Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina 27599, United States.
ACS Biomater Sci Eng. 2022 Apr 11;8(4):1573-1582. doi: 10.1021/acsbiomaterials.2c00015. Epub 2022 Mar 30.
Influenza virus is a major cause of death on a global scale. Seasonal vaccines have been developed to combat influenza; however, they are not always highly effective. One strategy to develop a more broadly active influenza vaccine is the use of multiple rounds of layered consensus buildings to generate recombinant antigens, termed computationally optimized broadly reactive antigen (COBRA). Immunization with the COBRA hemagglutinin (HA) can elicit broad protection against multiple strains of a single influenza subtype (e.g., H1N1). We formulated a COBRA H1 HA with a stimulator of interferon genes agonist cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) into a nasal gel for vaccination against influenza. The gel formulation was designed to increase mucoadhesion and nasal retention of the antigen and adjuvant to promote a strong mucosal response. It consisted of a Schiff base-crosslinked hydrogel between branched polyethyleneimine and oxidized dextran. Following a prime-boost-boost schedule, an intranasal gel containing cGAMP and model antigen ovalbumin (OVA) led to the faster generation of serum IgG, IgG1, and IgG2c and significantly greater serum IgG1 levels on day 42 compared to soluble controls. Additionally, OVA-specific IgA was detected in nasal, vaginal, and fecal samples for all groups, except the vehicle control. When the COBRA HA was given intranasally in a prime-boost schedule, the mice receiving the gel containing the COBRA and cGAMP had significantly higher serum IgG and IgG2c at day 41 compared to all groups, and only this group had IgA levels above the background in vaginal, nasal, and fecal samples. Overall, this study indicates the utility of an intranasal gel for the delivery of COBRAs for the generation of serum and mucosal humoral responses.
流感病毒是全球范围内导致死亡的主要原因。已经开发出季节性疫苗来对抗流感，但它们并不总是非常有效。开发更广泛有效的流感疫苗的一种策略是使用多轮分层共识构建来产生重组抗原，称为计算优化的广泛反应性抗原（COBRA）。用 COBRA 血凝素（HA）免疫可引发针对单一流感亚型（例如 H1N1）多种菌株的广泛保护。我们将 COBRA H1 HA 与干扰素基因激动剂环鸟苷单磷酸-腺苷单磷酸（cGAMP）制成鼻凝胶，用于流感疫苗接种。凝胶配方旨在增加抗原和佐剂的粘膜粘附性和鼻腔保留率，以促进强烈的粘膜反应。它由支化聚乙烯亚胺和氧化葡聚糖之间的席夫碱交联水凝胶组成。在进行一次加强接种后，含有 cGAMP 和模型抗原卵清蛋白（OVA）的鼻内凝胶导致更快地产生血清 IgG、IgG1 和 IgG2c，并且与可溶性对照相比，在第 42 天血清 IgG1 水平显著更高。此外，除了载体对照组之外，所有组的鼻、阴道和粪便样本中均检测到 OVA 特异性 IgA。当 COBRA HA 以一次加强接种方案经鼻内给予时，接受含有 COBRA 和 cGAMP 的凝胶的小鼠在第 41 天的血清 IgG 和 IgG2c 显著高于所有组，并且只有该组的阴道、鼻和粪便样本中的 IgA 水平高于背景。总体而言，这项研究表明，鼻内凝胶可用于递送 COBRAs 以产生血清和粘膜体液反应。
