mAbs and Ad-Vectored IFN-α Therapy Rescue Ebola-Infected Nonhuman Primates When Administered After the Detection of Viremia and Symptoms

Abstract

ZMAb is a promising treatment against Ebola virus (EBOV) disease that has been shown to protect 50% (two of four) of nonhuman primates (NHPs) when administered 2 days post-infection (dpi). To extend the treatment window and improve protection, we combined ZMAb with adenovirus-vectored interferon-a (Ad-IFN) and evaluated efficacy in EBOV-infected NHPs. Seventy-five percent (three of four) and 100% (four of four) of cynomolgus and rhesus macaques survived, respectively, when treatment was initiated after detection of viremia at 3 dpi. Fifty percent (two of four) of the cynomolgus macaques survived when Ad-IFN was given at 1 dpi, followed by ZMAb starting at 4 dpi, after positive diagnosis. The treatment was able to suppress viremia reaching~10 5 TCID 50 (median tissue culture infectious dose) per milliliter, leading to survival and robust specific immune responses. This study describes conditions capable of saving 100% of EBOV-infected NHPs when initiated after the presence of detectable viremia along with symptoms.

Post-exposure treatments for Ebola and Marburg virus infections

“…At the highest doses, 100% protection was observed even if treatment was initiated at day 3 after virus exposure. Intriguingly, systemic viral RNA was detected in only 33% of treated animals if GS-5734 treatment was initiated at day 3, which is inconsistent with other EBOV studies in rhesus macaques similarly challenged, in which a very high percent of animals are PCR-positive by day 3 (REFS 79,142,144,176). This makes the day 3 results of this study particularly hard to compare with other NHP post-exposure treatment and therapeutic studies.…”

“…In addition to the rVSV-EBOV vaccine, adenovirus serotype 5 (Ad5) vaccine vectors expressing either the EBOV GP (Ad5-EBOV) or an Ad5 vector adjuvanted with IFNα (Ad5-IFNα) have been used in post-exposure treatment studies in NHPs 176,199 . This work is discussed in the combination treatment section below.…”

“…ZMAb was combined with Ad5-IFNα to treat cynomolgus or rhesus monkeys beginning 3 days after exposure to EBOV (Kikwit strain) 176 . Notably, 75% (three of four) and 100% (four of four) of cynomolgus and rhesus macaques, respectively, survived challenge.…”

Potential Therapeutics: Toe Hold in the Fight against Zika Virus

“…We speculate that combinational treatments with monoclonal neutralizing antibody like ZIKV-117, Z23 or Z3L1 and an antiviral drug, such as an antiinfluenza drug, may result in better treatment outcomes in Zika infection. Early in the Ebola epidemic, several patients received a combination of ZMapp antibody and the anti-viral Favipiravir, which led to recovery [78,79]. Reports of enhanced production of proinflammatory cytokines/ chemokines [57,58,80], which are associated with Zika pathogenicity, suggest that anti-inflammatory treatments could ameliorate disease outcomes.…”

Experimental countermeasures against Ebola virus: current progress and an ethical conundrum

“…These are the chimpanzee adenovirus and vesicular stomatitis virus gene delivery systems (Vaccine Research Center, National Institutes of Health: unpublished data, 2014). 3,4 Combinations of biologic agents, such as monoclonal antibodies, 5 are about to enter phase I clinical trials within the next few months. Customdesigned small interfering RNA, a product of the Vancouver-based company Tekmira Pharmaceuticals Corporation, has been approved by the US Food and Drug Administration for accelerated clinical development.…”