Safety, immunogenicity, and optimal dosing of VLPCOV-02, a SARS-CoV-2 saRNA vaccine with modified 5-methylcytosine base.

Variant-adapted vaccines are becoming increasingly important for continued COVID-19 prevention. Part 1 of the phase 1/2 study with VLPCOV-02, a lipid nanoparticle-encapsulated, self-amplifying RNA (saRNA) vaccine with a modified 5-methylcytosine (5 mC) base, demonstrated lower reactogenicity and incidence of adverse events, and induction of antibody responses. We report results of part 2 with an expanded number of participants (N = 323 [3 μg VLPCOV-02: 53 non-elderly and 54 elderly; 7.5 μg VLPCOV-02: 55 non-elderly and 55 elderly; 30 μg Comirnaty ready to use: 52 non-elderly and 54 elderly]) to determine the optimal dose level. VLPCOV-02 induced robust immunoglobulin G titers against receptor-binding domain and neutralizing antibody titers against all variants of SARS-CoV-2 tested, and induced CD4(+) and CD8(+) T cell responses. These results indicate that the incorporation of a modified 5 mC base improves the safety profile of the saRNA vaccine without compromising immunogenicity, supporting further development of this platform as a booster vaccine.