Pena Erik S, Ontiveros-Padilla Luis, Lukesh Nicole R, Williamson Grace L, Murphy Connor T, Hendy Dylan A, Roque John A, Carlock Michael A, Ross Ted M, Ainslie Kristy M, Bachelder Eric M
Department of Biomedical Engineering, North Carolina State University and University of North Carolina, Chapel Hill, NC, USA.
Division of Pharmacoengineering & Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
J Control Release. 2025 Aug 10;384:113936. doi: 10.1016/j.jconrel.2025.113936. Epub 2025 Jun 6.
The influenza virus continues to impose a significant yearly burden on society due to the variable efficacy of seasonal vaccines. Further strains like H5N1, that are not included in the seasonal influenza vaccine, may spill over from animal reservoirs and more significantly impact human health. A broadly acting subunit vaccine can offer protection across multiple strains but would have low immunogenicity without an adjuvant, which are currently limited and require delivery systems to mitigate side effects. Further, antigen delivery can be enhanced with carrier systems to provide dose sparing, and thermostability. This study explores acetalated dextran microparticles (Ace-DEX MPs) encapsulating cGAMP and computational optimized broadly reactive antigen (COBRA) hemagglutinin (HA) proteins, to form a multivalent influenza vaccine. Previous research has shown that Ace-DEX cGAMP MPs with varying degradation kinetics can modulate the immune response. Here, we investigate the effects of mixing MPs with different degradation rates to optimize the immune response. Mice vaccinated with slower-degrading cGAMP MPs exhibited higher IgG2a titers and IL-2 producing splenocytes, while those vaccinated with a mix of fast and slow-degrading cGAMP MPs had the highest IFN-γ producing splenocytes. The protection afforded in mice was also shown in ferrets with a H1, H3 and H5 trivalent COBRA formulation adjuvanted by slow degrading cGAMP MPs. Furthermore, using Ace-DEX MPs encapsulating two broadly reactive COBRA H1 and H3 immunogens in particles with fast and slow degradation rates, co-delivered with cGAMP MPs, resulted in less single antigen dominance when the more dominant antigen was encapsulated in the slowest degrading MP. This work underscores the utility of Ace-DEX MPs as a vaccine delivery platform and the impact of MP degradation kinetics on vaccine efficacy.
由于季节性疫苗的效力存在差异，流感病毒每年仍给社会带来巨大负担。像H5N1这样未包含在季节性流感疫苗中的其他毒株，可能会从动物宿主中溢出，对人类健康产生更重大的影响。一种具有广泛作用的亚单位疫苗可以提供针对多种毒株的保护，但如果没有佐剂，其免疫原性会很低，而目前可用的佐剂有限，并且需要递送系统来减轻副作用。此外，载体系统可以增强抗原递送，以实现剂量节省和热稳定性。本研究探索了包裹cGAMP的乙酰化葡聚糖微粒（Ace-DEX MPs）和经过计算优化的广泛反应性抗原（COBRA）血凝素（HA）蛋白，以形成一种多价流感疫苗。先前的研究表明，具有不同降解动力学的Ace-DEX cGAMP MPs可以调节免疫反应。在这里，我们研究混合不同降解速率的MPs对优化免疫反应的影响。接种降解较慢的cGAMP MPs的小鼠表现出更高的IgG2a滴度和产生IL-2的脾细胞，而接种快速和慢速降解的cGAMP MPs混合物的小鼠产生IFN-γ的脾细胞最多。在雪貂中也显示出，用降解缓慢的cGAMP MPs佐剂的H1、H3和H5三价COBRA制剂对小鼠提供了保护。此外，使用包裹两种广泛反应性COBRA H1和H3免疫原的Ace-DEX MPs，其降解速率有快有慢，并与cGAMP MPs共同递送，当更占主导地位的抗原被包裹在降解最慢的MP中时，单一抗原的主导性会降低。这项工作强调了Ace-DEX MPs作为疫苗递送平台的实用性以及MP降解动力学对疫苗效力的影响。
