Intranasal gene therapy to prevent infection by SARS-CoV-2 variants

SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be less effective. Here we present an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by one of the many pre-emergent, ACE2-dependent CoVs that are poised for zoonosis. Author summary During the COVID-19 pandemic, variants of SARS-CoV-2 have emerged that are more deadly, more transmissible, and that evade immune response. These variants threaten to reduce the efficacy of first-generation vaccine and monoclonal antibody therapeutics. An additional problem with the existing vaccine strategy is that immune-compromised patients do not respond to active vaccinations. To address these issues, we developed a gene therapy-based strategy to prevent COVID-19 using a viral vector delivered by nasal spray. Unlike vaccines, this passive prophylaxis does not require that the patient mount an immune response. Instead, airway cells are engineered to secrete an antiviral decoy protein that can intercept viral particles before they cause infection. This decoy is based on human ACE2, the natural receptor for SARS-CoV-2. This design imparts resistance to SARS-CoV-2 viral evolution: viral mutations that evade the ACE2 decoy are unlikely to emerge because they would also render the virus less capable of infecting cells and therefore be less fit. Indeed, our ACE2 decoy neutralizes all SARS-CoV-2 variants that we tested and even binds distantly related coronaviruses that have not yet crossed over from animals to humans. This suggests that the ACE2 decoy gene therapy approach could be effectively deployed to vulnerable populations in the COVID-19 pandemic and potentially to broader populations at the outset of future coronavirus pandemics.