Mechanism of action of the ZMAb antibody cocktail

Abstract

Ebola virus (EBOV) causes Ebola virus disease (EVD) in humans. Outbreaks of EVD are sporadic and generally happened in Central Africa. These outbreaks often have mortality rates well above 50%. EBOV was not generally considered a major public health issue. However, between 2013 and 2016, an outbreak of EVD caused approximately 28,000 cases and 11,000 deaths in West Africa. This outbreak highlighted the urgent need for vaccines to stop the spread of outbreaks and treatments to reduce the fatality rates. We have developed a treatment for EVD based on monoclonal antibodies initially isolated from mice. The first version of this treatment, ZMAb, was able to fully protect cynomolgus macaques when the treatment was initiated 24 h. Further work, carried out in partnership with many groups, has led to the development of ZMapp, which fully protected rhesus macaques when the treatment was initiated as late as 5 days post-infection. The three antibodies from ZMAb were chosen, not because they were better at protecting mice, but because they were neutralizing and better at protecting guinea pigs. While neutralization is a useful mechanism that should be independent of the species receiving the treatment, it may not be the only, or even the most, important mechanism. Understanding which mechanism is involved in protection, can allow us to draw on existing knowledge to optimize the treatment so the main mechanisms can be made more efficient. Additionally, understanding how the antibodies affect the immune response is crucial in increasing our ability to manage outbreaks efficiently.