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The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule.

ABSTRACT: Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans and a Tier 1 select agent. The natural incidence of pneumonic tularemia worldwide is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCM) in human populations. Development and licensure of tularemia therapeutics and vaccines need to occur under the Food and Drug Administration's (FDA's) Animal Rule under which efficacy studies are conducted in well-characterized animal models that reflect the pathophysiology of human disease. The Tularemia Animal Model Qualification (AMQ) Working Group is seeking qualification of the cynomolgus macaque (Macaca fascicularis) model of pneumonic tularemia under Drug Development Tools Qualification Programs with the FDA based upon the results of studies described in this manuscript. Analysis of data on survival, average time to death, average time to fever onset, average interval between fever and death, and bacteremia; together with summaries of clinical signs, necropsy findings, and histopathology from the animals exposed to aerosolized F. tularensis Schu S4 in five natural history studies and one antibiotic efficacy study form the basis for the proposed cynomolgus macaque model. Results support the conclusion that signs of pneumonic tularemia in cynomolgus macaques exposed to 300-3,000 colony forming units (cfu) aerosolized F. tularensis Schu S4, under the conditions described herein, and human pneumonic tularemia cases are highly similar. Animal age, weight, and sex of animals challenged with 300-3,000 cfu Schu S4 did not impact fever onset in studies described herein. This study summarizes critical parameters and endpoints of a well-characterized cynomolgus macaque model of pneumonic tularemia and demonstrates this model is appropriate for qualification, and for testing efficacy of tularemia therapeutics under Animal Rule.

SUBMITTER: Guina T

PROVIDER: S-EPMC5893833 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule.

Guina Tina T Lanning Lynda L LL Omland Kristian S KS Williams Mark S MS Wolfraim Larry A LA Heyse Stephen P SP Houchens Christopher R CR Sanz Patrick P Hewitt Judith A JA

Frontiers in cellular and infection microbiology 20180404

<i>Francisella tularensis</i> is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans and a Tier 1 select agent. The natural incidence of pneumonic tularemia worldwide is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCM) in human populations. Development and licensure of tularemia therapeutics and vaccines need to occur under the Food and Drug Administration's (FDA's) Anima ...[more]

PMID: 29670861

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Project description: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.

Dataset Information

The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule.

Publications

The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule.

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