COVID-19 vaccines already in use or in clinical development may have reduced efficacy against emerging SARS-CoV-2 variants. In addition, although the neurotropism of SARS-CoV-2 is well established, the vaccine strategies currently developed have not taken into account protection of the central nervous system. Here, we generated a transgenic mouse strain expressing the human angiotensin-converting enzyme 2, and displaying unprecedented brain permissiveness to SARS-CoV-2 replication, in addition to high permissiveness levels in the lung. Using this stringent transgenic model, we demonstrated that a non-integrative lentiviral vector, encoding for the spike glycoprotein of the ancestral SARS-CoV-2, used in intramuscular prime and intranasal boost elicits sterilizing protection of lung and brain against both the ancestral virus, and the Gamma (P.1) variant of concern, which carries multiple vaccine escape mutations. Beyond induction of strong neutralizing antibodies, the mechanism underlying this broad protection spectrum involves a robust protective T-cell immunity, unaffected by the recent mutations accumulated in the emerging SARS-CoV-2 variants.

中文翻译：

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新型转基因小鼠中慢病毒疫苗对 SARS-CoV-2 变体的大脑交叉保护

已投入使用或处于临床开发阶段的 COVID-19 疫苗可能会降低针对新出现的 SARS-CoV-2 变种的功效。此外，尽管SARS-CoV-2的神经趋向性已得到充分证实，但目前开发的疫苗策略尚未考虑到对中枢神经系统的保护。在这里，我们产生了表达人类血管紧张素转换酶 2 的转基因小鼠品系，除了肺部的高容许水平之外，还表现出前所未有的大脑对 SARS-CoV-2 复制的容许度。使用这种严格的转基因模型，我们证明了一种非整合性慢病毒载体，编码祖先 SARS-CoV-2 的刺突糖蛋白，用于肌内初免和鼻内加强，可引起肺和脑针对祖先病毒的灭菌保护，以及令人关注的 Gamma (P.1) 变体，它携带多种疫苗逃逸突变。除了诱导强中和抗体之外，这种广泛保护谱的机制还涉及强大的保护性 T 细胞免疫，不受新出现的 SARS-CoV-2 变体中最近积累的突变的影响。