Safety and immunogenicity of VLPCOV-02, a SARS-CoV-2 self-amplifying RNA vaccine with a modified base, 5-methylcytosine, in healthy individuals

Abstract

Continuing emergence of variants of concern resulting in reduced SARS-CoV-2 vaccine efficacy necessitates additional prevention strategies. The structure of VLPCOV-01, a lipid nanoparticle-encapsulated, self-amplifying RNA COVID-19 vaccine with a comparable immune response to BNT162b2, was revised by incorporating a modified base, 5-methylcytosine to reduce reactogenicity, and an updated receptor-binding domain derived from Brazil (gamma) variant. Interim analyses of a phase 1 dose-escalation booster vaccination study with the resulting construct, VLPCOV-02, in healthy, previously vaccinated Japanese individuals (N=96) are reported (jRCT2051230005). A dose-related increase in solicited local and systemic adverse events was observed, which were generally rated mild or moderate. The most commonly occurring events were tenderness, pain, fatigue, and myalgia. Serum SARS-CoV-2 immunoglobulin titers increased during the 4 weeks post-immunization. VLPCOV-02 demonstrated a favorable safety profile compared with VLPCOV-01, with a lower frequency of adverse events and fewer fever events at an equivalent dose. These findings support further study of VLPCOV-02.

Incorporation of 5 methylcytidine alleviates innate immune response to self-amplifying RNA vaccine

“…Importantly, our phase I trial of saRNA-based SARS-CoV-2 vaccines has shown that they are safe and effectively elicit prolonged humoral immune responses against S RBD 14 . Furthermore, this study and another clinical trial have demonstrated that an saRNA-based vaccine with 5mC induces attenuated IFN-I responses in vitro and reduced systemic reactogenicity when injected to human, resulting in better safety profile 15 . This saRNA-based vaccine platform, particularly with modified RNA bases, will be useful to develop vaccines with long-lasting effectiveness and reduced reactogenicity against not only SARS-CoV-2 but also other pathogens.…”

“…Interestingly, m5C incorporation into saRNA attenuates IFN-I and proinflammatory responses in PBMCs mainly due to the limited activation of the IFN-I pathway in pDCs. Although further reactogenicity studies of saRNA-m5C in animal models are currently in progress, we have already observed attenuated systemic reactions such as fevers in a human clinical trial conducted with saRNA-m5C vaccines 15 . While we were preparing this manuscript, a preprint by McGee and colleagues has also shown that cytosine modification enables saRNA to show enhanced and prolonged antigen expression and attenuated IFN-I responses 39 .…”

“…Interestingly, m5C incorporation into saRNA attenuates IFN-I and proinflammatory responses in PBMCs mainly due to the limited activation of the IFN-I pathway in pDCs. Although further reactogenicity studies of saRNA-m5C in animal models are currently in progress, we have already observed attenuated systemic reactions such as fevers in a human clinical trial conducted with saRNA-m5C vaccines 15 .…”

“…PADRE encodes a short stretch of peptides that binds to most common leukocyte antigen-DR isotypes, and are designed to enhances adaptive immunity to S-RBD in an MHC-II-restricted manner 28 . Since this platform is currently in clinical testing 15 , the saRNA-PADRE vector is clinically more relevant. Note that there is no difference between saRNA and saRNA-PADRE (native and 5mC) in induction of innate immune responses in PBMCs (Fig.…”

“…In addition, in a Phase I study, 3 µg of saRNA encoding membrane anchored S-RBD as the antigen elicited robust IgG responses which were comparable to those induced by 30 µg BNT162b2 vaccine 14 . Importantly, a separate phase 1 study using saRNA encoding a membrane-anchored S-RBD containing 5mC showed reduced systemic reactogenicity while maintaining IgG responses 15 . Despite the promising clinical data with saRNA-based vaccines, the mechanisms of how saRNA vaccines induce reactogenicity and how incorporation of modified RNA bases attenuates systemic reactogenicity have remained unclear.…”