Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza.
Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza.
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DOI：
10.1126/scitranslmed.3006299
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发表时间：
2013-05-29
影响因子：
17.1
通讯作者：
Wilson JM
中科院分区：
文献类型：
--
作者：
Limberis MP;Adam VS;Wong G;Gren J;Kobasa D;Ross TM;Kobinger GP;Tretiakova A;Wilson JM
新的流感大流行的出现仍然是一种威胁，可能导致全世界大量生命损失和经济混乱。人类抗体分离的进步导致单克隆抗体 (mAb) 的发现，这些抗体对各种流感病毒株具有广泛的中和活性，尽管直接用于预防是不切实际的。为了克服这一限制，我们的方法是通过腺相关病毒（AAV）载体将抗体递送到初始感染部位，对于流感等呼吸道病毒来说，初始感染部位是鼻咽粘膜。基于血清型 9 的 AAV 载体经过工程改造，可表达先前分离的甲型流感病毒 FI6 广泛中和单克隆抗体的改良版本。我们证明，鼻内递送 AAV9.FI6 给小鼠提供了完全保护，并将 H5N1 的三种临床分离株和 H1N1 的两种临床分离株的病毒载量减少至 100 LD50（半数致死剂量），所有这些都与历史上的人类大流行（包括 1918 年 H1N1）有关。同样，受到致死剂量的 H5N1 和 H1N1 病毒攻击的雪貂也获得了完全保护。这种方法可以作为预防自然或故意呼吸道疾病的平台，针对这些疾病可以使用保护性抗体。
The emergence of a new influenza pandemic remains a threat that could result in a substantial loss of life and economic disruption worldwide. Advances in human antibody isolation have led to the discovery of monoclonal antibodies (mAbs) that have broad neutralizing activity against various influenza strains, although their direct use for prophylaxis is impractical. To overcome this limitation, our approach is to deliver antibody via adeno-associated virus (AAV) vectors to the site of initial infection, which, for respiratory viruses such as influenza, is the nasopharyngeal mucosa. AAV vectors based on serotype 9 were engineered to express a modified version of the previously isolated broadly neutralizing mAb to influenza A, FI6. We demonstrate that intranasal delivery of AAV9.FI6 into mice afforded complete protection and log reductions in viral load to 100 LD50 (median lethal dose) of three clinical isolates of H5N1 and two clinical isolates of H1N1, all of which have been associated with historic human pandemics (including H1N1 1918). Similarly, complete protection was achieved in ferrets challenged with lethal doses of H5N1 and H1N1. This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available.