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Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability

Abstract

While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.

Type Journal
ISBN 1097-4172 (Electronic) 0092-8674 (Linking)
Authors Zhao, X.; Howell, K. A.; He, S.; Brannan, J. M.; Wec, A. Z.; Davidson, E.; Turner, H. L.; Chiang, C. I.; Lei, L.; Fels, J. M.; Vu, H.; Shulenin, S.; Turonis, A. N.; Kuehne, A. I.; Liu, G.; Ta, M.; Wang, Y.; Sundling, C.; Xiao, Y.; Spence, J. S.; Doranz, B. J.; Holtsberg, F. W.; Ward, A. B.; Chandran, K.; Dye, J. M.; Qiu, X.; Li, Y.; Aman, M. J.
Responsible Garvan Author Dr Christopher Sundling
Publisher Name CELL
Published Date 2017-05-18
Published Volume 169
Published Issue 5
Published Pages 891-904.e15
Status Published in-print
DOI 10.1016/j.cell.2017.04.038
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28525756