Evaluation of Safety, Immunogenicity and Cross-Reactive Immunity of OVX836, a Nucleoprotein-Based Universal Influenza Vaccine, in Older Adults

Abstract

Background/Objectives: In a Phase 2a, double-blind, placebo-controlled study including healthy participants aged 18-55 years, OVX836, a nucleoprotein (NP)-based candidate vaccine, previously showed a good safety profile, a robust immune response (both humoral and cellular) and a preliminary signal of protection (VE = 84%) against PCR-confirmed symptomatic influenza after a single intramuscular dose of 180 µg, 300 µg or 480 µg. Methods: Using the same methodology, we confirmed the good safety and strong immunogenicity of OVX836 at the same doses in older adults (≥65 years), a key target population for influenza vaccination. Results: Significant humoral (anti-NP IgG) and cellular (interferon gamma (IFNγ) spot-forming cells per million peripheral blood mononuclear cells and specific CD4⁺ IFNγ⁺ T-cells) immune responses were observed at the three dose levels, without clear dose-response relationship. T-cell responses were shown to be highly cross-reactive against various influenza A strains, both seasonal and highly pathogenic avian strains. We also evaluated the effect of sex (stronger immune response in females) and age (stronger immune response in young adults) on the immune response to OVX836 after adjustment based on the pre-vaccination immune status. Conclusions: The results obtained with OVX836 lay the groundwork for a future placebo-controlled, field proof of concept efficacy Phase 2b trial.

Keywords: Phase 2a; cross-reactivity; healthy participants; immunogenicity; influenza; older adults; safety; universal vaccine.

Figure 1

CONSORT diagram of the OVX836-003 study (Part II consisting of participants aged 65 years and over).

Figure 2

Number of nucleoprotein (NP)-specific IFNγ spot-forming cells (SFCs) per million peripheral blood mononuclear cells (PBMCs) after a single intramuscular administration of OVX836 (180 μg, 300 μg or 480 μg) or placebo. Data are mean (standard deviation) and individual values on Day 1 (before vaccination) and Day 8 (7 days following vaccination). The three vaccine groups significantly differed from the placebo: p = 0.001 for OVX836 180 µg, p < 0.001 for OVX836 300 µg and p = 0.027 for OVX836 480 µg. The differences between the OVX836 groups themselves were not statistically significant (p = 1.000).

Figure 3

Percentage of nucleoprotein (NP)-specific CD4⁺ T-cells expressing at least interferon gamma (IFNγ) or IFNγ and interleukin-2 (IL-2) following a single intramuscular dose of OVX836 (180 µg, 300 µg or 480 µg) or placebo. Panel (A) shows the mean (standard deviation) and individual percentage of NP-specific CD4⁺ T-cells expressing at least IFNγ or IFNγ and IL-2 on Day 1 (prior to vaccination) and Day 8 (7 days following vaccination). Panel (B) shows the absolute differences (delta) between Day 8 and Day 1. The three vaccine groups significantly differed from the placebo (p < 0.001). The differences between the OVX836 groups themselves were not statistically significant (p = 1.000).

Figure 4

Anti-nucleoprotein (NP)-specific immunoglobulin G (IgG) titers determined at baseline (Day 1—pre-vaccination), Day 8 (7 days post-vaccination) and Day 29 (28 days post-vaccination) in the placebo and OVX836 vaccine groups (180 μg, 300 μg and 480 μg). Data are geometric mean titers ± 95% confidence intervals. At both post-vaccination timepoints (Day 8 and Day 29), GMTs in the three OVX836 dose groups were significantly higher than those in the placebo group (p < 0.001). The differences between the three OVX836 dose levels were not statistically significant (p > 0.05).

Figure 5

Correlation of the vaccine-induced interferon gamma (IFNγ) ELISpot responses (difference (delta) between Day 8 and Day 1) specific to the homologous nucleoprotein (NP) (H1N1-A/WSN 1933) versus the IFNγ responses (difference (delta) between Day 8 and Day 1) to NPs from heterologous influenza A strains (pH1N1-A/California, H3N2-A/Kansas and H5N1-A/Indonesia) and influenza B strain (B-Victoria). Panel (A) shows participants aged 18–55 years, while Panel (B) shows participants aged 65 years and older. The slope of the regression line is indicated in each figure (dotted green line: regression with slope = 1).

Figure 5

Correlation of the vaccine-induced interferon gamma (IFNγ) ELISpot responses (difference (delta) between Day 8 and Day 1) specific to the homologous nucleoprotein (NP) (H1N1-A/WSN 1933) versus the IFNγ responses (difference (delta) between Day 8 and Day 1) to NPs from heterologous influenza A strains (pH1N1-A/California, H3N2-A/Kansas and H5N1-A/Indonesia) and influenza B strain (B-Victoria). Panel (A) shows participants aged 18–55 years, while Panel (B) shows participants aged 65 years and older. The slope of the regression line is indicated in each figure (dotted green line: regression with slope = 1).

Figure 6

Influence of the baseline (pre-vaccination) immunological status on the response to OVX836 (180 µg, 300 µg and 480 µg). Panel (A) shows the differences between Day 8 and Day 1 (delta) in nucleoprotein (NP)-specific interferon gamma (IFNγ) spot-forming cells (SFCs) per million peripheral blood mononuclear cells (PBMCs). Panel (B) shows the differences between Day 8 and Day 1 (delta) in the percentage of CD4⁺ T-cells producing at least IFNγ. Panel (C) shows the geometric mean ratio (GMR) of anti-NP IgG titers (Day 8/Day 1 and Day 29/Day 1). Results are displayed as means with individual values for all participants, divided into four quartiles based on baseline ELISpot and CD4⁺ T-cell values, and as GMR with individual values based on the median baseline titer for anti-NP IgG.