Evaluation of Stabilized Prefusion Coronavirus Spike Trimers as Vaccine Antigens
Kizzmekia S. Corbett1, Olubukola M. Abiona1, Sarah R. Leist2, Nianshuang Wang3, Daniel Wrapp3, Rachel Graham2 Ande West2, Adam Cockrell2, Jacob Kocher2, Alex Schaefer2, Yaroslav Tsybovsky4, Osnat Rosen1, Lingshu Wang1, Wei Shi1, Jesper Pallesen5, Masaru Kanekiyo1, Wing-Pui Kong1, Andrew Ward5, Jason S. Mclellan3, John R. Mascola1, Ralph Baric2, Barney S. Graham1 1Vaccine Research Center; National Institutes of Allergy and Infectious Diseases; National Institutes of Health; Bethesda, MD, USA, 2Department of Epidemiology; University of North Carolina at Chapel Hill; Chapel Hill, NC, USA, 3Department of Molecular Biosciences; University of Texas at Austin; Austin, TX, USA, 4Electron Microscopy Laboratory; Cancer Research Technology Program; Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute; Frederick, MD, USA, 5Department of Integrative Structural and Computational Biology; The Scripps Research Institute; La Jolla, CA, USA
Coronaviruses (CoVs) thrive in animal reservoirs and represent a constant threat to human health as most recently exemplified the 2012 emergence of MERS-CoV, which is responsible for 2229 reported cases and 791 deaths worldwide. In anticipation of the next CoV outbreak, there is an imminent need for a vaccine solution. CoV spike (S) proteins mediate cellular attachment and membrane fusion and are therefore the primary target of protective antibodies. Instability and low expression of full-length CoV S proteins has historically hindered their development as vaccine antigens. Stabilizing other enveloped viral class, I fusion proteins (e.g. RSV fusion (F) glycoprotein) in the functional prefusion conformation has resulted in highly immunogenic protein subunit candidate vaccines. To that end, we sought to evaluate stabilized prefusion CoV S trimers as vaccine candidates. Using structure-guided protein engineering, stabilizing mutations were identified to maintain several CoV S proteins across genera as trimers in their prefusion conformation (pre-S). To date, we have stabilized S proteins of 5 CoVs that infect humans: MERS, SARS, HKU1, OC43, and 229E. This presentation details our efforts to characterize the immunogenicity of MERS pre-S in mice. We show pre-S elicits more robust neutralizing antibodies to multiple MERS strains than S1 monomer or wild-type versions of S trimers and protects mice from lethal challenge at low dose. Dissection of MERS pre-S immune mouse serum reveals MERS pre-S vaccination induces neutralizing antibodies to multiple domains of the trimer including to conserved regions outside of the receptor-binding domain. Additionally, we have optimized our MERS pre-S design for mRNA vaccine delivery, which yields robust neutralizing antibody responses. Looking forward to the next CoV outbreak, we are developing antigen design and vaccination strategies to target diverse neutralization-sensitive sites on pre-S and identifying sites that can elicit broadly neutralizing antibody responses. Our findings suggest that it may be possible to identify a generalizable solution for designing vaccine antigens for newly-emerging coronaviruses.
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