Structural Basis for a Convergent Immune Response against Ebola Virus

• Published in: Cell host & microbe 2020-03, Vol.27 (3), p.418-427.e4
• Main Authors: Cohen-Dvashi, Hadas, Zehner, Matthias, Ehrhardt, Stefanie, Katz, Michael, Elad, Nadav, Klein, Florian, Diskin, Ron
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; antibodies; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antibody Specificity; Cryoelectron Microscopy; Ebola Vaccines; Ebola virus; Ebolavirus; electron microscopy; Epitopes - immunology; HEK293 Cells; Humans; immune response; Protein Binding; protein structure; Protein Structure, Tertiary; Viral Envelope Proteins - immunology
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2020.01.007

Ebola virus disease is a severe health problem in Africa. Vaccines that display the Zaire ebolavirus glycoprotein spike complex are a prime component for the effort to combat it. The VH3-15/Vλ1-40-based class of antibodies was recently discovered to be a common response in individuals who received the Ebola virus vaccines. These antibodies display attractive properties, and thus likely contribute to the efficacy of the vaccines. Here, we use cryo-EM to elucidate how three VH3-15/Vλ1-40 antibodies from different individuals target the virus and found a convergent mechanism against a partially conserved site on the spike complex. Our study rationalizes the selection of the VH3-15/Vλ1-40 germline genes for specifically targeting this site and highlights Ebolavirus species-specific sequence divergences that may restrict breadth of VH3-15/Vλ1-40-based humoral response. The results from this study could help develop improved immunization schemes and further enable the design of immunogens that would be efficacious against a broader set of Ebolavirus species. [Display omitted] •People exposed to the GP spike complex of EBOV develop VH3-15/Vλ1-40 mAbs•Cryo-EM reveals VH3-15/Vλ1-40 mAbs target the NPC1-receptor binding site on GP•VH3-15/Vλ1-40 mAbs avoid using CDRH3 and mostly utilize the light chain for binding•Key interacting residues used by VH3-15/Vλ1-40 mAbs are already encoded by germline genes Cohen-Dvashi et al. elucidate the molecular basis for VH3-15/Vλ1-40 mAbs, a common and effective immune response in individuals vaccinated with, or exposed to, the glycoprotein spike complex of the Ebola virus. Structural data for various antibodies reveals a convergent mechanism of binding and insight into how this response is elicited.