Lung directed antibody gene transfer confers protection against SARS-CoV-2 infection

The novel coronavirus disease (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-SARS71 CoV-2 mAbs could enhance protection and prevent rapid mutational escape.