Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques

Abstract

Filovirus infections can cause a severe and often fatal disease in humans and nonhuman primates, including great apes. Here, three anti-Ebola virus mouse/human chimeric mAbs (c13C6, h-13F6, and c6D8) were produced in Chinese hamster ovary and in whole plant (Nicotiana benthamiana) cells. In pilot experiments testing a mixture of the three mAbs (MB-003), we found that MB-003 produced in both manufacturing systems protected rhesus macaques from lethal challenge when administered 1 h postinfection. In a pivotal followup experiment, we found significant protection (P < 0.05) when MB-003 treatment began 24 or 48 h postinfection (four of six survived vs. zero of two controls). In all experiments, surviving animals that received MB-003 experienced little to no viremia and had few, if any, of the clinical symptoms observed in the controls. The results represent successful postexposure in vivo efficacy by a mAb mixture and suggest that this immunoprotectant should be further pursued as a postexposure and potential therapeutic for Ebola virus exposure.passive immunization | therapy

Post-exposure treatments for Ebola and Marburg virus infections

“…The small numbers of control animals treated with nonspecific rVSV filovirus vaccines (seven collectively in the previous studies and three in this study) make it difficult to definitively say whether post-exposure protection by the rVSV filovirus vaccines is mediated by early activation of the innate immune system or by specific antigen responses, or whether the differing results are due to individual animal variability, as the case fatality rate for the Makona strain of EBOV in untreated rhesus macaque controls is not well established. As noted previously, there are occasional (although infrequent) untreated control rhesus monkeys that survive exposure to the Kikwit strain of EBOV 9,139 . Collectively, studies to date suggest that an early innate response is required to slow down virus replication and buy time for the host to mount a protective adaptive immune response.…”

“…This characteristic is consistent with human infection, as the 1976 needle-stick exposure resulted in a rapid and uniformly lethal disease 18 . For EBOV, there have been no reports of untreated cynomolgus monkeys surviving intramuscular challenge, whereas untreated rhesus monkeys occasionally do 9,139 .…”

“…Qiu et al 138 used a pool of three mouse mAbs (1H3, 2G4 and 4G7), designated as ZMAb, and demonstrated 50-100% protection (depending on dosing schedule) after EBOV infection of cynomolgus monkeys. Olinger et al 139 used a pool of three mouse-human chimeric mAbs (13C6, 13F6 and 6D8), designated MB-003, and demonstrated 67% protection (two of three animals) after EBOV infection of rhesus monkeys. Pettitt et al 140 also assessed the utility of MB-003 as a true therapeutic by administering the cocktail when EBOV (Kikwit strain)-infected rhesus monkeys were first determined to be febrile and PCR-positive for EBOV.…”

“…In this study, animals were given MB-003 on days 4, 7 and 10 after EBOV infection; three of the seven treated animals survived. Interestingly, evaluation of the two surviving animals from the Olinger et al study 139 identified the emergence of escape mutants in the two animals that did not survive EBOV challenge 141 .…”

Potential clinical treatment for Ebola pandemic

“…During this outbreak of Ebola virus in the West African countries, two Americans became infected, and they benefited from a cocktail antibody treatment, called ZMapp, which is a mixture of three humanized mouse monoclonal antibodies (c13C6, h-13F6, and c6D8). The three anti-Ebola virus monoclonal antibodies had significantly protected rhesus macaques from a lethal challenge of Ebola virus [4]; however, no human safety studies were performed before the drug was administered to these two patients. The FDA has approved ZMapp for the treatment of patients infected with Ebola virus in the current emergency situation.…”