Department of Food and Drug Sciences, University of Parma, Parco Area delle Scienze Parma, Italy; Interdepartmental Center Biopharmanet-tec, University of Parma, Parco Area delle Scienze Parma, Italy.
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze Parma, Italy; Interdepartmental Center Biopharmanet-tec, University of Parma, Parco Area delle Scienze Parma, Italy.
J Control Release. 2021 Dec 10;340:209-220. doi: 10.1016/j.jconrel.2021.11.002. Epub 2021 Nov 3.
Vaccines not requiring cold-chain storage/distribution and suitable for needle-free delivery are urgently needed. Pulmonary administration is one of the most promising non-parenteral routes for vaccine delivery. Through a multi-component excipient and spray-drying approach, we engineered highly respirable dry-powder vaccine particles containing a three-fold repeated peptide epitope derived from human papillomavirus (HPV16) minor capsid protein L2 displayed on Pyrococcus furious thioredoxin as antigen. A key feature of our engineering approach was the use of the amphiphilic endotoxin derivative glucopyranosyl lipid A (GLA) as both a coating agent enhancing particle de-aggregation and respirability as well as a built-in immune-adjuvant. Following an extensive characterization of the in vitro aerodynamic performance, lung deposition was verified in vivo by intratracheal administration in mice of a vaccine powder containing a fluorescently labeled derivative of the antigen. This was followed by a short-term immunization study that highlighted the ability of the GLA-adjuvanted vaccine powder to induce an anti-L2 systemic immune response comparable to (or even better than) that of the subcutaneously administered liquid-form vaccine. Despite the very short-term immunization conditions employed for this preliminary vaccination experiment, the intratracheally administered dry-powder, but not the subcutaneously injected liquid-state, vaccine induced consistent HPV neutralizing responses. Overall, the present data provide proof-of-concept validation of a new formulation design to produce a dry-powder vaccine that may be easily transferred to other antigens.
急需不需要冷链储存/分发且适合无针输送的疫苗。肺部给药是疫苗传递的最有前途的非肠胃途径之一。通过多组分赋形剂和喷雾干燥方法，我们设计了含有来自人乳头瘤病毒（HPV16）小衣壳蛋白 L2 的三倍重复肽表位的高度可呼吸干粉疫苗颗粒，该表位在 Pyrococcus furious 硫氧还蛋白上显示为抗原。我们的工程方法的一个关键特征是使用两亲性内毒素衍生物葡糖基脂质 A（GLA）作为增强颗粒解聚和可呼吸性的涂层剂，以及内置的免疫佐剂。在对体外空气动力学性能进行广泛表征后，通过气管内给药将含有抗原荧光标记衍生物的疫苗粉末给药到小鼠体内来验证体内肺部沉积。随后进行了短期免疫研究，该研究强调了 GLA 佐剂疫苗粉末能够诱导抗 L2 全身免疫反应的能力，与皮下给药的液体疫苗相当（甚至更好）。尽管进行此初步疫苗接种实验所采用的免疫时间很短，但气管内给予干粉，而不是皮下注射的液态疫苗，可诱导一致的 HPV 中和反应。总体而言，这些数据提供了生产干粉疫苗的新配方设计的概念验证，该疫苗可能很容易转移到其他抗原上。
