Evaluation of candidate vaccine approaches for MERS-CoV.

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

Index: Nat. Commun. 6 , 7712, (2015)

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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.