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

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.

Safety and immunogenicity of SARS-CoV-2 self-amplifying RNA vaccine expressing anchored RBD: a randomised, observer-blind, phase 1 study (preprint)

BACKGROUND VLPCOV-01 is a lipid nanoparticle-encapsulated self-amplifying (sa) RNA vaccine that expresses a membrane-anchored receptor-binding domain (RBD) derived from the SARS-CoV-2 spike protein. METHODS A phase 1 study of VLPCOV-01 was conducted at Medical Corporation Heishinkai OPHAC Hospital, Japan. The investigational vaccines were administered to participants, between February 16, 2022, and March 17, 2022. Participants aged 18 to 55 or [≥]65 years who had completed two doses of the BNT162b2 mRNA vaccine 6 to 12 months previously were randomised to receive one intramuscular vaccination of 0{middle dot}3, 1{middle dot}0, or 3{middle dot}0 {micro}g VLPCOV-01, 30 {micro}g BNT162b2, or placebo. Solicited adverse events were collected up to 6 days post-administration, with follow-up on all adverse events until week 4. Interim immunogenicity analyses following data cutoff at day 29 included SARS-CoV-2 IgG and neutralising antibody titres. (The trial is registered: jRCT2051210164). FINDINGS 92 healthy adults were enrolled, with 60 participants receiving VLPCOV-01. No serious adverse events were reported up to 26 weeks, and no prespecified trial-halting events were met. VLPCOV-01 induced robust IgG titres against SARS-CoV-2 RBD protein that were maintained up to 26 weeks in non-elderly participants, with geometric means ranging from 5037 (95% CI 1272-19,940) at 0{middle dot}3 {micro}g to 12,873 (95% CI 937-17,686) at 3 {micro}g, in comparison to 3166 (95% CI 1619-6191) with 30 {micro}g BNT162b2. Among elderly participants, IgG titres at 26 weeks post-vaccination with 3 {micro}g VLPCOV-01 were 9865 (95% CI 4396-22138) compared to 4183 (95% CI 1436-12180) following vaccination with 30 {micro}g BNT162b2. Pseudovirus-Neutralising antibody responses were observed against multiple SARS-CoV-2 variants and strongly correlated with anti-SARS-CoV-2 IgG (r=0{middle dot}950, p<0{middle dot}001). INTERPRETATION VLPCOV-01 is immunogenic following low dose administration, with anti-SARS-CoV-2 immune responses comparable to BNT162b2. These findings support further development of VLPCOV-01 as a COVID-19 booster vaccine and the potential for saRNA vectors as a vaccine platform. FUNDING Supported by AMED, Grant No. JP21nf0101627.

Naturally mutated spike proteins of SARS-CoV-2 variants show differential levels of cell entry (preprint)

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the angiotensin-converting enzyme-2 (ACE2) receptor and is cleaved by transmembrane protease serine 2 (TMPRSS2). However, whether S mutations affect SARS-CoV-2 infectivity remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural observations. Nevertheless, the D614G mutant remains susceptible to neutralization by antisera against prototypic viruses. Taken together, these data indicate that the D614G mutation enhances viral infectivity while maintaining neutralization susceptibility.