Combination therapy with remdesivir and monoclonal antibodies protects nonhuman primates against advanced Sudan virus disease

Cross, Robert W.; Bornholdt, Zachary A.; Prasad, Abhishek N.; Woolsey, Courtney; Borisevich, Viktoriya; Agans, Krystle N.; Deer, Daniel J.; Abelson, Dafna M.; Kim, Dowhan; Shestowsky, William S.; Campbell, Lioudmila; Bunyan, Elaine; Geisbert, Joan B.; Dobias, Natalie S.; Fenton, Karla A.; Porter, Danielle; Zeitlin, Larry; Geisbert, Thomas W.

doi:10.1172/jci.insight.159090

Cited by 26 publications

(17 citation statements)

References 57 publications

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“…However, treatment with both products in combination beginning 6 dpi showed 80% survival (n = 4/5). A similar result was seen when remdesivir was used in combination with a SUDV mAb cocktail MBP431 [54]. These data support further testing of combination therapies toward decreasing the case fatality of acute filovirus disease and urge similar evaluation in NHP EBOV challenge models.…”

Section: After the Palm Rct: Improving Outcomes In Severe Diseasesupporting

confidence: 68%

The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps

et al. 2022

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The Ebola virus disease outbreak that occurred in Western Africa from 2013–2016, and subsequent smaller but increasingly frequent outbreaks of Ebola virus disease in recent years, spurred an unprecedented effort to develop and deploy effective vaccines, therapeutics, and diagnostics. This effort led to the U.S. regulatory approval of a diagnostic test, two vaccines, and two therapeutics for Ebola virus disease indications. Moreover, the establishment of fieldable diagnostic tests improved the speed with which patients can be diagnosed and public health resources mobilized. The United States government has played and continues to play a key role in funding and coordinating these medical countermeasure efforts. Here, we describe the coordinated U.S. government response to develop medical countermeasures for Ebola virus disease and we identify lessons learned that may improve future efforts to develop and deploy effective countermeasures against other filoviruses, such as Sudan virus and Marburg virus.

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Section: After the Palm Rct: Improving Outcomes In Severe Diseasesupporting

confidence: 68%

The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps

et al. 2022

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“…This dose is significantly lower than the currently FDA approved mAb treatments, which are 50 mg/kg and 150 mg/kg for mAb114 and REGN-EB3, respectively [18]. It remains to be determined if lower doses of MBP431 tested here in combination with small molecule-based treatments like Remdesivir could amplify protective efficacy in more severe cases via augmented biodistribution, as was observed in recent combination studies for the treatment of SUDV and Marburgvirus infection [19,20]. Future experiments will also focus on the prophylactic utility of MBP431 when administered IM in NHP models of ebolavirus infection.…”

Section: Discussionmentioning

confidence: 83%

Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a Pan-Ebolavirus Immunotherapeutic

et al. 2022

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Intravenous (IV) administration of antiviral monoclonal antibodies (mAbs) can be challenging, particularly during an ongoing epidemic, due to the considerable resources required for performing infusions. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce the burdens associated with IV infusion and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a cocktail of two pan-ebolavirus mAbs, reverses the course of Sudan ebolavirus disease (Gulu variant) with a single IV or IM dose in non-human primates (NHPs) as late as five days post-exposure. We also investigate the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. When delivered as a post-exposure prophylactic or therapeutic, a single IM dose of MBP431 offered complete or significant protection in NHPs challenged with Zaire ebolavirus. In conjunction with previous studies, these results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known species of ebolavirus.

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“…The data from this study confirm the cynomolgus macaque model as an appropriate model for evaluation of MARV countermeasures and the clinical presentation is reproducible when compared to published studies [ 5 , 6 , 7 , 8 , 9 ]. The rapid time course of the disease in this model after onset of clinical signs makes the identification of triggers for medical intervention problematic, implying that time-based intervention, as used for the models to evaluate Ebola countermeasures, is most appropriate [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Development of medical countermeasures against filoviruses and other high-consequence pathogens poses an ethical challenge to the traditional pathway to regulatory approval through demonstration of efficacy in well-designed and monitored clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Natural History of Marburg Virus Infection to Support Medical Countermeasure Development

Comer

Brasel

Massey

et al. 2022

Viruses

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The Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, recognizes that the evaluation of medical countermeasures under the Animal Rule requires well-characterized and reproducible animal models that are likely to be predictive of clinical benefit. Marburg virus (MARV), one of two members of the genus Marburgvirus, is characterized by a hemorrhagic fever and a high case fatality rate for which there are no licensed vaccines or therapeutics available. This natural history study consisted of twelve cynomolgus macaques challenged with 1000 PFU of MARV Angola and observed for body weight, temperature, viremia, hematology, clinical chemistry, and coagulation at multiple time points. All animals succumbed to disease within 8 days and exhibited signs consistent with those observed in human cases, including viremia, fever, systemic inflammation, coagulopathy, and lymphocytolysis, among others. Additionally, this study determined the time from exposure to onset of disease manifestations and the time course, frequency, and magnitude of the manifestations. This study will be instrumental in the design and development of medical countermeasures to Marburg virus disease.

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Combination therapy with remdesivir and monoclonal antibodies protects nonhuman primates against advanced Sudan virus disease

Cited by 26 publications

References 57 publications

The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps

The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps

Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a Pan-Ebolavirus Immunotherapeutic

Natural History of Marburg Virus Infection to Support Medical Countermeasure Development

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