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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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