Dataset Information

Effects of Treatment Delay on Efficacy of Tecovirimat Following Lethal Aerosol Monkeypox Virus Challenge in Cynomolgus Macaques.

ABSTRACT: Background:Tecovirimat (ST-246) is being developed as an antiviral therapeutic for smallpox for use in the event of an accidental or intentional release. The last reported case of smallpox was 1978 but the potential for use of variola virus for biowarfare has renewed interest in smallpox antiviral therapeutics. Methods:Cynomolgus macaques were challenged with a lethal dose of monkeypox virus (MPXV) by aerosol as a model for human smallpox and treated orally with 10 mg/kg tecovirimat once daily starting up to 8 days following challenge. Monkeys were monitored for survival, lesions, and clinical signs of disease. Samples were collected for measurement of viremia by quantitative real-time polymerase chain reaction, and for white blood cell counts. Results:Survival in animals initiating treatment up to 5 days postchallenge was 100%. In animals treated starting 6, 7, or 8 days following challenge, survival was 67%, 100%, and 50%, respectively. Treatment initiation up to 4 days following challenge reduced severity of clinical manifestations of infection. Conclusions:Tecovirimat treatment initiated up to 8 days following a lethal aerosol MPXV challenge improves survival and, when initiated earlier than 5 days after challenge, provides protection from clinical effects of disease, supporting the conclusion that it is a promising smallpox antiviral therapeutic candidate.

SUBMITTER: Russo AT

PROVIDER: S-EPMC6151088 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Effects of Treatment Delay on Efficacy of Tecovirimat Following Lethal Aerosol Monkeypox Virus Challenge in Cynomolgus Macaques.

Russo Andrew T AT Grosenbach Douglas W DW Brasel Trevor L TL Baker Robert O RO Cawthon Andrew G AG Reynolds Erin E Bailey Tara T Kuehl Philip J PJ Sugita Victoria V Agans Krystle K Hruby Dennis E DE

The Journal of infectious diseases 20180901 9

<h4>Background</h4>Tecovirimat (ST-246) is being developed as an antiviral therapeutic for smallpox for use in the event of an accidental or intentional release. The last reported case of smallpox was 1978 but the potential for use of variola virus for biowarfare has renewed interest in smallpox antiviral therapeutics.<h4>Methods</h4>Cynomolgus macaques were challenged with a lethal dose of monkeypox virus (MPXV) by aerosol as a model for human smallpox and treated orally with 10 mg/kg tecovirim ...[more]

PMID: 29982575

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Project description:Most alphaviruses are mosquito-borne and can cause severe disease in humans and domesticated animals. In North America, eastern equine encephalitis virus (EEEV) is an important human pathogen with case fatality rates of 30-90%. Currently, there are no therapeutics or vaccines to treat and/or prevent human infection. One critical impediment in countermeasure development is the lack of insight into clinically relevant parameters in a susceptible animal model. This study examined the disease course of EEEV in a cynomolgus macaque model utilizing advanced telemetry technology to continuously and simultaneously measure temperature, respiration, activity, heart rate, blood pressure, electrocardiogram (ECG), and electroencephalography (EEG) following an aerosol challenge at 7.0 log10 PFU. Following challenge, all parameters were rapidly and substantially altered with peak alterations from baseline ranged as follows: temperature (+3.0-4.2°C), respiration rate (+56-128%), activity (-15-76% daytime and +5-22% nighttime), heart rate (+67-190%), systolic (+44-67%) and diastolic blood pressure (+45-80%). Cardiac abnormalities comprised of alterations in QRS and PR duration, QTc Bazett, T wave morphology, amplitude of the QRS complex, and sinoatrial arrest. An unexpected finding of the study was the first documented evidence of a critical cardiac event as an immediate cause of euthanasia in one NHP. All brain waves were rapidly (~12-24 hpi) and profoundly altered with increases of up to 6,800% and severe diffuse slowing of all waves with decreases of ~99%. Lastly, all NHPs exhibited disruption of the circadian rhythm, sleep, and food/fluid intake. Accordingly, all NHPs met the euthanasia criteria by ~106-140 hpi. This is the first of its kind study utilizing state of the art telemetry to investigate multiple clinical parameters relevant to human EEEV infection in a susceptible cynomolgus macaque model. The study provides critical insights into EEEV pathogenesis and the parameters identified will improve animal model development to facilitate rapid evaluation of vaccines and therapeutics.

Project description:Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.

Project description:UnlabelledTo evaluate new vaccines when human efficacy studies are not possible, the FDA's "Animal Rule" requires well-characterized models of infection. Thus, in the present study, the early pathogenic events of monkeypox infection in nonhuman primates, a surrogate for variola virus infection, were characterized. Cynomolgus macaques were exposed to aerosolized monkeypox virus (10(5) PFU). Clinical observations, viral loads, immune responses, and pathological changes were examined on days 2, 4, 6, 8, 10, and 12 postchallenge. Viral DNA (vDNA) was detected in the lungs on day 2 postchallenge, and viral antigen was detected, by immunostaining, in the epithelium of bronchi, bronchioles, and alveolar walls. Lesions comprised rare foci of dysplastic and sloughed cells in respiratory bronchioles. By day 4, vDNA was detected in the throat, tonsil, and spleen, and monkeypox antigen was detected in the lung, hilar and submandibular lymph nodes, spleen, and colon. Lung lesions comprised focal epithelial necrosis and inflammation. Body temperature peaked on day 6, pox lesions appeared on the skin, and lesions, with positive immunostaining, were present in the lung, tonsil, spleen, lymph nodes, and colon. By day 8, vDNA was present in 9/13 tissues. Blood concentrations of interleukin 1ra (IL-1ra), IL-6, and gamma interferon (IFN-γ) increased markedly. By day 10, circulating IgG antibody concentrations increased, and on day 12, animals showed early signs of recovery. These results define early events occurring in an inhalational macaque monkeypox infection model, supporting its use as a surrogate model for human smallpox.ImportanceBioterrorism poses a major threat to public health, as the deliberate release of infectious agents, such smallpox or a related virus, monkeypox, would have catastrophic consequences. The development and testing of new medical countermeasures, e.g., vaccines, are thus priorities; however, tests for efficacy in humans cannot be performed because it would be unethical and field trials are not feasible. To overcome this, the FDA may grant marketing approval of a new product based upon the "Animal Rule," in which interventions are tested for efficacy in well-characterized animal models. Monkeypox virus infection of nonhuman primates (NHPs) presents a potential surrogate disease model for smallpox. Previously, the later stages of monkeypox infection were defined, but the early course of infection remains unstudied. Here, the early pathogenic events of inhalational monkeypox infection in NHPs were characterized, and the results support the use of this surrogate model for testing human smallpox interventions.

Dataset Information

Effects of Treatment Delay on Efficacy of Tecovirimat Following Lethal Aerosol Monkeypox Virus Challenge in Cynomolgus Macaques.

Publications

Effects of Treatment Delay on Efficacy of Tecovirimat Following Lethal Aerosol Monkeypox Virus Challenge in Cynomolgus Macaques.

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