Research and Development Department, Osivax, Lyon, France.
Immunity and Cytotoxic Lymphocytes Team, Centre International de Recherche en Infectiologie, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Université de Lyon, Lyon, France.
Front Immunol. 2021 Jun 10;12:678483. doi: 10.3389/fimmu.2021.678483. eCollection 2021.
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.
组织驻留记忆 (TRM) CD8+ T 细胞在预防流感感染方面发挥着关键作用,但使用重组蛋白疫苗仍然难以引发。OVX836 是一种重组蛋白疫苗,通过将流感 A 核蛋白 (NP) 的 DNA 序列与 OVX313 七聚体结构域的 DNA 序列融合而获得。我们之前证明,OVX836 可提供针对流感病毒的广谱保护。在这里,我们表明,与分别形成单体和三聚体结构的突变型 NP (NPm) 和野生型 NP (NPwt) 相比,OVX836 肌肉内 (IM) 免疫接种可诱导肺中更多数量的 NP 特异性 IFNγ 产生的 CD8+ T 细胞。OVX836 诱导细胞毒性 CD8+ T 细胞和高频率的肺 TRM CD8+ T 细胞,同时提供针对致命流感病毒挑战的实质性保护至少 90 天。过继转移实验表明,OVX836 诱导的 NP 特异性 CD8+ T 细胞可从肺和脾脏中分离出来,针对不同的流感亚型提供保护,这些 T 细胞在接种 OVX836 疫苗后可长期预防流感病毒。OVX836 诱导大量的 NP 特异性肺 CD8+ TRM 细胞,可长期预防流感病毒。
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