Development of Membrane Anchored Cytokines as Novel Vaccine Adjuvants for the Elderly

白细胞介素-12（IL-12）和粒细胞巨噬细胞集落刺激因子（GM-CSF）是内源性免疫激活剂。 使用可溶性IL-12和GM-CSF作为疫苗佐剂的早期研究由于毒性或次优应答而不成功。 Metaclipse Therapeutic Corporation已经开发了IL-12和GM-CSF的变体，其中在羧基末端添加了糖基化磷脂酰肌醇（GPI）锚，允许掺入脂质双层，例如流感病毒样颗粒（VLP）。 先前在年轻和老年小鼠中使用GPI-GM-CSF和GPI-IL-12掺入的流感H1 VLP的研究诱导了强的体液和细胞免疫，保护年轻和老年小鼠免受同源和异源病毒攻击。 该SBIR项目将评估临床前动物模型的长期保护，并参与IND使能活动。 目前，老年患者对流感疫苗的反应不佳。 该SBIR项目将有助于开发安全有效的佐剂组合，可用于增强老年人急需的流感和其他抗病毒疫苗的效力。

Interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor (GM-CSF) are endogenous immune activators. Earlier studies using soluble IL-12 and GM-CSF as vaccine adjuvants were unsuccessful due to toxicity or suboptimal response. Metaclipse Therapeutic Corporation has developed versions of IL-12 and GM-CSF with a glycosylated phosphatidylinositol (GPI) anchor added at the carboxyl terminus, allowing incorporation into lipid bilayers such as in influenza virus-like particles (VLPs). Previous studies in young and aged mice using GPI-GM-CSF and GPI-IL-12 incorporated influenza H1 VLPs induced strong humoral and cellular immunity that protected both young and aged mice from homologous and heterologous viral challenge. This SBIR project will assess the long-term protection in preclinical animal models and engage in IND-enabling activities. Currently, elderly patients fail to respond well to influenza vaccines. This SBIR project will contribute to the development of safe and effective adjuvant combinations that can be used to enhance the efficacy of influenza and other antiviral vaccines critically needed for the elderly.