Early Work With Typhus And Scrub Typhus

Epidemic typhus has been a scourge throughout history and especially during times of armed conflict. During World War I, it is estimated that epidemic typhus killed 3 million Russians. With the advent of World War II, the US military created the US Army Typhus Commission and gave it the responsibility of protecting Allied troops from the potentially devastating effects of the infection. In 1943, Dr. Woodward was appointed to the commission and shortly thereafter was posted to North Africa as a junior medical officer. In Morocco, he tested one of the first effective typhus vaccines, one composed of an inactivated strain of Rickettsia prowazekii. In preliminary investigations comparing a French and a US vaccine, he demonstrated good antibody responses with the latter vaccine, which he then tested in healthy prison inmates who volunteered to receive challenges with live R. prowazekii. No control subjects were included, because there was, at that time, no treatment for the illness. The investigation demonstrated a high degree of protection afforded by the vaccine, which lasted for 6 months despite the disappearance of circulating antibodies. Because this work was classified, it was not published until 1986.

Scrub typhus, another infection that the US military had to contend with during World War II, remained a problem after the war had concluded. In the late 1940s, Dr. Joseph Smadel, later honored by the Infectious Diseases Society of America's Smadel Lecture Series (which, by the way, was established by Dr. Woodward), was then head of the Rickettsia Laboratory at the Walter Reed Army Research Center. During this time, he obtained samples of chloramphenicol for clinical studies shortly after it was shown to inhibit rickettsia (i.e., Rickettsia orientalis) in hens' eggs and mice. Having successfully treated 2 patients with scrub typhus in Mexico, Dr. Smadel arranged for a mission to Malaysia in 1948 to study further the treatment of scrub typhus with chloramphenicol. He selected Dr. Woodward as the team's clinician. The first patient treated in Malaysia responded within 24 h of initiating therapy with chloramphenicol. Many febrile patients were soon referred to the group for treatment. Dr. Woodward selected patients with clinical signs of scrub typhus, treating 40 patients; 30 with scrub typhus, 2 with murine typhus, 2 with malaria, 2 with leptospirosis, and 2 with typhoid fever. The conditions of 2 other patients were never diagnosed. These studies demonstrated conclusively the capacity of chloramphenicol to cure scrub typhus.

Typhoid Fever

Dr. Woodward's work with typhoid fever began fortuitously with the referral of 2 patients from a rubber plantation where scrub typhus was common. The patients arrived late one Saturday night in 1948. Woodward examined them by candlelight and began treatment. Neither had an eschar, but both had a toxic appearance. Within 24 h, one patient (with scrub typhus) was afebrile. The other patient's toxic appearance persisted, with abdominal distress and diarrhea. Enteric fever was suspected. Blood had been drawn and injected intraperitoneally in mice. Salmonella enterica serovar Typhi was isolated. The patient responded gradually over 48 h and was afebrile in 72 h. He received therapy for a total of only 5 days, because Dr. Smadel was annoyed that his minimal antibiotic supply was being used to treat an infection other than the one for which the mission had been organized. When the patient relapsed after 8 days, Dr. Smadel relented, and additional therapy was given, to which the patient responded. One additional patient recovered fully in <4 days and did not relapse. These 2 patients paved the way for the treatment of 8 others. Together, data on the 10 patients formed the basis of the first publication attesting to the efficacy of chloramphenicol as treatment for typhoid fever. Chloramphenicol was the only antibiotic effective against S. enterica serovar Typhi during the early years of the antibiotic era. However, as with most antibiotics, widespread use of chloramphenicol in areas of endemicity, where it was readily available without prescription, resulted in the emergence of resistant bacterial strains. Because of such resistance, chloramphenicol is no longer the treatment of choice for typhoid fever.

Influenced by the results of these early studies, Dr. Woodward used chloramphenicol in subsequent field trials demonstrating its efficacy against various forms of bacterial meningitis, a broad range of rickettsial infections, tularemia, and other serious gram-negative bacterial infections. He was attracted to the drug because it was well tolerated and had a broad spectrum of antibacterial activity. Moreover, he never personally saw a patient develop chloramphenicol-induced aplastic anemia.

Volunteer Studies In Baltimore

Dr. Woodward's work with chloramphenicol in typhoid fever was a preamble to vaccine trials conducted in volunteers in Baltimore. These trials were made possible as a result of arrangements made with the Maryland House of Corrections to build a research ward staffed full time by male nurses and covered by physicians from the Division of Infectious Diseases at the University of Maryland School of Medicine. This unique unit requires a short description. It was opened in 1962 and expanded from an initial 10-bed unit to one with 3 separate sections, totaling 24 beds. During its 13 years of existence, >1000 volunteers participated in studies involving S. enterica serovar Typhi, Vibrio cholerae strains, Shigella species, diarrheogenic Escherichia coli strains, Norwalk agent, Francisella tularensis, Coxiella burnetii, Rickettsia rickettsii, influenza viruses, rhinovirus, adenovirus, malaria species, and endotoxin. Many investigators were involved in these studies, most from the University of Maryland Medical School, others from Fort Detrick, the National Institutes of Health, and other medical schools. Many publications resulted from these studies, including, for example, 142 publications with R.B.H. listed among the authors. The inspiration for these investigations came from Dr. Woodward's work with prisoner volunteers in Morocco who were infected with scrub typhus. In Baltimore at the University Hospital, he tried unsuccessfully to induce typhoid fever experimentally in 2 volunteers by feeding them 6000 cfu of the Ty 2 strain, which was first isolated during the Spanish-American War and later used to produce the phenol-killed whole-organism vaccine. He suspended his challenge dose in milk and administered it with a meal in an effort to protect the bacterium from the destructive effects of gastric acid. Neither volunteer became ill. In later studies performed at the volunteer unit, a different strain of S. enterica serovar Typhi was used, one isolated from a chronic carrier, which came to be known as the “Quailes strain.”

A decade of investigation began with efforts to obtain precise data on the efficacy of typhoid vaccines by determining the number of organisms required to induce disease. This early work laid the foundation for the dose-response curve. Many vaccines were tested. The oral vaccine in use today was the last vaccine tested in the prison unit. It was shown to be highly effective in preventing disease in volunteers challenged with an inoculum of 10⁵ organisms in milk. (This dose induced disease in 25%–35% of control volunteers.) Of all the vaccines tested in the University of Maryland research unit, the oral vaccine gave the highest protection rate (87%). The old parenteral vaccines afforded 70% protection from disease. The volunteer model used to study typhoid provided opportunities to investigate aspects of the pathogenesis of typhoid fever, as well—not the least of which concerned the role of endotoxin in the pathogenesis of the illness.

Rocky Mountain Spotted Fever And Q Fever Vaccines

A number of other vaccines were evaluated in volunteers at the University of Maryland, including cholera, shigella, malaria, rhinovirus, and influenza vaccines, as well as 2 vaccines of special interest to Dr. Woodward: vaccines directed against Rocky Mountain spotted fever and Q fever. Vaccines against the latter 2 pathogens had been available for years but had never been evaluated. When finally tested, the Rocky Mountain spotted fever vaccines were shown only to prolong the incubation period of the illness and to prevent relapses. The disease produced solid immunity against rechallenge. The strain used to infect volunteers was prepared in the laboratory of Dr. Charles Wisseman, chair of the Department of Microbiology at the University of Maryland School of Medicine. As few as 10 organisms produced disease when injected intradermally. The Q fever vaccines studied were of 2 types: phase I and phase II strains. The phase I vaccine induced excellent protection against aerosol-induced infection. C. burnetii caused disease in 14 of 17 nonvaccinated volunteers challenged with a dose of aerosolized microorganisms of 3500 GPIPID₅₀ (50% guinea pig intraperitoneal infectious dose). When doses of 3500–350,000 GPIPID₅₀ were ingested by mouth, neither illness nor evidence of infection was detected. Thus, although it had previously been postulated that contaminated cows' milk might be a source of Q fever, these data suggested that drinking contaminated milk does not cause disease unless an aerosol is created when the milk is poured.

Before the advent of formal institutional review board committees, investigators at the University of Maryland established a protocol for obtaining permission to perform human studies by vigorously vetting protocols in critical discussions between senior faculty members, administrators, and community leaders, a procedure first used by Dr. Woodward in his initial volunteer studies. We were all well aware of the awesome responsibility we had to the volunteers who chose to participate in our studies, and we adhered closely to the Helsinki Code until the National Institutes of Health crystallized concepts that would lead to the formation of the modern institutional review board. Because of Dr. Woodward's influence, we had an effective “institutional review board” well before an official one was established at the University of Maryland. All publications stated our position regarding the ethical conduct necessary to perform studies involving prison inmates.

The Prison Volunteer Research Unit at the University of Maryland closed in 1974. At that time, the American Civil Liberties Union filed suit to prevent volunteer studies in all prisons. Our unit was named in the suit, one that we won in federal court because the American Civil Liberties Union was unable to prove any instance in which volunteers had been coerced. The presiding judge praised the studies for their public health and military value and agreed that the highest ethical standards had been maintained throughout the unit's entire period of operation. When the judge asked Dr. Woodward about the value of vaccines he had received as a member of the US military in World War II, Dr. Woodward said, “Judge, those vaccines were of little more value than water.” The judge chuckled at the comment that was so typical of Dr. Woodward's style—brief, to the point, and valid. May he rest in peace.