Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22213-8. doi: 10.1073/pnas.1015536108. Epub 2010 Dec 6.
Successful vaccination against respiratory infections requires elicitation of high levels of potent and durable humoral and cellular responses in the lower airways. To accomplish this goal, we used a fine aerosol that targets the entire lung surface through normal respiration to deliver replication-incompetent recombinant adenoviral vectors expressing gene products from several infectious pathogens. We show that this regimen induced remarkably high and stable lung T-cell responses in nonhuman primates and that it also generated systemic and respiratory tract humoral responses of both IgA and IgG isotypes. Moreover, strong immunogenicity was achieved even in animals with preexisting antiadenoviral immunity, overcoming a critical hurdle to the use of these vectors in humans, who commonly are immune to adenoviruses. The immunogenicity profile elicited with this regimen, which is distinct from either intramuscular or intranasal delivery, has highly desirable properties for protection against respiratory pathogens. We show that it can be used repeatedly to generate mucosal humoral, CD4, and CD8 T-cell responses and as such may be applicable to other mucosally transmitted pathogens such as HIV. Indeed, in a lethal challenge model, we show that aerosolized recombinant adenoviral immunization completely protects ferrets against H5N1 highly pathogenic avian influenza virus. Thus, genetic immunization in the lung offers a powerful platform approach to generating protective immune responses against respiratory pathogens.
成功预防呼吸道感染需要在下呼吸道引发高水平的强效和持久的体液和细胞反应。为了实现这一目标，我们使用了一种精细的气溶胶，通过正常呼吸将其输送到整个肺部表面，从而传递表达几种传染性病原体基因产物的复制缺陷型重组腺病毒载体。我们表明，这种方案在非人类灵长类动物中诱导了非常高且稳定的肺部 T 细胞反应，并且还产生了针对呼吸道和呼吸道的 IgA 和 IgG 同种型的体液反应。此外，即使在具有预先存在的抗腺病毒免疫的动物中，也能实现强大的免疫原性，克服了在人类中使用这些载体的关键障碍，因为人类通常对腺病毒具有免疫力。这种方案引起的免疫原性谱与肌肉内或鼻腔内给药不同，具有针对呼吸道病原体的保护作用的理想特性。我们表明，它可以重复使用以产生粘膜性体液、CD4 和 CD8 T 细胞反应，因此可能适用于其他粘膜传播的病原体，如 HIV。事实上，在致死性挑战模型中，我们表明，雾化重组腺病毒免疫完全保护雪貂免受 H5N1 高致病性禽流感病毒的侵害。因此，肺部的基因免疫为针对呼吸道病原体产生保护免疫反应提供了一种强大的平台方法。
