Orson Frank M, Kinsey Berma M, Densmore Charles L, Nguyen Tina, Wu Yan, Mbawuike Innocent N, Wyde Philip R
Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX 77030, USA.
J Gene Med. 2006 Apr;8(4):488-97. doi: 10.1002/jgm.864.
Conventional vaccine development for newly emerging pandemic influenza virus strains would likely take too long to prevent devastating global morbidity and mortality. If DNA vaccines can be distributed and delivered efficiently, genetic immunization could be an attractive solution to this problem, since plasmid DNA is stable, easily engineered to encode new protein antigens, and able to be quickly produced in large quantities.
We compared two novel genetic immunization methods in a mouse model of influenza to evaluate protective effects: aerosol delivery of polyethylenimine (PEI)-complexed hemagglutinin (HA)-expressing plasmid and intravenous (IV) delivery of the plasmid complexed with macroaggregated albumin/PEI. Serial serum samples were obtained for assay of neutralizing antibodies against HA. Mice were then challenged in the airway with influenza virus, and production of infectious virus in the lungs was titered.
Most mice immunized with HA plasmid alone by aerosol and all mice immunized IV developed protective immune responses, whereas none administered control plasmid were protected. Aerosol co-administration of HA plasmid with plasmids encoding the cytokines interleukin 12 (IL12) and granulocyte-macrophage colony stimulating factor (GM-CSF) markedly increased neutralizing antibody responses, so that all aerosol immunized mice were protected from high level virus proliferation.
Cytokine-enhanced aerosol delivery of plasmid vaccines can elicit robust protective immune responses against influenza. Thus, aerosol delivery has the potential to address the need for rapid widespread immunization against new influenza virus strains, and may have applications for other infectious and toxic disease processes.
针对新出现的大流行性流感病毒株研发传统疫苗可能耗时过长，无法预防全球范围内的严重发病和死亡情况。如果DNA疫苗能够高效分发和递送，基因免疫可能是解决这一问题的一个有吸引力的办法，因为质粒DNA稳定，易于设计编码新的蛋白质抗原，并且能够快速大量生产。
我们在流感小鼠模型中比较了两种新型基因免疫方法以评估保护效果：雾化递送与聚乙烯亚胺（PEI）复合的表达血凝素（HA）的质粒，以及静脉内（IV）递送与大颗粒白蛋白/PEI复合的质粒。采集系列血清样本检测针对HA的中和抗体。然后用流感病毒对小鼠进行气道攻击，并对肺中传染性病毒的产生进行滴定。
大多数通过雾化单独接种HA质粒的小鼠以及所有通过静脉内接种的小鼠都产生了保护性免疫反应，而接种对照质粒的小鼠均未受到保护。将HA质粒与编码细胞因子白细胞介素12（IL12）和粒细胞巨噬细胞集落刺激因子（GM-CSF）的质粒共同雾化给药显著增强了中和抗体反应，从而使所有雾化免疫的小鼠都免受高水平病毒增殖的影响。
细胞因子增强的质粒疫苗雾化递送可引发针对流感的强大保护性免疫反应。因此，雾化递送有潜力满足针对新型流感病毒株进行快速广泛免疫的需求，并且可能在其他感染性和中毒性疾病过程中具有应用价值。
