Topical adjuvants to enhance the efficacy of influenza vaccines

描述（由申请方提供）：对大流行性流感威胁的充分医疗应对包括监测和隔离、有效抗病毒药物的充足供应以及保护性疫苗的快速开发。在最佳情况下，生产足够保护美国人口的疫苗将需要6个月。从鉴定大流行毒株到提供充足的疫苗之间的6个月的滞后时间可能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，将减少这一问题。 我们已经确定了一个小的亲脂性分子，可以穿透完整的角质层和激活树突状细胞（DC）在正常小鼠皮肤。它使常驻DC能够处理注射到皮肤中的无促凝剂抗原，并使DC成熟并迁移到引流淋巴结，在那里它们激活noveT细胞。这种局部佐剂增加保护性抗体应答的速度、其低成本和疫苗抗原的物理独立性表明，它可能是用于增强由有限供应的流感疫苗提供的保护的理想佐剂。 该II期申请的目的是：1）确定该佐剂的作用机制; 2）确定其作为流感疫苗的局部佐剂在作为人皮肤模型的小型猪中的功效并优化其用途; 3）采用离体穿过人皮肤的透皮转运测定法以优化其用作局部佐剂的条件;和4）对该佐剂进行试验性临床前毒性测定。 如果我们的努力取得成功，该产品将是一种廉价的小分子，应用于疫苗注射部位的皮肤上，使疫苗更有效。 公共卫生相关性：应对大流行性流感的最佳公共卫生对策是有效的疫苗，但以目前的疫苗生产能力，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，可以扩大疫苗的有效剂量，以覆盖更多的人。 这就是拟议研究的目标。

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.