Integrase-Defective Lentiviral Vectors for Delivery of Monoclonal Antibodies against Influenza

Abstract

Delivering rapid protection against infectious agents to non-immune populations is a formidable public health challenge. Although passive immunotherapy is a fast and effective method of protection, large-scale production and administration of monoclonal antibodies (mAbs) is expensive and unpractical. Viral vector-mediated delivery of mAbs offers an attractive alternative to their direct injection. Integrase-defective lentiviral vectors (IDLV) are advantageous for this purpose due to the absence of pre-existing anti-vector immunity and the safety features of non-integration and non-replication. We engineered IDLV to produce the humanized mAb VN04-2 (IDLV-VN04-2), which is broadly neutralizing against H5 influenza A virus (IAV), and tested the vectors’ ability to produce antibodies and protect from IAV in vivo. We found that IDLV-transduced cells produced functional VN04-2 mAbs in a time- and dose-dependent fashion. These mAbs specifically bind the hemagglutinin (HA), but not the nucleoprotein (NP) of IAV. VN04-2 mAbs were detected in the serum of mice at different times after intranasal (i.n.) or intramuscular (i.m.) administration of IDLV-VN04-2. Administration of IDLV-VN04-2 by the i.n. route provided rapid protection against lethal IAV challenge, although the protection did not persist at later time points. Our data suggest that administration of mAb-expressing IDLV may represent an effective strategy for rapid protection against infectious diseases.

Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through

“…In a pre-clinical study, a single immunisation of NILVs encoded in a secreted form of the envelope of a virulent strain of West Nile virus (WNV) induced a strong B cell response, and a single immunisation was also sufficient to induce early and long-lasting protective immunity [ 78 , 79 ]. On the other hand, one in vivo study involving the H5 influenza A virus (IAV) demonstrated that the monoclonal antibody (mAb) administered through NILVs did not persist for longer time points [ 80 ]. However, this could be studied further to make it an effective strategy for rapid protection against infectious diseases in the future.…”

Integrase deficient lentiviral vector: prospects for safe clinical applications

“…Apart from pseudotyping, the expression of antibodies transgene carried by IDLV also elicits immune responses towards the targeted pathogens. Michelini et al (2020) vaccinated mice with engineered IDLV carrying genes encoding for VN04-2 monoclonal antibodies (mAbs) against influenza A virus (IAV). Expression of VN04-2 mAbs in the vaccinated mice provides some protection against H3N2 IAV, even though the mAbs are specific H5 HA.…”

Respiratory delivery of passive immunotherapies for SARS-CoV-2 prophylaxis and therapy

“… 7 , 8 Nasal delivery of viral vectors encoding anti-influenza IgG has also been tested successfully in mice. 9 More limited experiences have been reported for monkeypox virus 10 and respiratory syncytial virus. 11 Again, no clinical study has been run for those pathogens.…”