Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen

Pallesen, Jesper; Wang, Nianshuang; Corbett, Kizzmekia S.; Wrapp, Daniel; Kirchdoerfer, Robert N.; Turner, Hannah L.; Cottrell, Christopher A.; Becker, Michelle M.; Wang, Lingshu; Shi, Wei; Kong, Wing-Pui; Andres, Erica L.; Kettenbach, Arminja N.; Denison, Mark R.; Chappell, James D.; Graham, Barney S.; Ward, Andrew B.; McLellan, Jason S.

doi:10.1073/pnas.1707304114

Title: Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen

Journal Article · Mon Aug 14 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1707304114· OSTI ID:1390889

Pallesen, Jesper ^[1]; Wang, Nianshuang ^[2]; Corbett, Kizzmekia S. ^[3]; Wrapp, Daniel ^[2]; Kirchdoerfer, Robert N. ^[1]; Turner, Hannah L. ^[1]; Cottrell, Christopher A. ^[1]; Becker, Michelle M. ^[4]; Wang, Lingshu ^[3]; Shi, Wei ^[3]; Kong, Wing-Pui ^[3]; Andres, Erica L. ^[4]; Kettenbach, Arminja N. ^[5]; Denison, Mark R. ^[4]; Chappell, James D. ^[4]; Graham, Barney S. ^[3]; Ward, Andrew B. ^[1];

^[2]

The Scripps Research Inst., La Jolla, CA (United States)
Geisel School of Medicine at Dartmouth, Hanover, NH (United States)
National Inst. of Allergy and Infectious Diseases, Bethesda, MD (United States)
Vanderbilt Univ. Medical Center, Nashville, TN (United States)
Geisel School of Medicine at Dartmouth, Hanover, NH (United States); Geisel School of Medicine at Dartmouth, Lebanon, NH (United States)

Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ~36%. As in other coronaviruses, the spike (S) glycoprotein of MERS-CoV mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection. Here we use structure-based design to develop a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation and demonstrate that our engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV. We also determined high-resolution structures of the trimeric MERS-CoV S ectodomain in complex with G4, a stem-directed neutralizing antibody. The structures reveal that G4 recognizes a glycosylated loop that is variable among coronaviruses and they define four conformational states of the trimer wherein each receptor-binding domain is either tightly packed at the membrane-distal apex or rotated into a receptor-accessible conformation. As a result, our studies suggest a potential mechanism for fusion initiation through sequential receptor-binding events and provide a foundation for the structure-based design of coronavirus vaccines.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Inst. of Allergy and Infectious Diseases; National Inst. of General Medical Sciences

Grant/Contract Number:: AC02-06CH11357; AC02-76SF00515; R01AI127521; P20GM113132; HHSN261200800001E; P41GM103393

OSTI ID:: 1390889

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 35; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 568 works

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