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

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 the 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 reduced adverse events and fewer fever events at an equivalent dose. These findings support further study of VLPCOV-02.

Keywords: Immunology; Virology.

Graphical abstract

Figure 1

VLPCOV-02-0102 study design (A) Flow of transition between VLPCOV-02 dose levels. (B) Flow of transition from non-elderly to elderly participants, and from the sentinel to subsequent participants at each dose level. ^aThe protocol prespecified discussion criteria for allowing transition to the next VLPCOV-02 dose level (DL) were: (1) the sentinel participant developed an acute symptom requiring emergent measures; (2) a participant in either cohort at the current DL developed a solicited grade 4 AE (according to the relevant United States Food and Drug Administration (FDA) Guidance for Industry; 3) a participant in either cohort of the current DL developed a grade ≥3 AE (excluding solicited AEs) according to CTCAE v5.0; (4) ≥50% of participants in either cohort of the current DL developed solicited grade ≥3 AEs (according to the relevant FDA Guidance for Industry²⁰) or grade ≥2 AEs according to CTCAE v5.0; (5) the principal investigator determined it necessary (even in the absence of criteria 1–4). ^bIn the case of transition to DL5 or DL6, no sentinel participant was required. AE, adverse event; CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; DL(n), dose level n.

Figure 2

Solicited local and systemic adverse events reported up to 1 week after vaccination with VLPCOV-02 (A) Solicited local adverse events in the non-elderly and elderly cohorts, by dose level. (B) Solicited systemic adverse events in the non-elderly and elderly cohorts, by dose level. (C) Body temperature (measured orally) in the non-elderly and elderly cohorts, by dose level. Lines indicate mean value of the changes in the body temperature with 95% confidence intervals. Solicited adverse events were recorded using an E-Diary application. ^aFever was graded as follows: mild = 38.0°C–38.4°C; moderate = 38.5°C–38.9°C; severe = 39.0°C–40.0°C.

Figure 3

Serum immunoglobulin titers against SARS-CoV-2 RBD protein Serum SARS-CoV-2 IgG titers against SARS-CoV-2 RBD protein in the non-elderly and elderly cohorts at baseline and at 4 weeks after vaccination, by dose level. The black line indicates the change in geometric mean value of the IgG titers. The maximum titer measurable was 80,000; any values ≥ 80,000 were treated as 80,000 for the purposes of calculating the geometric mean titers and 95% confidence intervals. IgG, immunoglobulin; RBD, receptor binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.