Misasi J1, Leigh K1, Timm M1, Normandin E1, Cagigi A1, Schwing A1, Petrova Y1, Lucas S1, Madan B2, Fahad A2, Stanley DA1, Wang B3, Ellington A3, Ledgerwood J1, Tysbovsky Y4, Georgiou G3, Dekosky B1,2, Mascola, J1, Sullivan, NJ1 1National Institutes of Health, Vaccine Research Center, Bethesda, MD USA; 2The University of Kansas, Lawrence, Kansas USA; 3The University of Texas at Austin, Austin, TX USA; 4Electron Microscopy Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD USA
Chimpanzee adenovirus 3 (ChAd3) based Ebola Glycoprotein (GP) vaccination provides both acute and durable protection against lethal Ebola virus challenge. A Modified Vaccinia Ankara (MVA) GP boost enhances potency of this protection. While vaccine-induced protection is primarily T cell-mediated, antibody titers are correlated with protection in non-human primates (NHP). We hypothesized that vaccination induces the development of diverse set of antibody classes, including one previously shown to be protective in vivo; mAb114 isolated from a survivor of the Kikwit Ebola virus outbreak, is protective as monotherapy in NHP when given as late as 6 days after a lethal inoculation. To test this hypothesis, we used high-throughput emulsion-based paired heavy and light chain immunoglobulin sequencing coupled with yeast Fab display to interrogate the antibody repertoire, including the plasmablast repertoire, from a recipient of the ChAd3/MVA Ebola vaccine. We noted a highly diverse population of antigen-specific sequences as defined by unique HCDR3:LCDR3 clusters and Ebola GP-specific probe binding by yeast display. Yeast-based competition analysis identified antibodies targeting the membrane proximal region of GP, the base of GP and the glycan cap/GP1 core. Two of these antibodies were found to have moderate affinity and 6 showed high-affinity. One high affinity antibody, YD.04, was highly competitive with mAb114. Structural and functional analyses showed that YD.04 binds similarly to mAb114 that its binding prevents GP binding to the Ebola receptor, a defining feature of mAb114. While more vaccinees need to be studied, these data suggest that the ChAd3/MVA vaccine may induce broadly reactive antibodies whose epitopes that are the targets of protective antibody cocktail and monotherapy regimens.
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