Abstract
Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clinical trials. These include antibodies combining the IGHV3-15/IGLV1-40 immunoglobulin gene segments that were identified in all investigated individuals. Our findings will help to evaluate and direct current and future vaccination strategies and offer opportunities for novel EVD therapies.
| Original language | English |
|---|---|
| Pages (from-to) | 1589-1600 |
| Number of pages | 25 |
| Journal | Nature Medicine |
| Volume | 25 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 7 Oct 2019 |
Funding
We thank all study participants who devoted time to our research. We thank all members of the Klein, Becker, Diskin and Pfeifer Laboratories for helpful discussion; D. Weiland and S. Borregaard for help with recruitment and study implementation; C. Scheid and U. Holtig for supervising leukapheresis procedures of enrolled study participants; H. Janicki, K. Jain and C. Ruping for help with sample processing, antibody cloning and antibody production; the Cologne Center for Genomics (CCG) for sequencing support; M. Carroll for providing sera of EVD survivors and S. Fehling and T. Strecker for analysis of the neutralizing activity of sera from EVD survivors. Diffraction experiments were performed at beamline ID23-2 at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. We are grateful to S. Hutin at the ESRF for providing assistance in using beamline ID23-2. Electron microscopy studies were supported in part by the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. Coordinate files, structure factors and density maps of 3T0331-Fab, EBOV-GP/3T0331 and EBOV-GP/4m0368 were deposited and are available at the Protein Data Bank under accession codes 6QCU, 6QD7 and 6QD8, respectively. This work was funded by grants from the German Center for Infection Research (DZIF, M.M.A., S.B. and F.K.), the German Research Foundation (CRC 1279, F.K.; CRC 1310, F.K.; Heisenberg-Program KL2389/2-1, F.K.), the European Research Council (ERC-StG639961, F.K.) and the DFG Cluster of Excellence ‘Machine Learning—New Perspectives for Science’ (EXC 2064/1, project no. 390727645, N.P.).
All Science Journal Classification (ASJC) codes
- General Biochemistry,Genetics and Molecular Biology