Heterosubtypic protection against pathogenic human and avian influenza viruses via in vivo electroporation of synthetic consensus DNA antigens.
Heterosubtypic protection against pathogenic human and avian influenza viruses via in vivo electroporation of synthetic consensus DNA antigens.
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通过合成共识DNA抗原的体内电穿孔对致病性人类和鸟类流感病毒的杂型保护。
DOI：
10.1371/journal.pone.0002517
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发表时间：
2008-06-25
期刊：
影响因子：
3.7
通讯作者：
Weiner, David B.
中科院分区：
文献类型：
--
作者：
Laddy, Dominick J.;Yan, Jian;Kutzler, Michele;Kobasa, Darwyn;Kobinger, Gary P.;Khan, Amir S.;Greenhouse, Jack;Sardesai, Niranjan Y.;Draghia-Akli, Ruxandra;Weiner, David B.
高致病性禽流感（HPAI）的持续演变突出了对新型疫苗接种技术的需求，这些技术可以快速有效地应对新出现的病毒威胁。我们在小鼠、雪貂和非人灵长类动物三种动物模型中评估了使用优化的共有流感抗原来提供针对不同H5 N1流感毒株的广泛保护。我们还评估了使用体内电穿孔来递送这些疫苗，以克服在较大动物接种模型中遇到的免疫原性障碍。用表达H5血凝素（pH 5 HA）、N1神经氨酸酶（pN 1 NA）和核蛋白抗原（pNP）的共有质粒免疫小鼠、雪貂和非人灵长类动物。在小鼠中观察到对H5和NP的显著的基于IFN-γ的细胞免疫应答，其很大程度上依赖于CD 8 + T细胞。在所有物种中均观察到与保护作用经典相关的血凝抑制滴度（>1：40）。雪貂和猕猴中的应答证明了合成的共有抗原诱导能够抑制H5 N1亚型的不同毒株的抗体的能力，并且在小鼠和雪貂中的研究证明了合成的共有疫苗诱导保护的能力，即使在不存在这种中和抗体的情况下。攻毒后，在小鼠和雪貂中观察到发病率和死亡率保护，在接种疫苗的动物中观察到病毒脱落和疾病进展显著减少。通过将几种共有流感抗原与体内电穿孔相结合，我们证明了这些抗原在小鼠、雪貂和非人灵长类动物中诱导保护性细胞和体液免疫应答。我们还证明了这些抗原的能力，以保护从发病率和死亡率在雪貂模型的高致病性禽流感，在中和抗体的存在和不存在，这将是至关重要的抗原漂移，将可能发生之前，这些病毒跨越物种的障碍，以人类。
The persistent evolution of highly pathogenic avian influenza (HPAI) highlights the need for novel vaccination techniques that can quickly and effectively respond to emerging viral threats. We evaluated the use of optimized consensus influenza antigens to provide broad protection against divergent strains of H5N1 influenza in three animal models of mice, ferrets, and non-human primates. We also evaluated the use of in vivo electroporation to deliver these vaccines to overcome the immunogenicity barrier encountered in larger animal models of vaccination. Mice, ferrets and non-human primates were immunized with consensus plasmids expressing H5 hemagglutinin (pH5HA), N1 neuraminidase (pN1NA), and nucleoprotein antigen (pNP). Dramatic IFN-γ-based cellular immune responses to both H5 and NP, largely dependent upon CD8+ T cells were seen in mice. Hemaggutination inhibition titers classically associated with protection (>1:40) were seen in all species. Responses in both ferrets and macaques demonstrate the ability of synthetic consensus antigens to induce antibodies capable of inhibiting divergent strains of the H5N1 subtype, and studies in the mouse and ferret demonstrate the ability of synthetic consensus vaccines to induce protection even in the absence of such neutralizing antibodies. After challenge, protection from morbidity and mortality was seen in mice and ferrets, with significant reductions in viral shedding and disease progression seen in vaccinated animals. By combining several consensus influenza antigens with in vivo electroporation, we demonstrate that these antigens induce both protective cellular and humoral immune responses in mice, ferrets and non-human primates. We also demonstrate the ability of these antigens to protect from both morbidity and mortality in a ferret model of HPAI, in both the presence and absence of neutralizing antibody, which will be critical in responding to the antigenic drift that will likely occur before these viruses cross the species barrier to humans.
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