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Section 7

The Histories of the Commissions - Contents

Commissions on Immunization and Rickettsial Diseases


History of the Commissions on Immunization and Rickettsial Diseases

Theodore E. Woodward, M.D.

INTRODUCTION

Limitations of space do not allow inclusion of other commission historical accounts in this edition, which chronicles the activities of the Armed Forces Epidemiological Board (AFEB). Rather close identification with the Commissions on Immunization and Rickettsial Diseases prompted me to pre pare short accounts of their important contributions. These two Commissions made significant contributions to the AFEB and its research system that were most relevant for control of infectious diseases in the military services. No attempt has been made to discuss administrative and procedural details involving each of these commissions; rather, a few of their important activities, including the persons involved, are briefly considered.

COMMISSION ON IMMUNIZATION

My first exposure to AFEB activities was via its Commission on Immunization, which was first chaired by Drs. Joseph Smadel and then by Geoffrey Edsall and Bud Benenson. Because of past experience with Rickettsial infections, human vaccine efficacy trials, and work on scrub typhus and typhoid vaccines, I was asked to serve as a consulting member. The first meeting I attended was in Philadelphia at the Jefferson Medical College, when Dr. Ken Goodner served as host for a two-day meeting. At the time, I could not understand why two full days were needed. As it turned out, there were many scientific and strategic details that needed to be thoroughly evaluated, discussed, and agreed on before further studies on any specific problem could be approved.

During the meeting, the results of many ongoing projects were heard, evaluated, and ultimately put into action. There was close collaboration and complete understanding and trust between military and civilian scientific investigators; this was absolutely essential if an extensive program of this type could be successful. This collaboration and understanding was, and continues to be, a basic tenet or modus operandi of the AFEB, its commission members, and its military representatives.

So many scientific pioneers contributed to the commissions of the AFEB. Indeed, a 2-day meeting of any commission group represented the latest and best scientific review of a specific topic that could be heard anywhere.

Plague was an important topic at the time, and who among us could ever forget Dr. K. P Meyer's discussion of this ancient disease? Not only was plague then an infection of worldwide importance, but the plague bacillus ranked highly as an effective weapon for biologic warfare. This was a very hot topic in the early 1950s. Our Russian adversaries were highly sophisticated and very active in this general field.

In a discussion of the various means of transmission of the plague germ between humans, Dr. Meyer spoke of the "traffic of saliva at a Mexican funeral." He was describing a practice in Mexico and certain other ethnic settings in endemic areas of plague, including the Greek culture, where it was common practice to kiss the dead. There could be no better way to transmit plague than by this route.


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ABRAM S. BENENSON, M.D.

After he graduated from Cornell University Medical College in 1937, Bud Benenson trained at Bellevue Hospital, New York, and entered the U.S. Army Medical Corps in 1940. From then until 1962, he progressed through the ranks to colonel and served at Tripler General Hospital; the Medical Field Service School at Carlisle, Pennsylvania; the Fourteenth Field Hospital, Korea; the Army Medical Service Graduate School; the Second Army Area Medical Laboratory at Fort George G. Meade; the Tropical Research Medical Laboratory at San Juan, Puerto Rico; USAMRIID at Fort Detrick, Maryland; and the Walter Reed Army Institute of Research. His medical service embraced the fields of microbiology, virology, immunology, epidemiology, and tropical medicine. He made important contributions to cholera research in Dacca, Pakistan. The Jefferson Medical College of Thomas Jefferson University, the University of Kentucky College of Medicine, and the Gorgas Memorial Laboratory and the School of Public Health in San Diego have all had the advantage of his academic contributions.

Bud Benenson has served the AFEB and many of its commissions, and he directed the AFEB's Commission on Immunization for a number of years. He is an infectious-disease authority whose fundamental background is excellent, whose memory of historical findings is uncanny, and whose ability to correlate the old with the new is impressive. Bud now heads the AFEB's Subcommittee on Infections, a public service that merely highlights his long list of contributions to the AFEB.


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CHARLES L. WISSEMAN, JR., M.D.

At the University of Texas Southwestern Medical School at Dallas, Charlie Wisseman was a top student, and throughout his life he was a scholarly and productive scientist. He was Chairman of the Department of Microbiology at the University of Maryland for 38 years.

Following World War II, he worked with Joe Smadel at Walter Reed Army Institute of Research. He pursued the mysteries of typhus, encephalitis, leptospirosis, and other diseases of military importance both at the bench and in the fields of Malaya, Borneo, Pakistan, and Africa. He was Director of the Commission on Rickettsial Diseases from 1959 to 1973, when the commission system of the AFEB ceased. Since then, he has been a consultant to many governmental and international agencies, including the World Health Organization.


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GEOFFREY EDSALL, M.D.

Geoff Edsall graduated from Harvard Medical School in 1934 and served his house officership at the Massachusetts General Hospital from 1934 to 1936. Research fellowships at Harvard and instructorships in bacteriology and immunology at the Harvard Schools of Medicine and Public Health followed. From 1940 until 1942, he was Assistant Director of the Division of the Biologic Laboratories of the Massachusetts Department of Public Health, and was its Director until 1949. For several years, he was Professor and Chairman of the Department of Microbiology at Boston University School of Medicine, which was followed by his appointment as Director of the Division of Immunology at Walter Reed Army Institute of Research in 1951.

Geoff served the AFEB in many ways, particularly as the Director of its Commission on Immunization from 1952 to 1963. This Commission was graced by the membership of some of the leaders in American medicine in the fields of biology and immunology, and it accomplished, under Geoff's direction and in collaboration with other commissions, a vast amount of work. The three-day meetings that this Commission held at WRAIR were actually reviews of the contemporary work in immunology and vaccine development. Geoff also served as a member of the Commission on Epidemiological Survey, where his advice was put to good use. His research interests were broadly distributed throughout immunology, and his special contributions were in the purification of toxoids, particularly those of tetanus and diphtheria.


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JOSEPH E. SMADEL, M.D.

For 32 years, Joe Smadel was a physician and investigator whose contributions to medical science either saved or prolonged the lives of thousands of people. At the time of his death in 1963, Joe was recognized as one of the outstanding scientists of the mid-20th century. Expecting no reward, he performed research because he liked it, and his labors provided the essential bridge between the laboratory and the physician who cares for infected patients. One of his most satisfying experiences was the therapeutic triumph with chloramphenicol in the treatment of typhus and typhoid fevers, and the successful field trials that showed that this antibiotic effectively suppressed scrub typhus infection.

A major contributor to the AFES, he organized and directed three of its Commissions: those on Immunization, Rickettsial Diseases, and Epidemic Hemorrhagic Fever; each of these Commissions bears the indelible Smadel mark. He was also a member of the Commissions on Epidemiological Survey, Virus Diseases, and Influenza, and his stabilizing influence during the developmental phases of the poliomyelitis vaccine trials contributed significantly to that success.

Joe had little patience for armchair philosophy, and he crusaded against shallow thinking. He demanded unswerving performance from his associates, who were expected to exercise good judgment and to adhere to his work, and his enthusiasm sparked the enthusiasm of his associates. He worked intently and set an example for others.


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Just a year or two later I learned of another method of the spread of plague in Madagascar. It was a local custom there to remove a body from a family burial site each year, redrape the corpse, hold a family celebration, and return the body to the ground. This was another efficient way to transmit the germ of plague, which is hardy and resists drying. This practice led to governmental intervention that stipulated that patients dying of La Peste (plague) must be buried in a government burial site without chance for reburial.

During the meetings of the Commission on Immunization, Dr. Albert Sabin always had his say and argued effectively with anyone. Drs. John Paul and John Enders, the top gentlemen of the group, always made their points carefully, authoritatively, and painstakingly. Drs. Thomas Francis, Colin MacLeod, Gustave J. Dammin, John Dingle, and Charles Rammelkamp never failed to make important points, clarify the issues, and effectively summarize the known data of a problem. Dr. Smadel was not known for mincing words. Capable persons, such as these and many others, served the AFEB for many years and really represented a national resource of public health knowledge.

Out of the many commission meetings, came a much better understanding of immunological principles and the methods for developing new vaccines for such diseases as influenza, poliomyelitis, measles, mumps, adenovirus infections, rickettsial diseases, typhoid fever, tularemia, plague, and others. To evaluate efficacy, all such work was group supervised and carried through from its planning to implementation of field studies, and finally to testing in humans. The work of this Commission, which was performed in close collaboration with other commissions and the AFEB itself, represented some of the best work available on immunization for infectious diseases.

During these active and productive years of the Board and its commissions, Betty Gilbert was remarkably efficient in ensuring that the administrative affairs of the program ran well.


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CAPTAIN WILLIAM M. PARSONS, USN, MSC
Executive Secretary of the Board 1990 to 1992

 

COLONEL MICHAEL P. PETERSON, USAF, BSC, DVM
Executive Secretary of the Board 1992 to present


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BETTY L. GILBERT
Administrative Assistant

 

JEAN WARD
Administrative Assistant


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COMMISSION ON IMMUNIZATION
Fall Meeting 18-20 October 1972
Walter Reed Army Institute of Research,
Washington, DC

Standing, left to right: Drs. C. Harry Kempe; Robert O. Oseasohn; Bernard B. Levine; Willard F. Verwey; Thomas J. Gill III; Richard B. Hornick; Arthur M. Silverstein; Bruce Dull; and John C. Wagner.

Seated, left to right: Drs. Jonathon W. Uhr, Deputy Director; Abram S. Benenson, Commission Director; Margaret Pittman, and Elmer L. Becker.


COMMISSION ON RICKETTSIAL DISEASES

In 1954, the AFEB determined that Rickettsial diseases were of sufficient importance for a separate commission and, accordingly, transferred the older Rickettsial disease component of the viral and Rickettsial Disease Commission to a newly established commission on Rickettsial diseases with Dr. Joseph E. Smadel as director. Membership of the newly created commission drew heavily from the ranks of the World War II United States of America Typhus Fever Commission for initial membership. Dr. Charles L. Wisseman, Jr., became director beginning at the annual meeting of the Commission held at Walter Reed Army Institute of Research on 4 and 5 March, 1960.

This Commission of the AFEB has a proud heritage, and it was comprised of the leading rickettsiologists in the country. It was privileged to have the consultative advice of world leaders in this field such as Drs. Raymond Lewthwaite (United Kingdom), Marcel Baltazard (France), James Gear (South Africa), and Ralph Audi (United Kingdom). Drs. Smadel and Charles Wisseman were its directors for many years, with heavy and steady input from Jack Snyder, Bob Traub, John Fox, Charley Shepard, Buz Wheeler, Andy Yeomans, Ed Murray, Paul Fiset, Neil Philip, Willy Burgdorfer, Dick Ormsbee, Henry Fuller, and Lew Barker. I was privileged to serve as a full member of this Commission.

Epidemic typhus fever was not really a threat to our military forces during World War II because of better health standards, an effective vaccine, and the use of dichlorodiphenyltrichloroethane (DDT), which prevented louse infestation. Indeed, there were no deaths during the war from louse-borne typhus except those few suffered by our British allies. In North Africa alone, there were 33 cases in British Military Forces and 3 deaths that could have been avoided. During the war, louse typhus was quite prevalent in civilians in North Africa and in Southern Italy, particularly in Naples. When the British adopted use of the American typhus fever vaccine, this problem ceased.

Q fever was another concern in the Mediterranean area, particularly in Italy. Our forces experienced many cases of this illness, which was then known as the "Balkan grippe." The illness was manifested by headache, fever, muscle pains, and an atypical pneumonia-like syndrome. Fortunately, there were no deaths. Nevertheless, it was temporarily harassing and disabling for those infected. Dr. Fred Robbins worked with patients in Italy, and Dr. Chris Zarafonetis was responsible for obtaining a Q fever strain (carried in a blood specimen), which he obtained from Greek authorities at the Pasteur Institute in Athens.

Rocky Mountain spotted fever was never an epidemic threat nor was murine typhus, which involved a rat-flea-human cycle. However, scrub typhus, which is transmitted by mites, was another matter. During World War II, it was responsible for disabling and killing a number of American military personnel in the southwest Pacific area.

The Commission on Rickettsial Diseases helped solve many of these riddles. Actually, the typhus project mission in Malaya in 1948 was conducted under the umbrella of the Commission on Immunization of the AFEB. The important contributions that resulted from this work included

. the first known specific treatments of scrub typhus, murine typhus, and Rocky Mountain spotted fever,

. the first known specific treatment of typhoid fever, and

. the first known demonstration that an antibiotic given prophylactically and intermittently to persons exposed to scrub typhus fever in the field could prevent them from developing the illness.

The third item was a contribution of significant military importance. The total expenditure for the project was less than $50,000. Thus, potent weapons were now available that practically guaranteed protection against death from any rickettsial infection, particularly scrub typhus. Also, patients promptly responded to specific antibiotic treatment with full recovery. Better understanding of the pathologic and physiologic changes in patients even led to recovery in advanced cases.

Effective vaccines for the rickettsial diseases, particularly epidemic typhus, Rocky Mountain spotted fever, and Q fever, were developed under the auspices of the Commission.


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COMMISSION ON RICKETTSIAL DISEASES
Walter Reed Army Institute of Research, Washington, DC
March 1963

First row, left to right: John P Fox; Charles C. Shepard; Charles L. Wisseman, Jr.; Edwin H. Lennette; Joseph E. Smadel; and Gustave J. Dammin.

Second row, left to right: Unidentified; Edward S. Murray; Richard A. Ormsbee; Emilio Weiss; Unidentified; and Herbert L. Ley.

Third row, left to right: Unidentified; Henry S. Fuller; Colonel Adam Rapalski; Unidentified; Unidentified; and Colonel Stefano Vivona.


540

COMMISSION ON RICKETTSIAL DISEASES
Fall Meeting 30 November―1 December 1972
Walter Reed Army Institute of Research, Washington, DC

Seated, left to right: Drs. John P. Fox; Bennett L. Elisberg, Deputy Director; Charles L. Wisseman, Commission Director; Edwin H. Lennette; and Richard A. Ormsbee.

Standing, left to right: Mrs. Hope E. Hopps; Miss F. Marilyn Bozeman; Lewellys F. Barker; Robert Traub; Emilio Weiss; Richard A. Mason; Edward S. Murray; Sanford L. Berman; Joseph P. Lowenthal; Paul Fiset; Willy Burgdorfer; and Irene B. Fabrikant.


541

Strain E type epidemic typhus, an attenuated strain of Rickettsia prowazekii first identified and studied by Dr. Snyder, was developed further by Drs. Fox and Wisseman. This vaccine caused some reactions in humans, which limited its use.

A scrub typhus vaccine was never successfully developed because of difficulties in identifying specific antigens and problems related to producing pure vaccine material. Yet the Commission helped sponsor studies that were conducted by investigators at Walter Reed Army Institute of Research (WRAIR) and the University of Maryland. These studies showed that either chloramphenicol or tetracycline, given in single doses at an interval of once weekly for 5 weeks, prevented illness from developing in an infected person. This work involved classic human field trials conducted during several years in Malaya.

Under the Commission, the Maryland group tested older type vaccines for Rocky Mountain spotted fever, including the original tick tissue strain first used by Ricketts in Montana. It was shown not to be significantly protective when tested in volunteers in Baltimore, Maryland. Even the newer, whole rickettsial cell vaccines lacked full protective properties. Dr. Richard Hornick and his team conducted these studies under Commission sponsorship and encouragement.

The Commission's work on Q fever ranks very highly. A new and inactivated protective vaccine was developed at WRAIR and Ft. Detrick. Much good work that involved extensive studies in primates and in humans was initiated on attenuated vaccines. The work on humans first involved expo sure of volunteers at Ft. Detrick in a large sphere called the "8-ball" that could measure the exact number of Rickettsiae delivered to a single person. Such resultant infections could be quickly stopped with prompt antibiotic treatment. Later trials in the field, first with sheep and then with volunteers, were conducted in the salt flats in Utah just outside Salt Lake City. These studies conducted in the 1950s showed that a cloud laden with living Coxsiella burnetti (Q fever) could infect sheep and humans a number of miles downwind. Drs. William Tigertt and Bud Benenson spearheaded these studies along with Commission members Drs. Richard Shope, Smadel, MacLeod, Wisseman, and Woodward.

In addition, important and better understanding of Q fever resulted from the work of Dr. Paul Fiset, who showed that Q fever Rickettsiae could wear several faces, called Phase I and Phase II, a change that was important for vaccine development and accurate diagnosis.

These studies and those of others have pushed rickettsial diseases "backstage," but their potential threat remains. Even now, scrub typhus fever is a considerable problem in North Thailand, where it is endemic and accounts for about 25% of the cases of Fever of Unknown Origin (FUO).

In April 1970, on request, the Commission developed a revised mission statement.

To provide, through the AFEB, to the military department scientific and research assistance and to advise on all pertinent aspects of prevention, control, diagnosis and treatment of diseases caused by Rickettsia agents, Chlamydia and such other non-viral bacteria-like intracellular parasites which require similar methods of study, for example Ehrlichia.

Some of the first and significant contributions to better public health made by members of the Commissions on Immunization and Rickettsial Diseases (based on publication in leading medical journals)

. Reported a series of studies that showed that very small doses of diphtheria toxoid were effective in recalling established immunity and that adverse reactions were minimized by use of a purified toxoid.

. Developed tetanus and diphtheria toxoids and introduced their use in the military. These became the standard in the United States until an alum-adjuvanted tetanus and diphtheria toxoid later permitted significant extension of the booster intervals.

. Sponsored and assisted in the development of jet injectors with intradermal capability, a technique for vaccine administration that was instrumental in helping control smallpox and other microbial diseases.

. Demonstrated the first known specific cures of scrub typhus, murine typhus, and Rocky Mountain spotted fever with chloramphenicol in 1948.


542

Major General Edward J. Huycke, MC, (left) presents the
Commander's Civilian Service Award to Abram S. Benenson, M.D.
1 September 1983

 

Dr. Theodore Woodward presents the Smadel Award to
Abram S. Benenson, M.D.
1 February 1981


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. Reported the chemoprophylactic field studies that showed that the intermittent administration of chloramphenicol (later tetracycline) prevented scrub typhus in volunteers.

. Reported the first known effective cure of typhoid fever with chloramphenicol in 1948.

. Reported the infectious dose of Salmonella typhosa in a series of studies using volunteer subjects and demonstrated that inactivated typhoid vaccine (acetone-killed) resulted in short-term but limited immunity. (Because paratyphoid A- and B-type vaccines were of limited efficacy, newer vaccines used a monovalent, acetone-killed, dried product.)

. Developed the first specific chemoprophylaxis for leptospirosis.

. Reported that field surveillance studies magnified the importance of leptospirosis as a common cause of FUO in various geographic areas and that available antibiotics were ineffective as therapeutic agents.

. Reported the first therapeutic efficacy of chloramphenicol and tetracycline in bubonic, septicemic, and pulmonic plague using the oral route, which simplified the therapeutic regimen in the event of a sizable outbreak because streptomycin, a very effective antibiotic, must be injected.

. Demonstrated the importance of cellular immunity (as differentiated from humoral immunity) and the transferability of this cellular immunity by the subcellular "transfer factor." (These studies sparked the whole field of immunology.)

. Developed the entirely new immunological technique of fluorescent labeling of antibodies, which enhanced the confirmed diagnoses of many microbial diseases and clarified their pathogenesis.

. Sponsored the original studies of properdin, which was the basis for the greatly extended interest in complement pathways.

. Greatly clarified the differing strains of dengue virus and elucidated the concept of dengue-shock syndrome, an important cause of death among children in Asian countries.

. Developed new immunizing agents or vaccines for infectious diseases, including the following:

(a) vector-borne virus diseases such as dengue, yellow fever, St. Louis encephalitis, Western equine encephalitis, Eastern equine encephalitis, Venezuelan equine encephalitis, Japanese encephalitis, and others;

(b) the hemorrhagic fevers;

(c) the rickettsial diseases, such as epidemic typhus, Rocky Mountain spotted fever, Q fever;

(d) malaria;

(e) measles;

(f) mumps;

(g) diphtheria and tetanus toxoids;

(h) enteric infections such as bacillary dysentery, Shigella, Salmonella typhosa, Vibrio cholerae, Endamoeba histolytica;

(i) plague and Francisella tularensis;

(j) enteroviral diseases including poliomyelitis and others;

(k) meningococcal gonococcal diseases; and

(l) adenovirus infections.