Synergistic effect of two human-like monoclonal antibodies confers protection against orthopoxvirus infection

Abstract The eradication of smallpox was officially declared by the WHO in 1980, leading to discontinuation of the vaccination campaign against the virus. Consequently, immunity against smallpox and related orthopoxviruses like Monkeypox virus gradually declines, highlighting the need for efficient countermeasures not only for the prevention, but also for the treatment of already exposed individuals. We have recently developed human-like monoclonal antibodies (mAbs) from vaccinia virus-immunized non-human primates. Two mAbs, MV33 and EV42, targeting the two infectious forms of the virus, were selected for in vivo evaluation, based on their in vitro neutralization potency. A single dose of either MV33 or EV42 administered 3 days post-infection (dpi) provided full protection against lethal ectromelia virus challenge. Importantly, a combination of both mAbs conferred full protection even when provided 5 dpi. Whole-body bioimaging and viral load analysis revealed that combination of the two mAbs allowed for faster and more efficient clearance of the virus from target organs compared to either MV33 or EV42 separately. The combined mAbs treatment further conferred post-exposure protection against the currently circulating Monkeypox virus, highlighting their therapeutic potential against other orthopoxviruses.