Topical adjuvants to enhance the efficacy of influenza vaccines

描述(由申请人提供)：对大流行性流感威胁的适当医疗反应包括监测和隔离、充足的有效抗病毒药物供应以及迅速开发保护性疫苗。在最佳情况下，生产足够保护美国人口的疫苗需要6个月的时间。在确认大流行毒株和充足的疫苗供应之间的6个月的滞后时间可能会导致毁灭性的发病率、死亡率和经济损失。一种节省剂量的佐剂使有限的疫苗供应能够保护更多的人，这将减少这个问题。 我们已经确定了一种小的亲脂分子，它可以穿透完整的角质层并激活正常小鼠皮肤中的树突状细胞(DC)。它使常驻DC能够处理注射到皮肤中的无佐剂抗原，并使DC成熟并迁移到引流淋巴结，在那里它们激活NAOVE T细胞。这种局部佐剂增加保护性抗体反应的速度、其低成本以及疫苗抗原的物理独立性，表明它可能是一种理想的佐剂，可以加强有限的流感疫苗供应所提供的保护。 这项第二阶段应用的目的是：1)确定这种佐剂的作用机制；2)确定其效力，并优化其作为流感疫苗局部佐剂在小型猪身上的使用，以此作为人体皮肤的模型；3)采用体外经皮渗透试验，优化其用作局部佐剂的条件；4)对该佐剂进行临床前毒性试验。 如果我们的努力成功，这种产品将是一种廉价的小分子，通过疫苗注射部位涂在皮肤上，将使疫苗更有效。 与公共卫生相关：应对大流行性流感的最佳公共卫生对策是有效的疫苗，但以目前的疫苗制造能力，可能需要数年时间才能生产出足够的疫苗来保护美国人口。我们需要疫苗添加剂来扩大疫苗的有效剂量，以覆盖更多的人。这就是这项拟议研究的目标。

DESCRIPTION (provided by applicant): An adequate medical response to the threat of pandemic influenza includes surveillance and isolation, a sufficient supply of effective antiviral drugs, and rapid development of a protective vaccine. Under optimal circumstances, production of enough vaccine to protect the US population would take 6 months. A lag time of 6 months between identification of a pandemic strain and an adequate supply of vaccine could result in devastating morbidity, mortality, and economic loss. A dose-sparing adjuvant that enabled a limited supply of vaccine to protect more people would diminish this problem. We have identified a small lipophilic molecule that can penetrate the intact stratum corneum and activate the dendritic cells (DC) in normal mouse skin. It enables resident DC to process adjuvant-free antigens injected into the skin and causes the DC to mature and migrate to the draining lymph node where they activate naove T cells. The speed with which this topical adjuvant increases protective antibody responses, its low cost, and physical independence of the vaccine antigen, suggest that it might be an ideal adjuvant for enhancing the protection afforded by a limiting supply of influenza vaccine. The aims of this Phase II application are to: 1) define the mechanism of action of this adjuvant; 2) determine the efficacy and optimize its use as a topical adjuvant for an influenza vaccine in miniature pigs as a model for human skin; 3) employ assays of transdermal transport across human skin ex vivo to optimize the conditions for its use as a topical adjuvant; and 4) perform pilot pre-clinical toxicity assays on this adjuvant. If our efforts are successful, the product will be an inexpensive small molecule, applied to the skin over a vaccine injection site that will make vaccines more effective. PUBLIC HEALTH RELEVANCE: The best public health response to pandemic influenza is an effective vaccine, but with current vaccine manufacturing capabilities it could take years to produce enough vaccine to protect the US population. We need vaccine additives that can extend the effective dose of a vaccine to cover more people. That is the goal of the proposed research.