly evaluated and updated and should be maintained on file in the office of the AFEB. The following mission statement was prepared by the CES and submitted to the AFEB:
1. To advise The Surgeons General of the Armed Forces of the United States on the medical defense against biological warfare and on the effects of radiation on host response as related to infection and immunity.
2. To evaluate the threat to the Armed Forces of biological warfare and to recommend policies, procedures, and methods for providing an adequate defense against such attack.
3. To review the research program of the Army, and when requested, of the Navy and the Air Force, in the medical defense against biological warfare and the effects of radiation on the host response to infection and to advise The Surgeons General on their overall direction.
4. To review the research program of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID, formerly USAMU, renamed in February 1969) and advise The Surgeons General of the Army on the work being accomplished.
5. To advise The Surgeons General on volunteer studies in the medical defense against biological warfare and, when requested, review individual experimental protocols and recommend approval or disapproval.
6. To initiate and direct a contract research program in the medical defense against biological warfare and in the field of radiation and infection.
The mission statement was approved and became the formal basis for CES activities.
1970 ANNUAL MEETING
The 1970 annual meeting of the CES was held on 24 and 25 September at WRAIR and was devoted to a review of the completed work or work in progress at the U.S. Army Medical Research Institute of
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Infectious Diseases or by institutions under contract with the AFEB. The varied titles of the papers presented exemplify the wide scientific range of the research program being monitored by the CES. The following papers were presented:
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Infection and Thyroid Hormone Economy, Kenneth A. Woeber, USAMRIID;
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Trace Metals and Infection, Robert S. Pekavek, USAMRIID;
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Lipid Metabolism and Infection, Robert H. Fiser, Jr., USAMRIID;
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Amino Acid Metabolism and Infection, Robert W. Wannemacher, Jr., USAMRIID;
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Tryptophan Metabolism and Infection, Michael C. Powanda, USAMRIID;
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Nucleic Acid Metabolism and Infection, William L. Steinhart, USAMRIID;
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Renal Function and Infectious Illness, Gordon L. Bilbrey, USAMRIID;
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Pathogenesis and Cellular Membranes, Anne Buzzell, USAMRIID;
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Cellular Biology and Exogenous Proteins, Peter G. Canonico;
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Rapid Detection of Antibody or Viral Antigens by Cellulose Acetate Electrophoresis, Neil H. Levitt, USAMRIID;
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Studies of Cellular Immunity, Joseph Kaplan, USAMRIID;
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Cytochromes of Pasteurella Pestis, William H. Habig, USAMRIID;
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Mechanisms of Delayed-Type Hypersensitivity and Other Types of Cell Mediated Immunity, Alvin Volkmann and George B. Mackaness, Trudeau Institute;
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Plague Vaccine Program, John D. Marshall, Jr., USAMRIID;
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Status of M-44 Q-Fever Vaccine Studies, David M. Robinson, USAMRIID;
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Recent Arbovirus Vaccine Studies in Man, Peter J. Bartelloni, USAMRIID;
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The Role of the Liver in Endotoxin Fever and Tolerance, Sheldon E. Greisman and Celeste L. Woodward, University of Maryland;
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Studies of Rocky Mountain Spotted Fever Vaccine, Richard B. Hornick, University of Maryland;
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Studies of Oral Enteric Vaccines, Herbert L. DuPont, University of Maryland;
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Induced Human Cholera, Stanley Music, Joseph Libonati, Richard Wenzel, M. J. Snyder, Richard B. Hornick, and T. E. Woodward, University of Maryland;
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Effects of Acute Infectious Illnesses on Sustained Work Performance in Man, William R. Beisel, USAMRIID;
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The Use of Electron Spin Resonance in Infectious Disease Research, William J. Caspery, USAMRIID;
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Staphylococcal Toxin Program of the Pathology Division, Joseph F. Metzger, USAMRIID;
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Hypersensitivity Reactions to Staphylococal Entertoxin B, Joseph C. Denniston, Jr., Virginia G. McGann, Donald E. Kahn, and Richard O. Spertzel, USAMRIID; and
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Effect of In Utero Venezuelan Equine Encephalomyelitis Infection of Fetal and Neonatal Mice, Richard O. Spertzel, USAMRIID.
One of the projects reported at this meeting was a study of the effects of acute infectious illnesses on sustained work performance in humans. It was postulated that in the event of a successful biological warfare attack on U.S. troops in combat, it would be possible that a high percentage of the military personnel in the target area would become ill. It was felt that in such a situation, some of the infected individuals would be capable of carrying on, to some extent, with their assigned duties. A study was designed under contract with the Psychology Department of the University of Louisville to quantitate these effects. This group was well-known for its work in measuring sustained work performance of individuals under stress.
Studies conducted in 1966 and 1967 were designed to obtain baseline information. Continuing studies in 1969 and 1970 included similar testing in volunteers infected with sandfly fever or tularemia to compare performance decrements during infection with concomitant changes in specific metabolic and clinical parameters and to determine if symptomatic therapy would help to sustain an individual`s ability to perform work.
Teams of five members each worked for 4 hours followed by a4-hour rest and another 4-hour period of work each day. The volunteer started the study period monitoring blinking lights, warming lights, and meters. The work then built in intensity to a high-performance requirement during which
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Few among us possess the competence, commitment, wise outlook, and equanimity displayed by Dr. Gustave Dammin. His productive war record was followed by a stellar and remarkable career as an experimental pathologist at Washington University School of Medicine and Harvard. The AFEB was singularly fortunate to have him as a member, an important contributor to several of its Commissions, and its distinguished president from 1960 to 1972.
During this important 12 years of AFEB and CES activities, Gus steered a steady ship. Substance abuse in the military, immunization practices, and change of AFEB function were some of the important problems presented to the AFEB during his tenure.
Gus was always on top of all issues and problems; he took them in his steady hand and saw that the best solution to the problem was reached through wise appointments and choice of consultants. Under his guidance, the AFEB and its stellar commissions flourished. A careful and dedicated scientist, Gus Dammin not only advised able investigators in pursuit of their investigative problems but made major contributions on his own. Gus Dammin`s leadership role for the AFEB is a matter of historical significance.
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the volunteer was simultaneously performing three monitoring tasks, solving arithmetic problems, and working on code solving by crew effort. This peak of work then tapered off somewhat but again increased when target identification was substituted for the arithmetic calculations. After baseline studies, the volunteers were exposed to the agents of either sandfly fever ortularemia.
The individuals infected with sandfly fever became ill on day 2, while those with tularemia became febrile on day 3 and reached a peak of illness on day 4.With the onset of symptomatic illness, sustained performance began to deteriorate and, in the patients with tularemia, reached group-average nadirs of27% to 44% below baseline. Recovery in performance followed the initiation of specific therapy. Use of symptomatic therapy (aspirin and Darvon) that began with the onset of symptoms and fever was quite successful in reducing performance decrements.
At this same meeting, some interesting but preliminary studies of cholera conducted in volunteers under contract with the University of Maryland were reported. Dr. Stanley Music reviewed studies of induced human cholera designed to develop a human model for testing cholera vaccines. Oral doses of 1011 cholera vibrios were found to be required to produce clinical diseases in a significant percentage of exposed volunteers. By administering 2 g of sodium bicarbonate in 60 mL of water immediately before the challenge dose of vibrio, the number required to infect was reduced to 106organisms. In additional studies, it was determined that the serologic response of volunteers developing diarrheal disease was similar to that occurring in naturally acquired cholera and that the presence of vibriocidal antibody was highly effective in protecting individuals against rechallenge 4 to12 months later with a homologous strain of vibrio.
VENEZUELAN EQUINE ENCEPHALOMYELITIS VACCINE
The development of an effective live vaccine against VEE infection in humans occupied an important place in the research program of USAMU from its earliest days. A large amount of information was available on the effectiveness of vaccine for the protection of equines, but the vaccine had never been considered seriously for use in this species as a prophylactic procedure.
When this vaccine had been approved for routine use for the protection of laboratory personnel and other persons at risk of infection, a decision was made to prepare a production amount of vaccine under the contract with the National Drug Company in Swiftwater, Pennsylvania. This was considered practical because the strength of the vaccine as administered to humans was 103 to 104 of the strength of the original tissue culture material, depending on its titer. This allowed small quantities of the undiluted material to be stored in the frozen state and when needed, diluted and freeze-dried in practical size containers. Thus, a 30-mL vial of original material could produce 30,000 to 300,000 doses of vaccine. Enough of the concentrated material was prepared and stored at the National Drug Company to produce approximately 60,000,000 doses of vaccine.
In 1966, a decision was made to prepare a production lot of this vaccine in20- and 30-mL vials for use in the protection of at-risk personnel and to study its stability in the freeze-dried state. Approximately 3,000,000 doses were prepared. This decision was made at an ad hoc committee meeting of the CES and senior representatives of the Office of The Surgeon General and USAMU. This was a fortuitous decision because in July 1969 an unexpected request for the vaccine was received.
VEE in horses ordinarily ranges from a mild short-lived respiratory disease to a severe central nervous system infection frequently resulting in death. Outbreaks of the disease had been identified in Central and South America since 1935, but the first severe outbreak north of Panama occurred in 1969. In May 1969, equine deaths were reported in El Salvador and Guatemala. On 4 July 1969, with only a presumptive diagnosis of VEE, a request for the vaccine was submitted by these two countries through State Department channels, to the U.S. Army Medical Research and Development Command. The initial shipment of vaccine was made on 8 July and was accompanied by consultants from the Centers for
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Disease Control in Atlanta, Georgia, and USAMU in Frederick, Maryland. Lieutenant Colonel McKinney and Richard O. Spertzel from USAMU spent several months in Central America as consultants.
The host countries organized vaccination teams that, working ahead of the infected areas in the predicted direction of spread, established barrier zones by administration of the vaccine and restriction on the movements of equines. Mosquito control was instituted where feasible. Before the epizootic was brought under control, programs were instituted in Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Mexico.
This campaign represented the first large-scale use of the live attenuated strain of VEE (TC-83) for the protection of equines in an epizootic situation. Because of the urgency of the situation, controlled studies were not feasible, but careful field observation persuaded the U.S. consultants that the vaccine was effective. These observations showed that in isolated areas where the disease had not appeared, immunization provided complete protection. In areas where the disease had already appeared, new cases ceased to appear in 7to 10 days.
In 1970, additional spread of the epizootic occurred in Mexico, and in October of that year at a meeting of the U.S. Animal Health Association, Lieutenant Colonel Spertzel predicted that the disease would spread into the southern United States, particularly Texas, early the next year. Efforts to gain approval for the commercial manufacture of the vaccine for animal use were unsuccessful, so the CES and the staff of USAMU recommended additional vaccine be prepared for possible use in this country. This was approved, and when the disease appeared in Texas in June 1971, the vaccine was available.
By mid-July 1971, cases were being reported as far north as Houston. In late June, immunization was made available to responsible authorities on a voluntary basis. Several large ranch owners immediately immunized their animals and experienced no cases of VEE. In other areas, immunization was not as complete, and a number of animals contracted the disease. In mid-July, immunization was made compulsory in Texas and shortly afterwards several additional states made vaccination compulsory. Some human cases occurred, but by September, only sporadic cases were being reported, and the epizootic was considered to be under control.
This VEE incident was a situation in which a vaccine never seriously considered for use in animals was called on in an emergency. Considerable information was available from the limited laboratory studies, but the vaccine proved remarkably effective in control of the disease. The availability of the vaccine was the result of the foresight of members of the CES and the staff of USAMU and the U.S. Army Medical Research and Development Command.
1971 JOINT MEETING
The 1971 meeting of the CES was held on 23 and 24 September at WRAIR as a joint meeting with the Commission on Immunization.
Members of the CES who attended were as follows: Drs. Crozier, Elberg, Hirsch, Knight, Silverman, M. Tager, Tigertt, Woodward, Greisman, Hornick, and Wisseman.
The following members of the Commission on Immunization attended: K. F. Austen, Benenson, Edsall, T. J. Gill, III, C. H. Kempe, G. B. MacKaness, R. O. Oseasohn, J. W. Uhr,. F. Verwey, H. B. Dull, Gochenour, Jr., B.B. Levine, Marshall, A. M. Pappenheimer, Jr., F. S. Rosen, E. H. Sadun, J. P. Sanford, A. M. Silverstein, and J. C. Wagner.
In addition, representatives from the AFEB, U.S. Army, Navy, and Air Force, USAMRIID, and a number of invited guests attended.
The death of advisory member Dr. W. Barry Wood on 9 March 1971 was commemorated in a memorial minute presented by Dr. Woodward as follows:
On March 9, 1971, Dr. W. Barry Wood, Jr. died suddenly in Boston of a heart attack at the age of 60. This premature death ended the career of a distinguished physician who, for almost forty years, set an exceptionally high standard of performance as an investigator and educator. This Board and its family of Com-
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missions profited immeasurably from his willingness to become involved in problems of paramount importance to the United States.
There are few thoroughly versatile men in contemporary life. Barry was one. Excellence came naturally to him as a scholar, as a graceful, hard-nosed athlete, as a physician who related to the patient, as a scientist who related to the fundamental issues of problems, as a teacher revered by students, and as an administrator who recognized and solved problems logically.
Harvard graduated him with honors in 1936, and Grantland Rice recognized him as of the all-time athletes. Barry was a Hopkins medical graduate and house officer on the Osler Service. Special research experience in microbiology at Harvard under Hans Zinsser prepared him further, with a strong biomedical foundation, for Chairmanship of the Department of Medicine at Washington University in St. Louis in 1942. He was a superb teacher who stressed that a good physician, to properly care for his patients, must be thoroughly trained in medical science.
Barry Wood was a clinician and a fundamental biologist. Uniquely and with eminence he combined these fields. Perhaps he is best known for studies in the pathogenesis of fever. With colleagues, in seeking the molecular basis of pyrexia, he elucidated the mechanisms whereby an endogenous pyrogen from both rabbit polymorphonuclear leukocytes and mononuclear cells plays a major role in the pathogenesis of fever. Other research interests and contributions which significantly advanced knowledge were in the fields of antibacterial chemotherapy, experimental pneumonia and leukocyte phagocytosis. Medical students still recall that a former All American football player first described " surface phagocytosis."
Dr. Barry Wood gave his time and wise counsel unstintingly to the U.S. Army Surgeon General, to the Board and its Commissions. The "Board for the Investigation and Control of Influenza and Other Epidemic Diseases of the United States Army" and Commissions on Meningococcal Meningitis, Pneumonia, Streptococcal Diseases and Epidemiological Survey profited from his advice for years. Early, Barry recognized the need for special in-depth studies of the relationship of radiation and infection; he organized a new Commission and served productively as a member. For years, he carried his share and more as a full Board member. In spite of failing health, Barry, without flinching, retained membership on the Commission on Epidemiological Survey to lend his mature support, sorely needed in sensitive areas of investigation.
One very satisfying field experience came from his visit to Korea in the fall of 1952. Perceptive as a clinician, he detected the delicate balance between blood volume, shock, and the need for judicious fluid replacement in soldiers seriously ill with epidemic hemorrhagic fever. This was Barry`s forte, the ability to perceive a difficult problem and reach the closest possible solution. Unruffled in expression, his word was always respected. His questions were penetrating and often represented the important clues to the answers of puzzles.
Dignity and personal grace were his special gifts. Barry was a devoted husband and father; his family was closely woven. Years ago, a master at the Gilman School in Baltimore was annoyed with a group of awkward grade school kids whose football togs were ill-fitted. One boy volunteered to center the football and asked, "Which knee, right or left?" The ball came back to the proper knee like a bullet. On request, he answered, "My name is Wood, sir." All of the Woods are wonderful persons, a splendid legacy.
Barry Wood will be sorely missed by the medical profession and the scientific community, by every medical and academic institution which bears his mark with pride, by this Board and Commission members, by members of each service of the Department of Defense, and by the countless young men and women stimulated and taught by him. Fittingly, we express sympathy to his family and recall with pride that Barry Wood was a remarkable man.
The 2-day joint meeting of the two commissions reviewed the research programs being conducted by AFEB contractors of the commissions and by investigative staff of USAMRIID. Emphasis was placed on the scientific areas of mutual interest to members of both commissions. The scientific program re-
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Dr. W. Barry Wood was a proud alumnus of Harvard and Johns Hopkins. His career was marked by distinction in everything that concerned him. At Washington University, he excelled as an academician and Chairman of the Department of Medicine. One of his major contributions to the field of biology was the demonstration of the phenomenon of "surface phagocytosis." He contributed to the solutions of many infectious disease problems.
Barry was an early member of the AFEB and one of the charter members of the CES. His presence and stature alone were of considerable help to the AFEB and its Commissions.
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COMMISSION ON EPIDEMIOLOGICAL SURVEY
Fall meeting, 21 and 22 September 1972
Walter Reed Army Institute of Research
Washington, D.C.
Seated, left to right: Dr. James G. Hirsch, Gustave J. Dammin (President, AFEB), Dr. Theodore E. Woodward (CES Director), Dr. Sanford S. Elberg, Dr. J. Vernon Knight
Standing, left to right: Lieutenant Colonel Norman E. Wilks, (Executive Secretary, AFEB), Dr. Sheldon E. Greisman, Dr. Richard D. Stoner, Dr. Myron S. Silverman, Colonel Dan Crozier, MC (Deputy Director), Dr. Charles L. Wisseman, Jr.
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viewed the individual programs and discussed the status of VEE, antibody interaction, antibody formation and methods of assay, biochemical and humeral aspects of cell-mediated immunity and hypersensitivity reactions, development of vaccines for spotted fever, Q fever, gram-negative enteric infections, smallpox, mumps, plague, rabies and tetanus, status of epidemic hemorrhagic fever in Latin America, and the current knowledge of staphylococcal enterotoxoids and metabolic alterations in infection. The two commissions prepared separate annual reports.
Speakers reporting research conducted in programs monitored by the CES were as follows: Drs. Spertzel, Mary H. Wilkie, Stanley G. Rabimowitz, Kaplan, Neil H. Levitt, William H. Adler, Volkman, Canonico, Beisel, Pekerek, Richard H. Kenyon, David M. Robinson, Clarence J. Peters, Joseph F. Metzger, Richard B. Hornick, and Sheldon E. Greisman.
TERMINATION OF CES
In December 1970, Brigadier General Richard R. Taylor, the commanding general, U.S. Army Medical Research and Development Command informed the AFEB of projected changes in the structure and operation of the board and its commissions. This was the result of a congressional directive requiring a review of all consultative boards and commissions of the federal government.
During 1971 and 1972, a detailed examination of the AFEB and its commissions was conducted and at the December 1972 meeting of the board a report was submitted detailing a new advisory system for the Medical Research and Development Command.
In the fall of 1972, when it became apparent that the CES would end shortly, the commander of the USAMRID forwarded a letter to the commanding general, USAMRDC, with copies to the president of the AFEB and the chairman of the CES requesting that an advisory group be appointed to continue the advisory functions of the CES with regard to the in-house research program at USAMRIID. This was approved, and a new advisory group operating independently of the AFEB was appointed. This group, under the chairmanship of Dr. Woodward, was expected to consist of qualified experts in the various fields relating to the research programs of USAMRIID. They would have regularly scheduled meetings at Fort Detrick but, in addition, would have smaller ad hoc groups appointed to advise, when requested, on specific programs and to provide emergency consultations when considered appropriate. The first formal meeting of this group was scheduled to meet at Fort Detrick on 27 and 28 September 1973.
The CES ceased to exist on January 1, 1973. At the close of the last meeting of the CES on 21 and 22 September 1972, Dr. Woodward made the following statement:
Grateful appreciation is expressed to members of the commission who through many years have given much to the development of new leads useful for control of infectious diseases and who, through their unstinting contributions of time and effort, have helped keep the military service abreast of where the problems are and how they might be solved. The intellectual stimulus and counsel provided by the members are immeasurable in terms of benefit to the Armed Forces.
