Siddoway A C, Van Zanten A, Verhoeven D, Wannemuehler M J, Mallapragada S K, Narasimhan B
Department of Chemical & Biological Engineering, Iowa State University, Ames, IA 50011, USA; Nanovaccine Institute, Iowa State University, Ames, IA 50011, USA.
Department of Chemical & Biological Engineering, Iowa State University, Ames, IA 50011, USA.
Acta Biomater. 2025 Jul 22. doi: 10.1016/j.actbio.2025.07.042.
Influenza virus is a common source of respiratory illness and poses a major public health burden globally. Significant efforts have been dedicated towards developing and deploying effective vaccines. However, since being licensed in 1945, influenza vaccines have made limited progress and still suffer from several limitations, including suboptimal efficacy against variants. In this work, we report on two influenza A polyanhydride particle- and pentablock copolymer-based vaccine formulations intended for intranasal or subcutaneous administration. These nanovaccines are based on a newly discovered equine influenza A H3N8 hemagglutinin antigen (A/equine/1/KY/91), A/HK/1/68 nucleoprotein antigen, and a small molecule adjuvant. When these nanovaccines were administered to naïve mice, both formulations induced robust humoral and cellular immune responses that were protective against lethal challenges with influenza A/HK/1/68 (H3N2) or A/PR/8/34 (H1N1). This protection was characterized by reduced viral load, reduced airway disruption, and preservation of weight post-infection. Further studies with immunization and challenge of CD8T cell depleted mice and passive serum transfer into recipient mice reinforced that the observed protection was due to a combination of both vaccine-induced antibody responses and CD8T cell immunity. These findings demonstrate that intranasal and subcutaneous polymeric particle-based vaccines based on potentially universal influenza antigens are effective and promising platforms for supra-seasonal influenza vaccines. STATEMENT OF SIGNIFICANCE: We designed two influenza virus vaccine formulations based on polyanhydride microparticles and pentablock copolymer micelles for intranasal and subcutaneous administration. The intranasal vaccine is based on polyanhydride microparticles while the subcutaneous vaccine contains both polyanhydride microparticles and pentablock copolymer micelles. Both vaccines contain a newly discovered equine influenza H3N8 hemagglutinin antigen, a nucleoprotein antigen, and an adjuvant. Both vaccines induced robust antibodies and cellular immune responses and protected mice upon lethal challenge. The use of CD8T cell depleted mice and passive transfer of sera from vaccinated mice to recipient mice reinforced that the protection was driven by vaccine-induced antibody and CD8T cell responses. These findings demonstrate that polymeric particle- and micelle-based vaccines are promising supra-seasonal influenza vaccines.
流感病毒是呼吸道疾病的常见病因，在全球范围内构成重大公共卫生负担。人们已付出巨大努力来研发和推广有效的疫苗。然而，自1945年获得许可以来，流感疫苗进展有限，仍存在一些局限性，包括对变异株的疗效欠佳。在本研究中，我们报告了两种基于聚酸酐颗粒和五嵌段共聚物的甲型流感疫苗制剂，适用于鼻内或皮下给药。这些纳米疫苗基于一种新发现的马甲型H3N8流感血凝素抗原（A/equine/1/KY/91）、A/HK/1/68核蛋白抗原和一种小分子佐剂。当将这些纳米疫苗接种给未接触过抗原的小鼠时，两种制剂均诱导了强烈的体液免疫和细胞免疫反应，对甲型流感病毒A/HK/1/68（H3N2）或A/PR/8/34（H1N1）的致死性攻击具有保护作用。这种保护作用的特征是病毒载量降低、气道破坏减轻以及感染后体重得以维持。对CD8T细胞耗竭小鼠进行免疫和攻击以及将被动血清转移至受体小鼠体内的进一步研究强化了以下观点：观察到的保护作用归因于疫苗诱导的抗体反应和CD8T细胞免疫的共同作用。这些发现表明，基于潜在通用流感抗原的鼻内和皮下聚合物颗粒疫苗是季节性流感疫苗有效且有前景的平台。重要性声明：我们设计了两种基于聚酸酐微粒和五嵌段共聚物胶束的流感病毒疫苗制剂，用于鼻内和皮下给药。鼻内疫苗基于聚酸酐微粒，而皮下疫苗同时包含聚酸酐微粒和五嵌段共聚物胶束。两种疫苗均包含一种新发现的马流感H3N8血凝素抗原、一种核蛋白抗原和一种佐剂。两种疫苗均诱导了强烈的抗体和细胞免疫反应，并在致死性攻击时保护小鼠。使用CD8T细胞耗竭小鼠以及将接种疫苗小鼠的血清被动转移至受体小鼠体内强化了以下观点：保护作用是由疫苗诱导的抗体和CD8T细胞反应驱动的。这些发现表明，基于聚合物颗粒和胶束的疫苗是有前景的季节性流感疫苗。
