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、充足的抗病毒药物供应和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。我们已经鉴定出能够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)的亲脂小分子。它们使常驻DC能够在没有内源性佐剂的情况下处理注入皮肤的抗原，并使DC成熟并迁移到引流的淋巴结处，在那里它们激活NAVE T细胞。这些局部佐剂促进保护性T细胞免疫的速度、低成本和疫苗抗原的物理独立性表明，它们可能是增强有限的流感疫苗供应所提供的保护的理想佐剂。我们将测试我们的局部佐剂是否：1)加快对注射到小鼠皮肤的流感疫苗的T依赖抗体反应；2)在小鼠身上使用较低剂量的疫苗诱导相同浓度的流感特异性抗体；3)使较低剂量的疫苗能够保护小鼠免受流感病毒的致命攻击；以及4)显示出足以在体内激活人皮肤树突状细胞的体外人体皮肤透过率。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。作为独立的佐剂，如果我们的局部DC激活剂被发现对人类安全有效，它们应该会增强任何可以进入皮肤的疫苗的效力。应对大流行流感的最好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 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 small lipophilic molecules that penetrate the intact stratum corneum and activate the dendritic cells (DCs) in normal mouse skin. They enable resident DCs to process antigens injected into the skin without endogenous adjuvants, and cause the DCs to mature and migrate to the draining lymph node where they activate na¿ve T cells. The speed with which these topical adjuvants promote protective T cell immunity, their low cost, and physical independence of the vaccine antigen, suggest that they might be ideal adjuvants for enhancing the protection afforded by a limiting supply of influenza vaccine. We will test whether our topical adjuvants 1) accelerate the development of T-dependent antibody responses to influenza vaccine injected into mouse skin; 2) elicit the same concentration of influenza-specific antibodies using lower doses of vaccine in mice; 3) enable lower doses of vaccine to protect mice against a lethal challenge with influenza virus; and 4) exhibit a transdermal transport rate across human skin ex vivo sufficient to permit activation of human skin DCs in vivo. 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. As stand-alone adjuvants, if our topical DC activators are found to be safe and effective in humans, they should enhance the efficacy of any vaccine that can be delivered into the skin. 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.