Vectored Immunoprophylaxis and Treatment of SARS-CoV-2 Infection

Abstract

Vectored immunoprophylaxis was first developed as a means to establish engineered immunity to HIV through the use of an adeno-associated viral vector expressing a broadly neutralizing antibody. We have applied this concept to establish long-term prophylaxis against SARS-CoV-2 by adeno-associated and lentiviral vectors expressing a high affinity ACE2 decoy receptor. Administration of decoy-expressing AAV vectors based on AAV2.retro and AAV6.2 by intranasal instillation or intramuscular injection protected mice against high-titered SARS-CoV-2 infection. AAV and lentiviral vectored immunoprophylaxis was durable and active against recent SARS-CoV-2 Omicron subvariants. The AAV vectors were also effective when administered up to 24 hours post-infection. Vectored immunoprophylaxis could be of value for immunocompromised individuals for whom vaccination is not practical and as a means to rapidly establish protection from infection. Unlike monoclonal antibody therapy, the approach is expected to remain active despite continued evolution viral variants.

Evolution of Immune Evasion and Host Range Expansion by the SARS-CoV-2 B.1.1.529 (Omicron) Variant

“…To prolong the duration of action and increase the binding affinity for SARS-CoV-2, the ACE2 decoy protein fused with an albumin-binding domain (ABD), which is linked via a dimerization motif dodecapeptide (DDC) (ACE2 618-DDC-ABD), was developed, and the ACE2 618-DDC-ABD protein exhibited high efficacy for the protection of K18-hACE2 mice from lethal SARS-CoV-2 infection ( 36 ). Recently, vectored immunoprophylaxis for SARS-CoV-2 using adeno-associated virus (AAV) or lentiviral vectors expressing an ACE2 decoy receptor was reported, and the administration of ACE2 decoy-expressing AAV could protect mice from high-titer SARS-CoV-2 and Omicron variant challenges ( 37 ). Decoy-vectored immunoprophylaxis could be valuable for immunocompromised individuals for whom vaccination is not practical, and this approach is expected to remain active against newly emerging variants.…”

Rapid screening methods for universal binding peptide aptamers against SARS-CoV-2 variant spikes, including omicron variants, and their application to diagnostic and therapeutic agents.

“…In particular, XBB.1.5 has immune escape ability against neutralizing antibodies produced by omicrontype bivalent vaccines [(conventional strain (strain of origin)/Omicron strain BA.1) or (conventional strain (strain of origin)/Omicron strain BA.4-5)]. There are currently no antibody drugs that exhibit effective neutralizing antibody activity against XBB.1.5 (99,121,(125)(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144). This is because mutations in the Spike molecule change the conformation of the Spike, and the neutralizing activity of the antibody is easily lost.…”

Rapid screening methods for universal binding peptide aptamers against SARS-CoV-2 variant spikes, including omicron variants, and their application to diagnostic and therapeutic agents.

“…In particular, XBB.1.5 has immune escape ability against neutralizing antibodies produced by omicrontype bivalent vaccines [(conventional strain (strain of origin)/Omicron strain BA.1) or (conventional strain (strain of origin)/Omicron strain BA.4-5)]. There are currently no antibody drugs that exhibit effective neutralizing antibody activity against XBB.1.5 (99,121,(125)(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144). This is because mutations in the Spike molecule change the conformation of the Spike, and the neutralizing activity of the antibody is easily lost.…”