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、充足的抗病毒药物供应和快速开发保护性疫苗。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。我们已经确定了小的亲脂性分子，穿透完整的角质层和激活树突状细胞（DC）在正常小鼠皮肤。它们使常驻DC能够在没有内源性佐剂的情况下处理注射到皮肤中的抗原，并使DC成熟并迁移到引流淋巴结，在那里它们激活幼稚T细胞。这些局部佐剂促进保护性T细胞免疫的速度、它们的低成本和疫苗抗原的物理独立性表明，它们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。我们将测试我们的局部佐剂是否1）加速对注射到小鼠皮肤中的流感疫苗的T依赖性抗体应答的发展; 2）在小鼠中使用较低剂量的疫苗引发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;和4）表现出足以在体内激活人皮肤DC的离体穿过人皮肤的透皮转运速率。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。作为独立的佐剂，如果我们的局部DC激活剂被发现在人类中是安全有效的，它们应该会增强任何可以被递送到皮肤中的疫苗的功效。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 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.