Gene Therapy Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Transl Med. 2013 May 29;5(187):187ra72. doi: 10.1126/scitranslmed.3006299.
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.
新的流感大流行的出现仍然是一种威胁，可能导致全球大量生命损失和经济混乱。人类抗体分离技术的进步导致了广谱中和抗体（mAbs）的发现，尽管它们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）载体将抗体递送到感染的初始部位，对于流感等呼吸道病毒来说，这是鼻咽黏膜。基于血清型 9 的 AAV 载体被设计用来表达之前分离的广谱中和抗流感 A 单克隆抗体 FI6 的一种修饰版本。我们证明，将 AAV9.FI6 经鼻腔递送至小鼠体内，可完全保护小鼠免受三种 H5N1 临床分离株和两种 H1N1 临床分离株的感染，所有这些分离株都与历史上的人类大流行有关（包括 1918 年的 H1N1 大流行）。同样，在接受致死剂量 H5N1 和 H1N1 攻击的雪貂中也实现了完全保护。这种方法为预防有保护抗体的自然或故意呼吸道疾病提供了一个平台。
