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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 35; pp. 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: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.08.2017
• Series: PNAS Plus
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antigens; BASIC BIOLOGICAL SCIENCES; Binding; Biological Sciences; Conformation; Coronaviridae; Coronaviridae - immunology; coronavirus; Coronavirus Infections - virology; Coronaviruses; COVID-19; 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; Mortality; 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; X-ray crystallography; peplomer; coronavirus; neutralizing antibody; cryo-EM
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1707304114

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.