A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates

Abstract

SUMMARY Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses. MBP134AF could fully protect ferrets against lethal EBOV, SUDV, and BDBV infection, and a single 25-mg/kg dose was sufficient to protect NHPs against all three viruses. The development of MBP134AF provides a successful model for the rapid discovery and translational advancement of immunotherapeutics targeting emerging infectious diseases.

Prior vaccination with the rVSV-ZEBOV vaccine does not interfere with but improves the efficacy of postexposure antibody treatment in nonhuman primates exposed to Ebola virus

“…Outbreaks of filovirus disease have become increasingly difficult to manage due to increased connectivity in endemic regions coupled with inadequate public health infrastructures and lack of approved medical countermeasures including diagnostics, therapeutics, and vaccines. Due to the sporadic nature of these outbreaks, the development and efficacy testing of preventative vaccines and postexposure treatments has previously been limited to animal models, including nonhuman primates, in which complete protection from lethal EBOV challenge has been demonstrated 7-9 . The unprecedented magnitude of the 2013-16 West African EBOV epidemic offered a unique opportunity to assess the efficacy of some of the most promising medical countermeasures available at that time 7,8 .…”

“…In order to address the potential issue of vaccine/therapeutic or therapeutic/vaccine interference we employed a uniformly lethal rhesus macaque model of EBOV infection 9 . In brief, sixteen animals were divided into three experimental groups (n=5/group) and one control animal.…”

“…The single EBOV challenge control animal was not vaccinated or given mAb therapy and succumbed to disease 9 days postexposure. Importantly, 12 historical control rhesus macaques challenged via the same route with the same EBOV seed stock and target dose all succumbed 6 to 9 days after challenge ( Figure 1a ) 9,15 .…”

It Takes a Matured mAb to Treat Ebolavirus Infection

“…Pan-Ebolavirus immunotherapy would provide a rapid-response treatment during Ebola virus outbreaks. In this issue of Cell Host & Microbe, Wec et al (2019) and Bornholdt et al (2019) optimize the MBP134 mAb cocktail through antibody affinity maturation, improving its protective efficacy against three Ebolaviruses: EBOV, SUDV, and BDBV.…”

“…This candidate was combined with a second mAb to develop the MBP-134 cocktail with optimized effector functions, demonstrating protection mice and guinea pigs against all three viruses. The companion paper by Bornholdt et al (2019) demonstrates that the MBP-134 cocktail is highly protective in ferrets and non-human primates against EBOV, BDBV, and SUDV.…”