@article{8d492db1ccb6471c876888394557b09d,
title = "Rationally designed immunogens enable immune focusing following SARS-CoV-2 spike imprinting",
abstract = "Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit the spread of related viruses with pandemic potential. Here we leverage rational immunogen design to focus humoral responses on conserved epitopes. Using glycan engineering and epitope scaffolding in boosting immunogens, we focus murine serum antibody responses to conserved receptor binding motif (RBM) and receptor binding domain (RBD) epitopes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike imprinting. Although all engineered immunogens elicit a robust SARS-CoV-2-neutralizing serum response, RBM-focusing immunogens exhibit increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV; structural characterization of representative antibodies defines a conserved epitope. RBM-focused sera confer protection against SARS-CoV-2 challenge. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses without compromising SARS-CoV-2 protection. These engineering strategies are adaptable to other viral glycoproteins for targeting conserved epitopes.",
keywords = "coronavirus, CP: Immunology, glycan, immune focusing, immunogen design, SARS-CoV-2",
author = "Hauser, {Blake M.} and Maya Sangesland and {St. Denis}, {Kerri J.} and Lam, {Evan C.} and Case, {James Brett} and Windsor, {Ian W.} and Jared Feldman and Caradonna, {Timothy M.} and Ty Kannegieter and Diamond, {Michael S.} and Balazs, {Alejandro B.} and Daniel Lingwood and Schmidt, {Aaron G.}",
note = "Funding Information: We thank members of the Schmidt Laboratory for helpful discussions. We thank Catherine Jacob-Dolan for critical reading of the manuscript. We thank Dr. Jason McLellan from the University of Texas, Austin for the spike plasmid. We thank Nir Hacohen and Michael Farzan for the kind gift of the ACE2-expressing 293T cells. We thank the beamline staff at the Advanced Photon Source (APS) NE-CAT 24-ID for support. We acknowledge funding from NIH R01 grants AI146779 (to A.G.S.); AI124378 , AI137057 , and AI153098 (to D.L.); and AI157155 (to M.S.D.), and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant (to A.G.S.). This work was also supported by training grants NIGMS T32 GM007753 (to B.M.H. and T.M.C.), T32 AI007245 (to J.F.), F31 Al138368 (to M.S.), and F30 AI160908 (to B.M.H.). A.B.B. is supported by National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254 , the MGH Transformative Scholars Program, as well as funding from the Charles H. Hood Foundation . This independent research was supported by the Gilead Sciences Research Scholars Program in HIV (to A.B.B.). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. This work is based on research conducted at the NE-CAT, which is funded by NIGMS ( P30 GM124165 ). The Eiger 16M detector on 24-ID-E is funded by a NIH-ORIP HEI grant ( S10OD021527 ). This research used resources of the APS, a DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357. Funding Information: We thank members of the Schmidt Laboratory for helpful discussions. We thank Catherine Jacob-Dolan for critical reading of the manuscript. We thank Dr. Jason McLellan from the University of Texas, Austin for the spike plasmid. We thank Nir Hacohen and Michael Farzan for the kind gift of the ACE2-expressing 293T cells. We thank the beamline staff at the Advanced Photon Source (APS) NE-CAT 24-ID for support. We acknowledge funding from NIH R01 grants AI146779 (to A.G.S.); AI124378, AI137057, and AI153098 (to D.L.); and AI157155 (to M.S.D.), and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant (to A.G.S.). This work was also supported by training grants NIGMS T32GM007753 (to B.M.H. and T.M.C.), T32 AI007245 (to J.F.), F31 Al138368 (to M.S.), and F30 AI160908 (to B.M.H.). A.B.B. is supported by National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the MGH Transformative Scholars Program, as well as funding from the Charles H. Hood Foundation. This independent research was supported by the Gilead Sciences Research Scholars Program in HIV (to A.B.B.). J.B.C. is supported by a Helen Hay Whitney Foundation postdoctoral fellowship. This work is based on research conducted at the NE-CAT, which is funded by NIGMS (P30 GM124165). The Eiger 16M detector on 24-ID-E is funded by a NIH-ORIP HEI grant (S10OD021527). This research used resources of the APS, a DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357. Conceptualization, B.M.H. and A.G.S.; methodology, B.M.H. E.C.L. I.W.W. J.B.C. T.M.C. A.B.B. D.L. and A.G.S.; investigation, B.M.H. M.S. K.J.S.D. E.C.L. J.F. T.K. I.W.W. J.B.C. and T.M.C.; writing ? original draft, B.M.H. and A.G.S.; writing ? review and editing, all authors; funding acquisition, M.S.D. A.B.B. D.L. and A.G.S.; supervision, M.S.D. A.B.B. D.L. and A.G.S. B.M.H. T.M.C. and A.G.S. have filed a provisional patent for the described immunogens. M.S.D. is a consultant for Inbios, Vir Biotechnology, 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 Vir Biotechnology, Moderna, and Emergent BioSolutions. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = mar,
day = "22",
doi = "10.1016/j.celrep.2022.110561",
language = "English",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
number = "12",
}