Early human B cell response to Ebola virus in four U.S. survivors of infection

Creators: Williamson, Lauren E.; Flyak, Andrew I.; Kose, Nurgun; Bombardi, Robin; Branchizio, Andre; Reddy, Srikar; Davidson, Edgar; Doranz, Benjamin J.; Fusco, Marnie L.; Saphire, Erica O.; Halfmann, Peter J.; Kawaoka, Yoshihiro; Piper, Ashley E.; Glass, Pamela J.; Crowe, James E., Jr.

Abstract

The human B cell response to natural filovirus infections early after recovery is poorly understood. Previous serologic studies suggest that some Ebola virus survivors exhibit delayed antibody responses with low magnitude and quality. Here, we sought to study the population of individual memory B cells induced early in convalescence. We isolated monoclonal antibodies (MAbs) from memory B cells from four survivors treated for Ebola virus disease (EVD) 1 or 3 months after discharge from the hospital. At the early time points postrecovery, the frequency of Ebola-specific B cells was low and dominated by clones that were cross-reactive with both Ebola glycoprotein (GP) and with the secreted GP (sGP) form. Of 25 MAbs isolated from four donors, only one exhibited neutralization activity. This neutralizing MAb, designated MAb EBOV237, recognizes an epitope in the glycan cap of the surface glycoprotein. In vivo murine lethal challenge studies showed that EBOV237 conferred protection when given prophylactically at a level similar to that of the ZMapp component MAb 13C6. The results suggest that the human B cell response to EVD 1 to 3 months postdischarge is characterized by a paucity of broad or potent neutralizing clones. However, the neutralizing epitope in the glycan cap recognized by EBOV237 may play a role in the early human antibody response to EVD and should be considered in rational design strategies for new Ebola virus vaccine candidates.

Additional Information

© 2019 American Society for Microbiology. Received 27 September 2018; Accepted 21 January 2019; Accepted manuscript posted online 6 February 2019. We thank the Emory Serious Communicable Diseases team for their efforts to collect samples from these patients and the members of the Rafi Ahmed laboratory at Emory who separated and cryopreserved the survivor PBMCs. We thank Hannah King, Rebecca Lampley, and Gopal Sapparapu for technical support with antibody protein preparation. This work was supported by U.S. NIH grants U19 AI109711 (to J.E.C.) and U19 AI109762 (to E.O.S.), Defense Threat Reduction Agency grant HDTRA1-13-1-0034 (to J.E.C.), HHS contract HHSN272201400058C (to J.E.C. and B.J.D.), and Defense Advanced Research Project Agency grant W31P4Q-14-1-0010 (to J.E.C. and Y.K.). Flow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource, supported by NIH grants P30 CA68485 and DK058404. L.E.W., A.I.F., P.J.G. Y.K., and J.E.C. planned the studies. L.E.W., A.I.F., N.K., R.B., S.R., E.D., M.L.F., E.O.S, P.J.H., A.E.P., and P.J.G. conducted the experiments. A.B. generated the Circos plots. L.E.W., E.D., B.J.D., P.J.H, Y.K, P.J.G., and J.E.C. interpreted the studies. L.E.W. and J.E.C. wrote the first draft of the paper. E.O.S., B.J.D., Y.K., P.J.G., and J.E.C. obtained funding. S.R., E.D., and B.D. are employees of Integral Molecular. B.J.D. is a shareholder of Integral Molecular. J.E.C. is a consultant for Sanofi, is on the Scientific Advisory Boards of PaxVax, CompuVax, GigaGen, and Meissa Vaccines, is a recipient of previous unrelated research grants from Moderna and Sanofi, and is founder of IDBiologics. All other authors declare no competing interests. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the DOD.

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