Phase 1, first-in-human, randomized, placebo-controlled, dose-escalating study to evaluate OVX033, a nucleocapsid-based SARS-CoV-2 candidate vaccine.

BACKGROUND: OVX033 is a potential universal sarbecovirus vaccine candidate targeting the highly conserved SARS-CoV-2 nucleocapsid (N) protein. Preclinical studies have demonstrated cross-variant protection and favorable tolerability. This first-in-human trial evaluated the safety and immunogenicity of a single intramuscular dose of OVX033 in healthy adults (18-49 years). METHODS: In this randomized, placebo-controlled, observer-blind, sequential, dose-escalation study, 48 participants, previously vaccinated with SARS-CoV-2 licensed vaccines, received either OVX033 (100µg, 250µg or 500µg; n=12 per cohort) or placebo (n=12, 4 per cohort). Solicited reactogenicity was recorded for 7 days, unsolicited adverse events (AEs) for 28 days, and serious AEs (SAEs) for 6 months. Immunogenicity assessments included anti-N IgG and N-specific T-cell responses. RESULTS: OVX033 was safe and well-tolerated whatever the dose-level. Injection site pain was the most common local reaction; fatigue, headache, and myalgia were the most frequent systemic symptoms. No severe reactogenicity, treatment-related SAEs, or safety signals were identified. OVX033 elicited a robust anamnestic anti-N IgG response, with titers peaking at Day 29, and 4-fold rises versus baseline observed in 67-100% of vaccinees. Modest increases of N-specific IFNγ CD4+ T-cell responses were measured on Days 8 and 29 after vaccination, while CD8+ T-cell responses remained below the limit of quantification. No clear OVX033 dose-effect was evidenced. CONCLUSIONS: OVX033 demonstrated a favorable safety profile and strong boosting of pre-existing N-specific humoral immunity. Although a N-specific T-cell-mediated immune response was achieved, it remained of limited amplitude. This limitation could be addressed by implementing a two-dose regimen, or through the adjuvantation of the vaccine.