流感仍然是全球公共卫生威胁。尽管季节性流感疫苗是目前预防严重疾病的最佳手段,标准护理疫苗由于抗原漂移而需要频繁更新,并且可能具有低效力,特别是在弱势群体中。这里,我们证明,表达计算优化的广泛反应性抗原(COBRA)衍生的流感H1血凝素(HA)的重组腺病毒相关病毒(rAAV)载体的单次给药在具有预先存在的流感免疫力的幼稚小鼠和雪貂中诱导强烈中和和广泛保护性抗体。在致命的病毒挑战之后,rAAV-COBRA疫苗可显著降低上呼吸道和下呼吸道的病毒载量,并在疫苗接种后至少5个月内完全预防发病率和死亡率.在这项研究中,我们没有观察到抗体减弱的迹象。抗原的CpG基序富集可以充当内部佐剂以进一步增强免疫应答,以允许较低的疫苗剂量,同时诱导对HA头部和茎肽序列具有特异性的独特的产生干扰素的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实用性。
目的:开发一种改良的季节性流感疫苗仍然是研究人员和临床医生的宏伟目标。流感通常会引起严重的流行病,有可能上升到大流行水平,创建一个有效的,广泛的保护,和持久疫苗,以改善全球公共卫生。作为一个潜在的解决方案,我们创建了一个rAAV病毒载体,该载体表达COBRA优化的流感血凝素抗原,该抗原具有适度富集的CpG基序,可在单次肌内注射后引发稳健且持久的免疫应答,而无需增强或佐剂.重要的是,rAAV疫苗增强了具有预先存在的流感免疫力的雪貂未来毒株的抗体宽度.一起,我们的数据支持进一步研究病毒载体作为改进季节性流感疫苗的潜在途径的效用.
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.
OBJECTIVE: 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.