Abstract
Ebola virus (EBOV) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. Today, there is neither a licensed vaccine nor a treatment available for Ebola hemorrhagic fever (EHF). Single monoclonal antibodies (MAbs) specific for Zaire ebolavirus (ZEBOV) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. In this study, we used two clones of human-mouse chimeric MAbs (ch133 and ch226) with strong neutralizing activity against ZEBOV and evaluated their protective potential in a rhesus macaque model of EHF. Reduced viral loads and partial protection were observed in animals given MAbs ch133 and ch226 combined intravenously at 24 hours before and 24 and 72 hours after challenge. MAbs circulated in the blood of a surviving animal until virus-induced IgG responses were detected. In contrast, serum MAb concentrations decreased to undetectable levels at terminal stages of disease in animals that succumbed to infection, indicating substantial consumption of these antibodies due to virus replication. Accordingly, the rapid decrease of serum MAbs was clearly associated with increased viremia in non-survivors. Our results indicate that EBOV neutralizing antibodies, particularly in combination with other therapeutic strategies, might be beneficial in reducing viral loads and prolonging disease progression during EHF.
Highlights
Ebola virus (EBOV) has a non-segmented, single strand negative-sense RNA genome and, together with Marburg virus, constitutes the family Filoviridae [1]
It seems possible that antibody-dependent enhancement (ADE) may diminish the efficacy of neutralizing antibodies [10,12] and polyclonal serum may not aid in passive immune therapy for EBOV
Passive transfer of antibodies leads to either complete inhibition of virus replication, resulting in sterile immunity, or incomplete protection in which the virus replicates at a reduced level, allowing the host to mount virus-induced immune responses resulting in virus clearance
Summary
Ebola virus (EBOV) has a non-segmented, single strand negative-sense RNA genome and, together with Marburg virus, constitutes the family Filoviridae [1]. The protective efficacy of passive immunization with hyperimmune sera or purified polyclonal antibodies was evaluated using rodent models and shown to be effective in mice and guinea pigs, whereas evidence of protective efficacy in primates, including humans, remains elusive [6,7,8]. It seems possible that ADE may diminish the efficacy of neutralizing antibodies [10,12] and polyclonal serum may not aid in passive immune therapy for EBOV. MAb production is easier to scale up with keeping the quality consistent while preparation of polyclonal serum is not. This is an important factor for commercial production of emergency immunotherapeutics. Quantities of any particular polyclonal serum are finite and serum from different animals would have to be pooled for a large supply
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