saRNA vaccine expressing membrane-anchored RBD elicits broad and durable immunity against SARS-CoV-2 variants of concern.

Several vaccines have been widely used to counteract the global pandemic caused by SARS-CoV-2. However, due to the rapid emergence of SARS-CoV-2 variants of concern (VOCs), further development of vaccines that confer broad and longer-lasting protection against emerging VOCs are needed. Here, we report the immunological characteristics of a self-amplifying RNA (saRNA) vaccine expressing the SARS-CoV-2 Spike (S) receptor binding domain (RBD), which is membrane-anchored by fusing with an N-terminal signal sequence and a C-terminal transmembrane domain (RBD-TM). Immunization with saRNA RBD-TM delivered in lipid nanoparticles (LNP) efficiently induces T-cell and B-cell responses in non-human primates (NHPs). In addition, immunized hamsters and NHPs are protected against SARS-CoV-2 challenge. Importantly, RBD-specific antibodies against VOCs are maintained for at least 12 months in NHPs. These findings suggest that this saRNA platform expressing RBD-TM will be a useful vaccine candidate inducing durable immunity against emerging SARS-CoV-2 strains.

Functional changes in cytotoxic CD8+ T-cell cross-reactivity against the SARS-CoV-2 Omicron variant after mRNA vaccination.

Understanding the T-cell responses involved in inhibiting COVID-19 severity is crucial for developing new therapeutic and vaccine strategies. Here, we characterized SARS-CoV-2 spike-specific CD8+ T cells in vaccinees longitudinally. The BNT162b2 mRNA vaccine can induce spike-specific CD8+ T cells cross-reacting to BA.1, whereas the T-cell receptor (TCR) repertoire usages decreased with time. Furthermore the mRNA vaccine induced spike-specific CD8+ T cells subpopulation expressing Granzyme A (GZMA), Granzyme B (GZMB) and Perforin simultaneously in healthy donors at 4 weeks after the second vaccination. The induced subpopulation was not maintained at 12 weeks after the second vaccination. Incorporating factors that efficiently induce CD8+ T cells with highly cytotoxic activity could improve future vaccine efficacy against such variants.

mRNA vaccine induces cytotoxic CD8+ T-cell cross-reactivity against SARS-CoV-2 Omicron variant and regulates COVID-19 severity (preprint)

Understanding the T-cell responses involved in inhibiting COVID-19 severity is crucial for developing new therapeutic and vaccine strategies. Here, we characterized SARS-CoV-2 spike-specific CD8+ T cells interacting with overlapping peptides on peripheral blood mononuclear cells from acute-phase COVID-19 patients. Relative to severe COVID-19, patients with mild COVID-19 had more frequent antigen-specific CD8+ T cells, and significantly increased SARS-CoV-2 spike-specific CD8+ T cells simultaneously expressing granzyme A, granzyme B, and perforin, suggesting that inducing highly cytotoxic CD8+ T cells during early infection suppresses COVID-19 severity. The BNT162b2 mRNA vaccine induced these antigen-specific CD8+ T cells in healthy donors, although lesser than in infected patients, and the induced subpopulation was not maintained long-term after second vaccination. Importantly, these CD8+ T cells showed cross-reactivity with the Delta and Omicron strains of SARS-CoV-2. Incorporating factors that efficiently induce CD8+ T cells with polyfunctional cytotoxic activity may improve future vaccine efficacy against such variants.