Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 4211 Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina, 27599, USA.
Florida Research and Innovation Center, Port Saint, Cleveland Clinic Florida, Port St. Lucie, Florida, USA.
AAPS J. 2023 Jan 31;25(1):22. doi: 10.1208/s12248-023-00786-6.
Influenza is a global health concern with millions of infections occurring yearly. Seasonal flu vaccines are one way to combat this virus; however, they are poorly protective against influenza as the virus is constantly mutating, particularly at the immunodominant hemagglutinin (HA) head group. A more broadly acting approach involves Computationally Optimized Broadly Reactive Antigen (COBRA). COBRA HA generates a broad immune response that is capable of protecting against mutating strains. Unfortunately, protein-based vaccines are often weekly immunogenic, so to help boost the immune response, we employed the use of acetalated dextran (Ace-DEX) microparticles (MPs) two ways: one to conjugate COBRA HA to the surface and a second to encapsulate cGAMP. To conjugate the COBRA HA to the surface of the Ace-DEX MPs, a poly(L-lactide)-polyethylene glycol co-polymer with a vinyl sulfone terminal group (PLLA-PEG-VS) was used. MPs encapsulating the STING agonist cGAMP were co-delivered with the antigen to form a broadly active influenza vaccine. This vaccine approach was evaluated in vivo with a prime-boost-boost vaccination schedule and illustrated generation of a humoral and cellular response that could protect against a lethal challenge of A/California/07/2009 in BALB/c mice.
流感是一个全球性的健康问题，每年都有数百万人感染。季节性流感疫苗是对抗这种病毒的一种方法；然而，由于病毒不断突变，特别是在免疫显性血凝素（HA）头部，它们对流感的保护作用很差。一种更广泛的方法是计算优化的广泛反应性抗原（COBRA）。COBRA HA 产生广泛的免疫反应，能够抵御变异株。不幸的是，基于蛋白质的疫苗通常每周具有免疫原性，因此为了帮助增强免疫反应，我们采用了乙酰化葡聚糖（Ace-DEX）微粒（MPs）的两种方法：一种是将 COBRA HA 连接到表面，另一种是将 cGAMP 封装。为了将 COBRA HA 连接到 Ace-DEX MPs 的表面，使用了末端带有乙烯砜基团的聚（L-丙交酯）-聚乙二醇共聚物（PLLA-PEG-VS）。将 STING 激动剂 cGAMP 包封在 MPs 中，与抗原共同给药，形成一种广泛有效的流感疫苗。这种疫苗方法在体内进行了评估，采用了一次加强接种的方案，并说明了产生体液和细胞反应的能力，可以保护 BALB/c 小鼠免受 A/California/07/2009 的致命挑战。
