Vectored Immunoprophylaxis of SARS-CoV-2 with receptor decoys

SUMMARY Monoclonal antibody therapy for severe COVID-19 and for prophylaxis in immunocompromised individuals was initially of great value but was sidelined by the rapid emergence of virus variants with mutations in the spike gene that rendered the antibodies ineffective. Receptor decoys offer a means to overcome this problem. Because the viral spike protein needs to conserve its high affinity for ACE2, there is a high genetic barrier for the virus to escape from neutralization by the decoy. The project will develop vectored immunoprophylaxis (VIP) in which high affinity ACE2 receptor decoys will be expressed by adeno-associated virus (AAV) and lentiviral viral vectors. These will be used to protect against and to treat SARS-CoV-2 infection. The decoys consist of the extracellular domain of ACE-2 fused to a truncated immunoglobulin heavy chain Fc region. The "microbody" neutralizes the virus by binding to the viral spike protein and will be active against all variants. Because the decoys are composed entirely of human-derived protein components, they will be well-tolerated by the human immune system. The decoys will be optimized to increase their affinity for the spike protein and will be produced with Fc regions that alter their tissue localization, half-life, antiviral activity and antibody effector functions. The decoys will be tested as recombinant protein for prophylactic and therapeutic efficacy in ACE2 transgenic mouse and hamster models against a panel of SARS-CoV-2 variants. Tissue localization and half-life of vector-expressed decoy proteins will be determined by live-imaging of decoy-luciferase fusions. Long-term protection against infection will be established with decoy-expressing AAV and lentiviral vectors in mice and hamsters by intranasal instillation and intramuscular injection. The animals will then be challenged with live virus up to a year post- administration. Serum and lung concentrations of the decoy will be measured and the host antibody response to the decoy protein will be tested. An optimized decoy will be designed based on the findings obtained with modified decoy proteins and its effectiveness will be studied in rhesus macaques, a model that closely resembles humans. The decoy approach will be valuable for rapidly establishing long-term protection, and will be of value to immunocompromised individuals for whom vaccination is less effective. The approach offers an off-the-shelf means with which to rapidly protect the population in the event of a novel zoonotic coronavirus pandemic. The lessons learned will be broadly applicable to other viruses for which a decoy receptor can be generated.