Abstract
The COVID-19 pandemic is a worldwide health emergency which calls for an unprecedented race for vaccines and treatment. In developing a COVID-19 vaccine, we applied technology previously used for MERS-CoV to produce a prefusion-stabilized SARS-CoV-2 spike protein, S-2P. To enhance immunogenicity and mitigate the potential vaccine-induced immunopathology, CpG 1018, a Th1-biasing synthetic toll-like receptor 9 (TLR9) agonist was selected as an adjuvant candidate. S-2P in combination with CpG 1018 and aluminum hydroxide (alum) was found to be the most potent immunogen and induced high titer of neutralizing antibodies in sera of immunized mice against pseudotyped lentivirus reporter or live wild-type SARS-CoV-2. In addition, the antibodies elicited were able to cross-neutralize pseudovirus containing the spike protein of the D614G variant, indicating the potential for broad spectrum protection. A marked Th1 dominant response was noted from cytokines secreted by splenocytes of mice immunized with CpG 1018 and alum. No vaccine-related serious adverse effects were found in the dose-ranging study in rats administered single- or two-dose regimens of S-2P combined with CpG 1018 alone or CpG 1018 with alum. These data support continued development of CHO-derived S-2P formulated with CpG 1018 and alum as a candidate vaccine to prevent COVID-19 disease.
Highlights
The COVID-19 pandemic is a worldwide health emergency which calls for an unprecedented race for vaccines and treatment
The S-2P proteins produced in CHO cells and their structure displayed typical spike trimers under cryo-EM (Supplementary Figure S1), resembling that of 293-expressed SARS-CoV-2 S protein[9], suggesting that CHO cells are feasible in production of S-2P
We showed that in mice, two injections of a subunit vaccine consisting of the prefusion spike protein (S-2P) adjuvanted with CpG 1018 and alum were effective in inducing potent neutralization activity against both pseudovirus expressing wild-type and D614G variant spike proteins, and wild-type SARS-CoV-2
Summary
The COVID-19 pandemic is a worldwide health emergency which calls for an unprecedented race for vaccines and treatment. No vaccine-related serious adverse effects were found in the dose-ranging study in rats administered single- or two-dose regimens of S-2P combined with CpG 1018 alone or CpG 1018 with alum These data support continued development of CHO-derived S-2P formulated with CpG 1018 and alum as a candidate vaccine to prevent COVID-19 disease. A stabilized prefusion form of the MERS spike protein was achieved in 2017 by transferring two proline substitutions between heptad repeat 1 and the central helix analogous to those defined in the HKU1 spike protein These mutations together with a C-terminus foldon trimerization domain stabilized the spike ectodomain in its prefusion state resulting in a more potent immunogen with dose-sparing properties compared to protein made with the original wild-type sequence[8]. The analogous mutations in the SARS-CoV-2 spike resulted in a homogeneous population of proteins allowing the atomic-level structure to be solved by cryo-electron m icroscopy[9]
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