Scientists Find Smart Human Antibody Neutralizes Ebola and Its Deadly Relatives

A research team's latest study shows that two human antibodies can simultaneously target two Ebola viruses: Ebola and Sudan. These two species have caused the largest and deadliest outbreaks. The new report suggests that researchers could combine these two potent antibodies to create an effective antiviral therapy. The work is published in Cell in the paper, “Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses.”

The Ebolavirus genus has caused more than two dozen human disease outbreaks, each of which was unpredictable in terms of location, timing, scale, and the identity of the causative virus. Six different Ebola viruses are known, with Ebola virus (EBOV), Sudan virus (SUDV), and Bundibugyo virus (BDBV) known to cause more frequent severe disease episodes (Feldmann et al., 2020). EBOV caused ongoing outbreaks in West Africa in 2013-2016 and in the Democratic Republic of Congo in 2018-2020, and reemerged in survivors of two outbreaks in 2021 (CDC, 2021a; Keita et al., 2021; World Health Organization, 2021). SUDV has caused five outbreaks since its discovery in 1976, and BDBV has been associated with two outbreaks, one in 2007 and one in 2012 (CDC, 2021b). The glycoprotein (GP) amino acid sequences of SUDV and BDBV differ from EBOV by 50% and 30%, respectively.

Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies.

These scientists previously identified and characterized a single anti-EBOV monoclonal antibody that appeared in human survivors of the 2013-2016 EVD outbreak within the first year after infection (Davis et al, 2019). For this study, they examined subsequent samples from the same patient cohort.

By sorting memory B cells from EBOV infection survivors, these researches isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.

Both antibodies performed very well outside the lab. Study collaborators found that combining 1C3 and 1C11 in an antibody therapy prevented Ebola and Sudan virus disease in non-human primates, reversing severe symptoms. The broad-spectrum effects of the two antibodies make them a promising treatment in cases where doctors don't have time to figure out which Ebola virus is causing it.

Even better, these antibodies may be effective even in the advanced stages of the disease. Such belated treatment will be extremely valuable, as many patients infected with Ebola or Sudan have already progressed to the stage of infection at the time of diagnosis.

Reference

1. Milligan, Jacob C., et al. Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses. Cell. 2022. 995-1007.