Zhang Xiaojian, Shi Hua, Hendy Dylan A, Bachelder Eric M, Ainslie Kristy M, Ross Ted M
Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA.
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, USA.
bioRxiv. 2024 Feb 29:2024.02.27.582355. doi: 10.1101/2024.02.27.582355.
Influenza viruses cause a common respiratory disease known as influenza. In humans, seasonal influenza viruses can lead to epidemics, with avian influenza viruses of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a universal influenza vaccine that provides protection against seasonal and pre-pandemic influenza virus strains. The cyclic GMP-AMP (cGAMP) is a promising adjuvant for subunit vaccines that promotes type I interferons production through the stimulator of interferon genes (STING) pathway. The encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to generate H1, H3, and H5 vaccine candidates. Monovalent and multivalent COBRA HA vaccines formulated with cGAMP Ace-DEX MPs were evaluated in a mouse model for antibody responses and protection against viral challenge. Serological analysis showed that cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccines elicited robust antigen-specific antibody responses after a prime-boost vaccination and antibody titers were further enhanced after second boost. Compared to COBRA vaccine groups with no adjuvant or blank MPs, the cGAMP MPs enhanced HAI antibody responses against COBRA vaccination. The HAI antibody titers were not significantly different between cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccine groups for most of the viruses tested in panels. The cGAMP MPs adjuvanted COBRA vaccines groups had higher antigen-specific IgG2a binding titers than the COBRA vaccine groups with no adjuvant or blank MPs. The COBRA vaccines formulated with cGAMP MPs mitigated disease caused by influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA vaccines plus cGAMP MPs is a promising universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains.
流感病毒会引发一种常见的呼吸道疾病，即流感。在人类中，季节性流感病毒可导致流行病，而禽流感病毒尤其令人担忧，因为它们可感染多种物种并引发不可预测的严重疾病。因此，迫切需要一种通用流感疫苗，以提供针对季节性和大流行前流感病毒株的保护。环鸟苷酸-腺苷酸（cGAMP）是一种有前景的亚单位疫苗佐剂，可通过干扰素基因刺激物（STING）途径促进I型干扰素的产生。将cGAMP封装在乙酰化葡聚糖（Ace-DEX）微粒（MPs）中可增强其细胞内递送。在本研究中，采用计算优化的广泛反应性抗原（COBRA）方法生成H1、H3和H5疫苗候选物。用cGAMP Ace-DEX MPs配制的单价和多价COBRA HA疫苗在小鼠模型中评估抗体反应和对病毒攻击的保护作用。血清学分析表明，cGAMP MPs佐剂的单价和多价COBRA疫苗在初次免疫-加强免疫接种后引发了强烈的抗原特异性抗体反应，第二次加强免疫后抗体滴度进一步提高。与无佐剂或空白MPs的COBRA疫苗组相比，cGAMP MPs增强了针对COBRA疫苗接种的血凝抑制（HAI）抗体反应。在检测的大多数病毒中，cGAMP MPs佐剂的单价和多价COBRA疫苗组之间的HAI抗体滴度没有显著差异。cGAMP MPs佐剂的COBRA疫苗组比无佐剂或空白MPs的COBRA疫苗组具有更高的抗原特异性IgG2a结合滴度。用cGAMP MPs配制的COBRA疫苗减轻了流感病毒攻击引起的疾病，并降低了小鼠肺部的病毒滴度。因此，COBRA疫苗加cGAMP MPs的制剂是一种有前景的通用流感疫苗，可引发针对人类季节性和大流行前毒株的保护性免疫反应。
