St. Jude Graduate School of Biomedical Sciences, Memphis, Tennessee, USA.
Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
J Virol. 2024 Aug 20;98(8):e0078124. doi: 10.1128/jvi.00781-24. Epub 2024 Jul 30.
Influenza remains a worldwide public health threat. Although seasonal influenza vaccines are currently the best means of preventing severe disease, the standard-of-care vaccines require frequent updating due to antigenic drift and can have low efficacy, particularly in vulnerable populations. Here, we demonstrate that a single administration of a recombinant adenovirus-associated virus (rAAV) vector expressing a computationally optimized broadly reactive antigen (COBRA)-derived influenza H1 hemagglutinin (HA) induces strongly neutralizing and broadly protective antibodies in naïve mice and ferrets with pre-existing influenza immunity. Following a lethal viral challenge, the rAAV-COBRA vaccine allowed for significantly reduced viral loads in the upper and lower respiratory tracts and complete protection from morbidity and mortality that lasted for at least 5 months post-vaccination. We observed no signs of antibody waning during this study. CpG motif enrichment of the antigen can act as an internal adjuvant to further enhance the immune responses to allow for lower vaccine dosages with the induction of unique interferon-producing CD4+ and CD8+ T cells specific to HA head and stem peptide sequences. Our studies highlight the utility of rAAV as an effective platform to improve seasonal influenza vaccines.
Developing an improved seasonal influenza vaccine remains an ambitious goal of researchers and clinicians alike. With influenza routinely causing severe epidemics with the potential to rise to pandemic levels, it is critical to create an effective, broadly protective, and durable vaccine to improve public health worldwide. As a potential solution, we created a rAAV viral vector expressing a COBRA-optimized influenza hemagglutinin antigen with modestly enriched CpG motifs to evoke a robust and long-lasting immune response after a single intramuscular dose without needing boosts or adjuvants. Importantly, the rAAV vaccine boosted antibody breadth to future strains in ferrets with pre-existing influenza immunity. Together, our data support further investigation into the utility of viral vectors as a potential avenue to improve our seasonal influenza vaccines.
流感仍然是全球公共卫生威胁。尽管季节性流感疫苗目前是预防严重疾病的最佳手段，但由于抗原漂移，标准护理疫苗需要频繁更新，并且在脆弱人群中的效果可能较低。在这里，我们证明，单次施用表达经计算优化的广泛反应性抗原（COBRA）衍生的流感 H1 血凝素（HA）的重组腺相关病毒（rAAV）载体在具有先前存在的流感免疫力的幼稚小鼠和雪貂中诱导强烈的中和和广泛的保护性抗体。在致命性病毒挑战后，rAAV-COBRA 疫苗可使上呼吸道和下呼吸道中的病毒载量显着降低，并完全防止发病率和死亡率，至少在接种疫苗后 5 个月内保持不变。在这项研究中，我们没有观察到抗体衰减的迹象。抗原中的 CpG 基序富集可以作为内部佐剂进一步增强免疫反应，从而允许使用较低的疫苗剂量诱导针对 HA 头部和茎肽序列的独特干扰素产生的 CD4+和 CD8+T 细胞。我们的研究强调了 rAAV 作为改善季节性流感疫苗的有效平台的重要性。
开发改良的季节性流感疫苗仍然是研究人员和临床医生的雄心勃勃的目标。由于流感常规引起严重的流行，并有可能上升到大流行水平，因此必须创建一种有效，广泛保护和持久的疫苗，以改善全球公共卫生。作为一种潜在的解决方案，我们创建了一种 rAAV 病毒载体，该载体表达 COBRA 优化的流感血凝素抗原，其中适度富集了 CpG 基序，可在单次肌肉内剂量后引发强大而持久的免疫反应，而无需增强剂或佐剂。重要的是，rAAV 疫苗增强了具有先前存在的流感免疫力的雪貂对未来株的抗体广度。总之，我们的数据支持进一步研究病毒载体作为改善季节性流感疫苗的潜在途径的效用。
