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.
Highlights
Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans
Previous exposure of animals to F. tularensis was examined by determination of anti-F. tularensis antibody titers using a tube agglutination test with F. tularensis antigen (BD, Franklin Lakes, NJ) at Battelle Biomedical Research Center (BBRC); or by ELISA, which measured binding of serum antibodies to the heat-inactivated whole cell preparation of F. tularensis subsp. holarctica Live Vaccine Strain (LVS) at Lovelace Respiratory Research Institute (LRRI)
Clinical signs of pneumonic tularemia in animals exposed to aerosolized F. tularensis Schu S4 typically started on Day 2 or 3 after challenge and included hunched posture, followed by lethargy, coughing, weakness, loss of appetite and weight loss, lower activity, labored breathing, and in some cases respiratory distress
Summary
Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans. Infections with highly virulent F. tularensis strains are lethal in 30–60% of individuals infected by the inhalation route if not treated with antibiotics, and F. tularensis strains have been weaponized for potential use as a biothreat agent (Stuart and Pullen, 1945; Hornick, 1998; Dennis et al, 2001). For these reasons, F. tularensis has been designated a Tier 1/Category A select agent by the Centers for Disease Control (CDC) and the National Institutes of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Animal models are important components of preparedness as they are used for testing candidate MCM in response to public health emergencies (e.g., anthrax, Ebola, pandemic influenza)
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