@article{e391eb4556584b8596d961c95f6abdc1,
title = "Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo",
abstract = "Zika virus (ZIKV) is a flavivirus that can cause severe disease, but there are no approved treatments or vaccines. A complication for flavivirus vaccine development is the potential of immunogens to enhance infection via antibody-dependent enhancement (ADE), a process mediated by poorly neutralizing and cross-reactive antibodies. Thus, there is a great need to develop immunogens that minimize the potential to elicit enhancing antibodies. Here we utilized structure-based protein engineering to develop “resurfaced” (rs) ZIKV immunogens based on E glycoprotein domain III (ZDIIIs), in which epitopes bound by variably neutralizing antibodies were masked by combinatorial mutagenesis. We identified one resurfaced ZDIII immunogen (rsZDIII-2.39) that elicited a protective but immune-focused response. Compared to wild type ZDIII, immunization with resurfaced rsZDIII-2.39 protein nanoparticles produced fewer numbers of ZIKV EDIII antigen-reactive B cells and elicited serum that had a lower magnitude of induced ADE against dengue virus serotype 1 (DENV1) Our findings enhance our understanding of the structural and functional determinants of antibody protection against ZIKV.",
keywords = "combinatorial mutagenesis, DENV, flavivirus, immune focusing, immunogen resurfacing, nanoparticle, phage display, protein engineering, vaccine, ZIKV",
author = "Georgiev, {George I.} and Malonis, {Ryan J.} and Wirchnianski, {Ariel S.} and Wessel, {Alex W.} and Jung, {Helen S.} and Cahill, {Sean M.} and Nyakatura, {Elisabeth K.} and Olivia Vergnolle and Dowd, {Kimberly A.} and David Cowburn and Pierson, {Theodore C.} and Diamond, {Michael S.} and Lai, {Jonathan R.}",
note = "Funding Information: The NMR analysis made use of NMRbox: National Center for Biomolecular NMR Data Processing and Analysis, a Biomedical Technology Research Resource (BTRR), which is supported by NIH grant P41GM111135 (NIGMS). We gratefully acknowledge technical assistance from the Einstein Analytical Imaging Facility and the Einstein Flow Cytometry Core, which are supported in part by NIH grant P30CA013330 . This work was supported by the National Institutes of Health ( R01-AI158194 to J.R.L, R01 AI073755 to M.S.D., and intramural program of NIAID to T.C.P.). G.I.G. and A.S.W. were supported in part by NIH training grants ( T32-GM99749 and T32-AI070117 ). R.J.M. was supported in part by NIH training grants ( T32GM007288 and F30AI150055 ). A.W.W. was supported by an NIH pre-doctoral training grant ( T32 5T32AI007172-38 ) and the Medical Scientist Training Program . E.K.N. was supported in part by a postdoctoral fellowship from the Deutscher Akademischer Austauschdienst (German Academic Exchange Service). The Bruker 600-MHz NMR instrument in the Structural NMR Resource at the Albert Einstein College of Medicine was purchased using funds from NIH award 1S10OD016305 and is supported by a Cancer Center Support Grant ( P30 CA013330 ). Funding Information: The NMR analysis made use of NMRbox: National Center for Biomolecular NMR Data Processing and Analysis, a Biomedical Technology Research Resource (BTRR), which is supported by NIH grant P41GM111135 (NIGMS). We gratefully acknowledge technical assistance from the Einstein Analytical Imaging Facility and the Einstein Flow Cytometry Core, which are supported in part by NIH grant P30CA013330. This work was supported by the National Institutes of Health (R01-AI158194 to J.R.L, R01 AI073755 to M.S.D. and intramural program of NIAID to T.C.P.). G.I.G. and A.S.W. were supported in part by NIH training grants (T32-GM99749 and T32-AI070117). R.J.M. was supported in part by NIH training grants (T32GM007288 and F30AI150055). A.W.W. was supported by an NIH pre-doctoral training grant (T32 5T32AI007172-38) and the Medical Scientist Training Program. E.K.N. was supported in part by a postdoctoral fellowship from the Deutscher Akademischer Austauschdienst (German Academic Exchange Service). The Bruker 600-MHz NMR instrument in the Structural NMR Resource at the Albert Einstein College of Medicine was purchased using funds from NIH award 1S10OD016305 and is supported by a Cancer Center Support Grant (P30 CA013330). G.I.G. A.S.W. and J.R.L. designed the research. G.I.G. R.J.M. A.S.W. A.W.W. H.S.J. S.M.C. E.K.N. O.V. K.A.D. D.C. and T.C.P. performed the research. G.I.G. A.S.W. A.W.W. S.M.C. E.K.N. O.V. K.A.D. T.C.P. M.S.D. and J.R.L. analyzed data. G.I.G. and J.R.L. wrote the manuscript. A US Patent Application describing the rsZDIII clones has been submitted, with J.R.L. G.I.G. A.S.W. and E.K.N. as co-inventors. J.R.L. is a consultant for Celdara Medical, LLC.M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = may,
day = "19",
doi = "10.1016/j.chembiol.2022.02.004",
language = "English",
volume = "29",
pages = "811--823.e7",
journal = "Cell Chemical Biology",
issn = "2451-9456",
number = "5",
}