Evaluation of candidate vaccine approaches for MERS-CoV.

Lingshu Wang,Mark R Denison,Kanta Subbarao,Daniel J Mollura,Tongqing Zhou,Masaru Kanekiyo,Kwanyee Leung,Michelle M Becker,Srinivas S Rao,Jeffrey Solomon,Christopher R Lees,Leatrice Vogel,Wei Shi,Hadi M Yassine,Kayvon Modjarrad,Xuejun Chen,Yi Zhang,Peter D Kwong,John R Mascola,Barney S Graham,Joshua C Johnson,Ulaş Bağcı ,Megan Culler Freeman ,Zhi Yong Yang ,Peter B Jahrling ,Lisa E Hensley ,Gene G Olinger ,Wing Pui Kong ,John Paul Todd ,Michael Joyce

doi:10.1038/ncomms8712

Abstract

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.Supplementary informationThe online version of this article (doi:10.1038/ncomms8712) contains supplementary material, which is available to authorized users.

Highlights

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development
We originally designed five vaccine constructs on the basis of sequences from the MERS-CoV Spike glycoprotein (Fig. 1a)
To test the immunogenicity of our vaccine candidates against multiple MERS-CoV strains—without the requirement of a biosafety level 3 facility—we developed a pseudotyped reporter virus neutralization assay, as we did previously for SARS-CoV19–22

Summary

Introduction

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. We show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serumneutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development

Methods

Results

Conclusion