NDCLS, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China.
Thorax. 2022 Dec;77(12):1229-1236. doi: 10.1136/thoraxjnl-2021-217650. Epub 2022 Feb 14.
The COVID-19 pandemic continues to be a worldwide threat and effective antiviral drugs and vaccines are being developed in a joint global effort. However, some elderly and immune-compromised populations are unable to raise an effective immune response against traditional vaccines.
We hypothesised that passive immunity engineered by the in vivo expression of anti-SARS-CoV-2 monoclonal antibodies (mAbs), an approach termed vectored-immunoprophylaxis (VIP), could offer sustained protection against COVID-19 in all populations irrespective of their immune status or age.
We developed three key reagents to evaluate VIP for SARS-CoV-2: (i) we engineered standard laboratory mice to express human ACE2 via rAAV9 in vivo gene transfer, to allow in vivo assessment of SARS-CoV-2 infection, (ii) to simplify in vivo challenge studies, we generated SARS-CoV-2 Spike protein pseudotyped lentiviral vectors as a simple mimic of authentic SARS-CoV-2 that could be used under standard laboratory containment conditions and (iii) we developed in vivo gene transfer vectors to express anti-SARS-CoV-2 mAbs.
A single intranasal dose of rAAV9 or rSIV.F/HN vectors expressing anti-SARS-CoV-2 mAbs significantly reduced SARS-CoV-2 mimic infection in the lower respiratory tract of hACE2-expressing mice. If translated, the VIP approach could potentially offer a highly effective, long-term protection against COVID-19 for highly vulnerable populations; especially immune-deficient/senescent individuals, who fail to respond to conventional SARS-CoV-2 vaccines. The in vivo expression of multiple anti-SARS-CoV-2 mAbs could enhance protection and prevent rapid mutational escape.
COVID-19 大流行继续对全球构成威胁，正在全球共同努力开发有效的抗病毒药物和疫苗。然而，一些老年和免疫功能低下的人群无法对传统疫苗产生有效的免疫反应。
我们假设通过体内表达抗 SARS-CoV-2 单克隆抗体（mAb）产生的被动免疫，即所谓的载体免疫预防（VIP），可以为所有人群提供针对 COVID-19 的持续保护，而与他们的免疫状态或年龄无关。
我们开发了三种关键试剂来评估 VIP 对 SARS-CoV-2 的作用：（i）我们通过 rAAV9 体内基因转移工程改造标准实验室小鼠表达人 ACE2，以允许体内评估 SARS-CoV-2 感染，（ii）为简化体内挑战研究，我们生成了 SARS-CoV-2 刺突蛋白假型慢病毒载体，作为真实 SARS-CoV-2 的简单模拟物，可在标准实验室控制条件下使用，（iii）我们开发了体内基因转移载体来表达抗 SARS-CoV-2 mAb。
单次鼻腔内给予 rAAV9 或 rSIV.F/HN 载体表达抗 SARS-CoV-2 mAb 可显著降低表达 hACE2 的小鼠下呼吸道中 SARS-CoV-2 模拟物感染。如果得到转化，VIP 方法可能为高度脆弱人群（特别是免疫缺陷/衰老个体，他们对传统的 SARS-CoV-2 疫苗没有反应）提供针对 COVID-19 的高度有效、长期保护。体内表达多种抗 SARS-CoV-2 mAb 可以增强保护作用并防止快速的突变逃逸。
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