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

Abstract

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.

Oral administration of obeldesivir protects nonhuman primates against Sudan ebolavirus

“…The 2013–2016 West African epidemic of EVD that resulted in 28,600 cases and 11,325 deaths demonstrated that filoviruses represent real and great threats to public health. Although progress has been made in developing pan-filovirus mAb-based treatments that can protect NHPs against multiple species of ebolaviruses ( 21 , 22 , 24 ), broad coverage of an anti-filovirus mAb that can also protect against MARV has not yet been formulated.The success of RDV in protecting NHPs against ebolaviruses ( 19 , 33 ) and MARV ( 34 , 35 ) when given after virus exposure shows the promise of small-molecule antivirals that target the filovirus RNA-dependent RNA polymerase. In this work, we show that ODV, an oral prodrug of GS-441524 that is converted into the same active nucleotide triphosphate as RDV, has broad in vitro antiviral activity against EBOV, SUDV, and MARV and can protect NHPs against SUDV when administered 24 hours after virus exposure.…”

“…For statistical comparisons, survival data from 21 historical positive-control cynomolgus macaques ( 16 , 24 , 31 ) challenged by the same route with the same virus stock and dose were added to the in-study control cohorts. All statistical analyses were performed in GraphPad Prism v10.0.0 and Microsoft Excel.…”

“…Much of the preclinical work to develop treatments against SUDV has focused on mAbs, which have shown protective efficacy in small-animal (20)(21)(22) and NHP models (19,20,22,23). A pan-ebolavirus mAb cocktail, MBP134, consisting of two individual mAbs, was demonstrated to confer significant (80%) rescue from lethal SUDV disease in rhesus macaques when administered as a single intravenous dose 5 days after virus challenge (24). We also recently showed that the therapeutic window can be extended as late as 6 DPI by combining the pan-ebolavirus mAb cocktail MBP431 with RDV, where 80% protection was observed in rhesus monkeys (19).…”