低剂量小鼠攻毒模型中的减毒疫苗保护作用。
Attenuated vaccine protection in a low-dose murine challenge model.
作者信息
Vidal Samuel J, Sellers Daniel, Yu Jingyou, Wakabayashi Shoko, Sixsmith Jaimie, Aid Malika, Barrett Julia, Stevens Sage F, Liu Xiaowen, Li Wenjun, Plumlee Courtney R, Urdahl Kevin B, Martinot Amanda J, Barouch Dan H
机构信息
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
出版信息
iScience. 2023 May 28;26(6):106963. doi: 10.1016/j.isci.2023.106963. eCollection 2023 Jun 16.
Bacillus Calmette-Guérin (BCG) remains the only approved tuberculosis (TB) vaccine despite limited efficacy. Preclinical studies of next-generation TB vaccines typically use a murine aerosol model with a supraphysiologic challenge dose. Here, we show that the protective efficacy of a live attenuated (Mtb) vaccine ΔLprG markedly exceeds that of BCG in a low-dose murine aerosol challenge model. BCG reduced bacterial loads but did not prevent establishment or dissemination of infection in this model. In contrast, ΔLprG prevented detectable infection in 61% of mice and resulted in anatomic containment of 100% breakthrough infections to a single lung. Protection was partially abrogated in a repeated low-dose challenge model, which showed serum IL-17A, IL-6, CXCL2, CCL2, IFN-γ, and CXCL1 as correlates of protection. These data demonstrate that ΔLprG provides increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low-dose murine challenge model.
卡介苗（BCG）仍是唯一获批的结核病（TB）疫苗，尽管其疗效有限。下一代结核病疫苗的临床前研究通常使用超生理攻击剂量的小鼠气溶胶模型。在此，我们表明，在低剂量小鼠气溶胶攻击模型中，减毒活结核分枝杆菌（Mtb）疫苗ΔLprG的保护效力明显超过卡介苗。卡介苗可降低细菌载量，但在此模型中并不能预防感染的建立或扩散。相比之下，ΔLprG可预防61%的小鼠发生可检测到的感染，并使100%的突破性感染在解剖学上局限于单个肺脏。在重复低剂量攻击模型中，保护作用部分丧失，该模型显示血清IL-17A、IL-6、CXCL2、CCL2、IFN-γ和CXCL1与保护作用相关。这些数据表明，在低剂量小鼠攻击模型中，与卡介苗相比，ΔLprG提供了更强的保护作用，包括减少可检测到的感染和解剖学上的局限。
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