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

Komori, Mai; Morey, Amber L.; Sekida, Takashi; Ishimoto, Keiko; Hassett, Matthew R.; Masuta, Yuji; Ode, Hirotaka; Tamura, Tomokazu; Suzuki, Rigel; Alexander, Jeff; Kido, Yasutoshi; Matsuda, Kenta; Fukuhara, Takasuke; Iwatani, Yoshinori; Yamamoto, Takuya; Smith, Jonathan; Akahata, Wataru

doi:10.1038/s41467-023-38457-x

Cited by 15 publications

(14 citation statements)

References 32 publications

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“…9,10 A novel COVID-19 vaccine, VLPCOV-01, was developed using the LNP-encapsulated saRNA platform derived from an alphavirus amplification system that encodes replicase and transcriptase functions comprising the alphavirus nonstructural proteins (nsp1-4) from the attenuated TC-83 strain of Venezuelan equine encephalitis virus (VEEV), and which expresses a membrane-anchored receptor-binding domain (RBD). 11,12 When delivered as a booster vaccine in the phase 1 VLPCOV-01-0102 clinical trial, VLPCOV-01 induced strong and persistent immune responses in both non-elderly and elderly healthy participants who had received primary vaccination with BNT162b2; neutralizing antibody titers to Wuhan, Delta, and Omicron variants of SARS-CoV-2 were observed. 11 The immune response achieved was comparable to that observed with BNT162b2 and with a similar safety profile, but at one-tenth of the vaccine dose.…”

Section: Introductionmentioning

confidence: 99%

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

Aboshi,

Matsuda,

Kawakami

et al. 2023

Preprint

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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.

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Section: Introductionmentioning

confidence: 99%

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

Aboshi,

Matsuda,

Kawakami

et al. 2023

Preprint

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“…This vector expresses the VEEV replication machinery to replicate and transcribe the saRNA, resulting in efficient expression of the gene(s) of interest. Due to this self-amplification process, the level and duration of expression of target antigens are expected to be higher and more durable than that observed with nonreplicating mRNA vaccine platforms 10 . One clinical trial using an saRNA vector expressing the whole SARS S protein demonstrated that 5 µg of the saRNA induced significant amounts of neutralizing antibodies 13 .…”

Section: Introductionmentioning

confidence: 99%

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

Komori,

Morey,

Quiñones-Molina

et al. 2023

Preprint

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In order to improve vaccine effectiveness and safety profile of existing synthetic RNA-based vaccines, we have developed a self-amplifying RNA (saRNA)-based vaccine expressing membrane-anchored receptor binding domain (RBD) of SARS-CoV-2 S protein (S-RBD) and have demonstrated that a minimal dose of this saRNA vaccine elicits robust immune responses. Results from a recent clinical trial with 5-methylcytidine (5mC) incorporating saRNA vaccine demonstrated reduced vaccine-induced adverse effects while maintaining robust humoral responses. In this study, we investigate the mechanisms accounting for induction of efficient innate and adaptive immune responses and attenuated adverse effects induced by the 5mC-incorporated saRNA. We show that the 5mC-incorporating saRNA platform leads to prolonged and robust expression of antigen, while induction of type-I interferon (IFN-I), a key driver of reactogenicity, is attenuated in peripheral blood mononuclear cells (PBMCs), but not in macrophages and dendritic cells. Interestingly, we find that the major cellular source of IFN-I production in PBMCs is plasmacytoid dendritic cells (pDCs), which is attenuated upon 5mC incorporation in saRNA. In addition, we demonstrate that monocytes also play an important role in amplifying proinflammatory responses. Furthermore, we show that the detection of saRNA is mediated by a host cytosolic RNA sensor, RIG-I. Importantly, 5mC-incorporating saRNA vaccine candidate produced robust IgG responses against S-RBD upon injection in mice, thus providing strong support for the potential clinical use of 5mC-incorporating saRNA vaccines.

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“…In this way, the absorbance measurement of blue TMB ox1 catalyzed by HRP is strongly time-dependent, leading to unreliable readout in practical applications. To address this problem, a terminator, typically a strong acid, is generally required, which unfortunately not only compromises sensing accuracy but also causes safety hazards in bioassays. ,, Therefore, selective catalytic oxidation of TMB via a direct two-electron pathway is highly envisioned but challenging because of the thermodynamically favorable complexation between TMB ox2 and unreacted TMB back to TMB ox1 .…”

Section: Introductionmentioning

confidence: 99%

“…Precise regulation of chemical reaction processes helps to realize controllable chemical synthesis with high selectivity and efficiency. − As a typical substrate and chromogenic probe, 3,3′,5,5′-tetramethylbenzidine (TMB) features particular interest, due to its low toxicity and high sensitivity of response. − Meanwhile, horseradish peroxidase (HRP) has been widely used in immunochemistry due to its high catalytic efficiency and specificity under mild reaction conditions. − Along this line, HRP-H 2 O 2 -TMB has become the standard chromogenic system in the well-known clinical enzyme-linked immunosorbent assay (ELISA), which generally detects the absorbance of the one-electron oxidation product of TMB (TMB ox1 ). − Notably, TMB ox1 is essentially a blue charge-transfer complex, consisting of the parent diamine (TMB) and the two-electron oxidation product of diimine (TMB ox2 ) in rapid thermodynamical equilibrium with a radical cation (Figure a) . After all free TMB is completely oxidized in bulk solution, blue TMB ox1 undergoes one more electron oxidation into the final stable yellow product (TMB ox2 ).…”

Section: Introductionmentioning

confidence: 99%

Decoupling of the Confused Complex in Oxidation of 3,3′,5,5′-Tetramethylbenzidine for the Reliable Chromogenic Bioassay

Zhu,

Yang,

Cao

et al. 2023

Anal. Chem.

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Regulation of the reaction pathways is a perennial theme in the field of chemistry. As a typical chromogenic substrate, 3,3′,5,5′-tetramethylbenzidine (TMB) generally undertakes one-electron oxidation, but the product (TMB ox1 ) is essentially a confused complex and is unstable, which significantly hampers the clinic chromogenic bioassays for more than 50 years. Herein, we report that sodium dodecyl sulfate (SDS)-based micelles could drive the direct two-electron oxidation of TMB to the final stable TMB ox2 . Rather than activation of H 2 O 2 oxidant in the one-electron TMB oxidation by common natural peroxidase, activation of the TMB substrate by SDS micelles decoupled the thermodynamically favorable complex between TMB ox2 with unreacted TMB, leading to an unusual direct two-electron oxidation pathway. Mechanism studies demonstrated that the complementary spatial and electrostatic isolation effects, caused by the confined hydrophobic cavities and negatively charged outer surfaces of SDS micelles, were crucial. Further cascading with glucose oxidase, as a proof-of-concept application, allowed glucose to be more reliably measured, even in a broader range of concentrations without any conventional strong acid termination.

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

Cited by 15 publications

References 32 publications

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

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

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

Decoupling of the Confused Complex in Oxidation of 3,3′,5,5′-Tetramethylbenzidine for the Reliable Chromogenic Bioassay

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