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

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 memb...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-08, Vol.114 (35), p.E7348-E7357
Main Authors: 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.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Neutralizing - immunology
Antibodies, Viral - immunology
Antigens
BASIC BIOLOGICAL SCIENCES
Binding
Biological Sciences
Conformation
Coronaviridae
Coronaviridae - immunology
coronavirus
Coronavirus Infections - virology
Coronaviruses
cryo-EM
Crystallography
Crystallography, X-Ray - methods
Glycoproteins
Human populations
Humans
Immune response
Immune response (humoral)
Immune system
Immunity, Humoral - immunology
Immunogenicity
Immunoglobulin G - metabolism
Immunoglobulins
Membrane fusion
Mice, Inbred BALB C
Middle East Respiratory Syndrome Coronavirus - immunology
Neutralizing
neutralizing antibody
Outbreaks
peplomer
PNAS Plus
Protein Binding
Protein Conformation
Proteins
Receptors, Virus - metabolism
Respiratory diseases
Spike Glycoprotein, Coronavirus - immunology
Structure-Activity Relationship
Studies
Vaccination
Vaccines
Viral Vaccines - immunology
X-ray
X-rays
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Summary: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. 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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1707304114