Phase 1 Randomized, Placebo-Controlled, Dose-Escalating Study to Evaluate OVX836, a Nucleoprotein-Based Influenza Vaccine: Intramuscular Results.

BACKGROUND: OVX836 is a recombinant protein vaccine targeting the highly conserved influenza nucleoprotein (NP), which could confer broad-spectrum protection against this disease. METHODS: A randomized, placebo-controlled, double-blind, dose-escalating, single- center, first-in-human study was conducted in 36 healthy adults aged 18-49 years. Twelve subjects per cohort (9 vaccine and 3 placebo) received 2 OVX836 intramuscular administrations on days 1 and 28 at the dose level of 30 µg, 90 µg, or 180 µg. Safety and immunogenicity were assessed after each vaccination and for 150 days in total. RESULTS: OVX836 was safe and well tolerated at all dose levels, with no difference in solicited local and systemic symptoms, and unsolicited adverse events between the first and second administration, or between dose levels. All subjects presented pre-existing NP-specific immunity at baseline. OVX836 induced a significant increase in NP-specific interferon-gamma T cells and anti-NP immunoglobulin G at all dose levels after the first vaccination. The second vaccination did not further increase the response. There was a trend for a dose effect in the immune response. CONCLUSIONS: The safety and reactogenicity profile, as well as the humoral and cellular immune responses, encourage further evaluation of OVX836 in a larger Phase 2a study.

OVX033, a nucleocapsid-based vaccine candidate, provides broad-spectrum protection against SARS-CoV-2 variants in a hamster challenge model.

Spike-based COVID-19 vaccines induce potent neutralizing antibodies but their efficacy against SARS-CoV-2 variants decreases. OVX033 is a recombinant protein composed of the full-length nucleocapsid (N) protein of SARS-CoV-2 genetically fused to oligoDOM®, a self-assembling domain which improves antigen immunogenicity. OVX033 including N as an antigenic target is proposed as new vaccine candidate providing broad-spectrum protection against sarbecoviruses. OVX033 demonstrated its ability to trigger cross-reactive T cell responses and cross-protection against three variants of SARS-CoV-2 (B.1 Europe, Delta B.1.617.2, and Omicron B.1.1.529) in a hamster challenge model, as evidenced by lower weight loss, lower lung viral loads, and reduced lung histopathological lesions.

OVX836 Heptameric Nucleoprotein Vaccine Generates Lung Tissue-Resident Memory CD8+ T-Cells for Cross-Protection Against Influenza.

Tissue-resident memory (TRM) CD8+ T-cells play a crucial role in the protection against influenza infection but remain difficult to elicit using recombinant protein vaccines. OVX836 is a recombinant protein vaccine, obtained by the fusion of the DNA sequence of the influenza A nucleoprotein (NP) to the DNA sequence of the OVX313 heptamerization domain. We previously demonstrated that OVX836 provides broad-spectrum protection against influenza viruses. Here, we show that OVX836 intramuscular (IM) immunization induces higher numbers of NP-specific IFNγ-producing CD8+ T-cells in the lung, compared to mutant NP (NPm) and wild-type NP (NPwt), which form monomeric and trimeric structures, respectively. OVX836 induces cytotoxic CD8+ T-cells and high frequencies of lung TRM CD8+ T-cells, while inducing solid protection against lethal influenza virus challenges for at least 90 days. Adoptive transfer experiments demonstrated that protection against diverse influenza subtypes is mediated by NP-specific CD8+ T-cells isolated from the lung and spleen following OVX836 vaccination. OVX836 induces a high number of NP-specific lung CD8+ TRM-cells for long-term protection against influenza viruses.