Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics
Abstract
:1. Ectromelia virus
Mousepox as a model of smallpox
2. The animal efficacy rule
3. Mousepox severity is dependent on mouse strain
4. Importance of route and infectious dose in animal models of smallpox
4.1. Route of infection
4.2. Infectious Dose
5. Indicators of disease progression and recovery from infection
5.1. Disease progression
5.2. Recovery from infection
6. Selecting a trigger for therapeutic intervention
Marker | Route | A/Ncr | C57BL/6 |
Disease Progression | |||
Day of death | IN | 7-8 (1000 PFU); 7-12 (20 PFU) | 9-14 (1000 PFU); |
FP | 7-8 (1000 PFU) | N/A | |
Weight change | IN | Lose weight from day 5 (5-1000 PFU) | Lose weight from day 7 (1000 PFU) |
FP | Lose weight from day 5 (1000 PFU) | N/A | |
Infectivity titres | IN | Day 2 spleen, liver and lung (1000 PFU) | (Day 3 liver; day 4 spleen and lung 1000 PFU) |
FP | Day 2 spleen; day 4 liver; and day 6 lung (1000 PFU) | N/A | |
ALT/AST | IN | Day 6 (1500 PFU) | >Day 7 (1500 PFU); day 5 (1x106 PFU) |
Blood viral DNA | IN | Day 6 (5 PFU) | Day 4 (6500 PFU) |
FP | Day 5 (1000 PFU) | - | |
Host Response | |||
IFN-γ | IN | Day 4 (20 PFU) | Day 4 (1x106 PFU) |
SC | - | Day 2 (1x106 PFU) | |
Neutrophilia | IN | By day 8 (20 PFU) | By day 6 (1x106 PFU) |
PLN IFN-γ | FP | Day 2 (1000 PFU) | Day 1 (1000 PFU) |
PLN Rantes | FP | No change (1000 PFU) | Day 1 (1000 PFU) |
PLN IL-9 | FP | Day 1 (1000 PFU) | No change (1000 PFU) |
PLN gene regulation | FP | 22 gene changes from 6-24 hours p.i. (1000 PFU) | 80 gene changes from 6-24 hours p.i. (1000 PFU) |
Antigen presentation | IN | MLN no presentation up to day 3 (1x106 PFU) | MLN no presentation up to day 3 (1x106 PFU) |
FP | PLN no presentation up to day 3 (1x106 PFU) | PLN presentation from day 1 (1x106 PFU) | |
Spleen mass | IN | No change | Doubled from day 4-7 |
FP | No change | Trebled from day 4-7 | |
CD4 splenic intracellular IFN-γ | FP | 2x105 IFN- γ + cells by day 8 (3000 PFU attenuated virus EV-138) | 5x104 IFN-γ + cells by day 6 (3000 PFU attenuated virus EV-138) |
CD8 splenic intracellular IFN-γ | FP | 2.5x105 IFN- γ + cells by day 8 (3000 PFU attenuated virus EV-138) | 2.5x106 IFN-γ+ cells by day 6 (3000 PFU attenuated virus EV-138) |
Antibody | FP | N/A (1000 PFU) | Seroconversion by day 21 |
7. Evaluation of prophylactics and therapeutics in the ectromelia model
7.1. Efficacy testing in ECTV infected immunocompetent mice
7.2. Efficacy testing smallpox antivirals in immunodeficient animals
References and Notes
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Criteria for use of animal model | Issues relating to smallpox |
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There is reasonably well understood pathophysiological mechanism for the toxicity of the substance and its prevention or substantial reduction by the product. |
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The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well characterized animal model for predicting human response. |
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The animal study endpoint is related clearly to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity. |
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The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allow selection of an effective human dose. |
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Parker, S.; Siddiqui, A.M.; Painter, G.; Schriewer, J.; Buller, R.M. Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics. Viruses 2010, 2, 1918-1932. https://doi.org/10.3390/v2091918
Parker S, Siddiqui AM, Painter G, Schriewer J, Buller RM. Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics. Viruses. 2010; 2(9):1918-1932. https://doi.org/10.3390/v2091918
Chicago/Turabian StyleParker, Scott, Akbar M. Siddiqui, George Painter, Jill Schriewer, and R. Mark Buller. 2010. "Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics" Viruses 2, no. 9: 1918-1932. https://doi.org/10.3390/v2091918