Retrospective Analysis of Pneumonic Tularemia in Operation Whitecoat Human Subjects: Disease Progression and Tetracycline Efficacy

Abstract

Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans. The incidence of tularemia is very low with a lack of comprehensive data that describe disease in humans due to difficulty in understanding time and routes of exposure. Under the title Operation Whitecoat, researchers at Ft. Detrick, MD conducted 40 clinical studies of tularemia from 1958 to 1968. In these studies, one of the objectives was to evaluate candidate countermeasures for treatment or prophylaxis of disease after exposure to Francisella tularensis strain Schu S4 by inhalation. These studies were reviewed retrospectively to delineate the early signs and symptoms or natural history of pneumonic tularemia and examine the efficacy of tetracycline in controlled human clinical studies. Using vital signs, onset of fever was objectively defined and calculated for each subject, while Adverse Events reported after exposure were also used to define the timing of disease onset and symptoms of early disease. There was a dose response relationship between time to fever onset and exposed dose at 200 cfu (172.8 h), 700 cfu (163.2 h), 2,500 cfu (105.3 h), and 25,000 cfu (75.5 h). Onset of fever was typically the earliest sign of disease at all doses but was often accompanied by symptoms such as headache, myalgia, chest pain, and nausea, irrespective of dose except at 200 cfu where only 50% of subjects exhibited fever onset or symptoms. Examining the efficacy of different treatment regimens of tetracycline, ineffective treatments were indicated by relapse of disease (fever and Adverse Events) after cessation of antibiotic treatment. Stratification of the data suggested that treatment for <14 days or doses <2g/day was associated with increased percentage of subjects with relapse of disease symptoms. Although these types of human challenge studies would not be ethically possible now, the climate post-World War II supported human testing under rigorous conditions with informed consent. Thus, going back and analyzing these unique clinical human challenge studies has helped describe the course of infection and disease induced by a biothreat pathogen and possible countermeasures for treatment under controlled conditions.

Novel Transcriptional and Translational Biomarkers of Tularemia Vaccine Efficacy in a Mouse Inhalation Model: Proof of Concept

“…Currently, only LVS has been shown to protect humans against inhalation of virulent Ftt. This data stems solely from experiments conducted between 1960-1975 in which volunteers or tularemia researchers immunized by various routes with LVS were subsequently exposed to SCHU S4 [16][17][18]21,52,53]. These studies showed that LVS administered by scarification provided the simplest and safest means of eliciting protection, though it proved sub-optimal against aerosol challenge.…”

Longitudinal phase 2 clinical trials of live, attenuated tularemia vaccine in otherwise healthy research laboratory workers operating in containment laboratories

“…challenge experiments on healthy volunteers, participants in 'Operation White Coat', exposed to various doses over 10 years starting in 1958 (10). There is a clear infectious dose-response relationship with reduced time of onset and more severe disease occurring at higher exposures.…”

“…There is a clear infectious dose-response relationship with reduced time of onset and more severe disease occurring at higher exposures. Aerosolized tularemia may relapse if not treated with 10-14 days of sufficient antibiotic therapy equivalent to > 2 grams per day tetracycline (10). Though tetracycline itself is no longer recommended, doxycycline continues to be a treatment option as well as fluoroquinolones and aminoglycosides (11).…”

“…Recommended treatment duration is 10-21 days depending on the stage of illness and medication used, though it is unclear how well conventional antibiotics would perform in a deliberate aerosol attack. Substantial insights on its potential for weaponization were gained in part by 40 challenge experiments on healthy volunteers, participants in ‘Operation White Coat’, exposed to various doses over 10 years starting in 1958 (10). There is a clear infectious dose-response relationship with reduced time of onset and more severe disease occurring at higher exposures.…”

Working correlates of protection predict SchuS4-derived-vaccine candidates with improved efficacy against an intracellular bacterium, Francisella tularensis

“…LVS represents the most advanced tularemia vaccine candidate in western countries but is still investigational in the U.S. Remarkably, human challenge studies that exposed naive and LVS-vaccinated people to virulent Type A tularemia were performed in the 1960’s, during military-sponsored studies known as Operation Whitecoat 5 . These studies suggested LVS can provide partial protection in an experimental setting 6 – 8 , but its efficacy has not been evaluated in field trials.…”