Animal Models for Assessing Countermeasures to Bioterrorism Agents (2011) / Chapter Skim
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2 Evaluation of Current and Future TMT-Used Animal Models
2 Evaluation of Current and Future TMT-Used Animal Models
Pages 15-38
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From page 15... ...
, these models most likely represent the best approach to develop and test countermeasures and the current efforts have performed as well as could be expected given the limitations listed below. These limitations are critical components to be considered when evaluating the utility of an animal model for efficacy studies1 of the known or unknown pathogens of interest to the TMT: • Lack of sufficient human clinical data (that is, reliable and sophisticated human clinical markers)
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From page 16... ...
. Because the preclinical data would be evaluated in the context of knowledge from human studies, any deficiencies in data correlation and extrapolation from the animal models to the human condition would presumably be compensated for by the actual data collected during the human studies.
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• The restrictions imposed by biocontainment and the strong reliance on nonhuman primates limit the number of animal studies that could be done. ANIMAL MODELS ARE ANALOGOUS, NOT HOMOLOGOUS SYSTEMS On a number of occasions the Animal Rule has been misread resulting in the unrealistic expectation that animal efficacy studies accurately and completely reflect the human condition.
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expected to react with a response predictive for humans unless the effect is demonstrated in animals belonging to a single animal species that represent a sufficiently well characterized animal model for predicting the response in humans (FDA 2002)
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The lack of basic human pathophysiological information raises the disconcerting possibility that current animal systems for filovirus infections could be only crude approximations of the human First disease case in an epidemic within a population (NIH 2011)
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Thus, in the case of filoviruses, the dearth of information on the human patient prevents the development of a clinically defendable animal model. Furthermore, additional collection of human clinical data may render these animals ill-suited for the evaluation of pharmaceuticals or vaccines under the premises of the Animal Rule.
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From page 21... ...
Symptoms of filovirus disease are unspecific, are easily confused with many other diseases, and lack a pathognomonic marker that allows for the unequivocal diagnosis of filovirus infection. Unfortunately, autopsies of fatally infected humans have only rarely been performed, partly due to cultural constraints and partly due to safety concerns.
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response directed against the viral nucleoprotein (NP) and matrix protein VP40, followed by clearance of viral antigen and activation of cytotoxic T cells; in fatal cases, no antibody response was observed concomitant with massive activation of monocytes and macrophages and subsequent massive lymphocyte apoptosis.
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68 62 Abdominal pain 5 2 Abortion 47 43 Anorexia 0 7 Anuria 79 50 Arthralgia or myalgia 95 85 Asthenia 5 8 Bleeding from puncture sites 0 15 Bleeding from the gums 5 7 Bloody stools 5 10 Chest pain 47 42 Conjuctival infection 0 2 Convulsions 26 7 Cough 84 86 Diarrhea 5 0 Dysesthesia 0 2 Epistaxis 95 93 Fever 74 52 Headaches 11 5 Hearing loss 0 13 Hematemesis 0 2 Hematoma 16 7 Hematuria 11 0 Hemoptysis 5 2 Hepatomegaly 5 17 Hiccups 26 12 Lumbar pain 16 14 Maculopapular rasha 16 8 Melena 68 73 Nausea and vomiting 0 8 Petechiae 58 56 Sore throat, odynophagia, or dysphagia 5 2 Splenomegaly 0 31 Tachypnea 11 1 Tinnitus a variable detection may be attributed to skin color SOURCE: Adapted from Bwaka et al.
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From page 24... ...
. The majority of published data from well-established animal models,8 including detailed data on pathogenesis and pathology of disease from African green and rhesus monkeys and cynomolgus macaques, stem from experiments with EBOV or MARV strains (Ebola virus references: Alves et al.
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Cynomolgus monkey (macaca fascicularis) Established lethal model, published Rhesus monkey (Macaca mulatta)
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, published SOURCE: Adapted from Kuhn 2008 and references therein. TABLE 2-7 Animal-Specific Hematological Differences in Nonhuman Primate Models of Ebola Virus Disease, Infected with 1-10 LD50 Animal Mean Time to Death Hematological Disturbance Cynomolgus macaque (Macaca 10-14 days Fibrin depositions fascicularis)
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From page 27... ...
Despite these data, there is currently no consensus in the field on which nonhuman primate model better approximates the course of human infection, in part because of the paucity of cytokine data from the various nonhuman primate models that could be compared with the human data collected in the studies mentioned above. Specifically, biochemical analysis of blood from EBOV-infected cynomolgus macaques and rhesus monkeys revealed increased concentrations of IL -6, whereas IL-2 and IL-10 were
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Nonhuman primates and mice are the most prevalent animal models for primary pulmonary tularemia. Laboratory mice have been extremely useful for dissecting the immune response to F
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. Guinea pigs are used in potency assays for the licensed AVA The National Institute for Allergy and Infectious Diseases' efforts to fund research into the standardization of 9 biodefense-related animal models for product development under the Animal Rule deserve credit for advancing the anthrax model in particular and for raising awareness of all models more generally (see Appendix C)
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From page 30... ...
Although the rabbits and nonhuman primates appear to be the best models for medical countermeasure development under the regulatory provisions of the Animal Rule, their use poses significant challenges with regard to housing capacity, number of animals needed for statistically meaningful results, and cost of procurement and care. Moreover, societal sensitivities toward the use of nonhuman primates in research pose additional impediments to the continued use of these animals in the development and production of medical countermeasures for emerging infections and biothreats.
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From page 31... ...
As discussed on page 19, the collection of more detailed clinical data for filovirus infections has been attempted multiple times in the past and failed. At this time, there is no reason to believe that collection of data from filovirus disease outbreaks may improve in the immediate future.
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2010. Aerosol exposure to the Angola strain of Marburg virus causes lethal viral hemorrhagic fever in cynomolgus macaques.
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1999. Pathogenesis of experimental Ebola virus infection in guinea pigs.
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1995. Lethal experimental infection of rhesus monkeys by aerosolized Ebola virus.
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In: Pattyn SR, ed. Ebola Virus Haemorrhagic Fever: Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers, December 6-8, 1977, Antwerp, Belgium.
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1996a. Ebola virus infection in guinea pigs: Presumable role of granulomatous inflammation in pathogenesis.
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2010. Human fatal Zaire Ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis.
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