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

Guina, Tína; Lanning, Lynda L.; Omland, Kristian Shawn; Williams, Mark S.; Wolfraim, Larry A.; Heyse, Stephen P.; Houchens, Christopher R.; Sanz, Patrick; Hewitt, J.

doi:10.3389/fcimb.2018.00099

Cited by 9 publications

(20 citation statements)

References 48 publications

(61 reference statements)

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“…Such human challenge studies are not ethically feasible today and intensive efforts are in place to establish animal models for testing of vaccines and countermeasures in the future. Thus, the data provide support to the use of the cynomolgus macaque model under the Animal Rule, since the data in this report for human disease are also comparable to the reports of pneumonic tularemia in the non-human primate model (11, 26).…”

Section: Discussionsupporting

confidence: 82%

“…Therefore NIAID, in partnership with the government agency BARDA, are working with the FDA to establish an animal model for pneumonic tularemia to be used for medical countermeasure testing under the Animal Rule (10). Specifically, the efforts are to qualify the cynomolgus macaque model for pneumonic tularemia (11) in the FDA's Animal Model Qualification (AMQ) program, which is one of the Drug Development Tools Qualification Programs (12). An integral part of the Animal Rule and the AMQ process is to ensure that the animal species reacts and responds to infection in a manner that is predictive for humans.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Models of tularemia disease have been evaluated in a variety of animal species, including mice, rabbits, rats, guinea pigs, and monkeys [14]. In a previous study, we compared the LD 50 and disease outcome of inhalational tularemia in three nonhuman primate (NHP) species (cynomolgus and rhesus macaques, and African green monkeys) [15,16]. Thus, to more extensively characterize the disease progression and pathogenesis in a cynomolgus macaque model, we exposed groups of cynomolgus macaques to three different target doses (50 CFU, 500 CFU, and 5000 CFU) of aerosolized F. tularensis SCHU S4.…”

Section: Introductionmentioning

confidence: 99%

The Natural History of Aerosolized Francisella tularensis Infection in Cynomolgus Macaques

et al. 2021

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Tularemia is a severe, zoonotic infection caused by the Gram-negative bacterium Francisella tularensis. Inhalation results in a rapid, severe bacterial pneumonia and sepsis, which can be lethal. Because the cynomolgus macaque is the accepted nonhuman primate model for tularemia, we conducted a natural history study of pneumonic tularemia by exposing macaques to target inhaled doses of 50, 500, or 5000 colony forming units (CFU) of F. tularensis subsp. tularensis SCHU S4. Two animals within the 50 CFU group (calculated doses of 10 and 11 CFU) survived the challenge, while the remainder succumbed to infection. Exposure of cynomolgus macaques to aerosolized SCHU S4 resulted in fever, anorexia, increased white blood cell counts, lymphopenia, thrombocytopenia, increased liver enzymes, alterations in electrocardiogram (ECG), and pathological changes typical of infection with F. tularensis, regardless of the challenge dose. Blood pressure dropped during the febrile phase, particularly as temperature began to drop and macaques succumbed to the disease. ECG analysis indicated that in 33% of the macaques, heart rate was not elevated during the febrile phase (Faget’s sign; pulse-temperature disassociation), which has been reported in a similar percentage of human cases. These results indicated that infection of cynomolgus macaques with aerosolized F. tularensis results in similar disease progression and outcome as seen in humans, and that cynomolgus macaques are a reliable animal model to test medical countermeasures against aerosolized F. tularensis.

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“…In this model, a fever early in the disease course was used as a trigger for antibiotic treatment. Late in the disease course, hypothermia was consistently observed and was incorporated into euthanasia criteria [ 81 ].…”

Section: Refinement Opportunitiesmentioning

confidence: 99%

Opportunities for Refinement of Non-Human Primate Vaccine Studies

et al. 2021

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Non-human primates (NHPs) are used extensively in the development of vaccines and therapeutics for human disease. High standards in the design, conduct, and reporting of NHP vaccine studies are crucial for maximizing their scientific value and translation, and for making efficient use of precious resources. A key aspect is consideration of the 3Rs principles of replacement, reduction, and refinement. Funders of NHP research are placing increasing emphasis on the 3Rs, helping to ensure such studies are legitimate, ethical, and high-quality. The UK’s National Centre for the 3Rs (NC3Rs) and the Coalition for Epidemic Preparedness Innovations (CEPI) have collaborated on a range of initiatives to support vaccine developers to implement the 3Rs, including hosting an international workshop in 2019. The workshop identified opportunities to refine NHP vaccine studies to minimize harm and improve welfare, which can yield better quality, more reproducible data. Careful animal selection, social housing, extensive environmental enrichment, training for cooperation with husbandry and procedures, provision of supportive care, and implementation of early humane endpoints are features of contemporary good practice that should and can be adopted more widely. The requirement for high-level biocontainment for some pathogens imposes challenges to implementing refinement but these are not insurmountable.

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

Cited by 9 publications

References 48 publications

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

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

The Natural History of Aerosolized Francisella tularensis Infection in Cynomolgus Macaques

Opportunities for Refinement of Non-Human Primate Vaccine Studies

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