AAV-mediated delivery of a broadly neutralizing anti-flavivirus antibody protects against dengue and Zika viruses in a mouse model

Abstract

Flaviviruses contain many important human pathogens such as dengue virus (DENV) and Zika virus (ZIKV), for which effective and safe vaccines are still lacking, mainly because preexisting cross-reactive non-neutralizing antibodies may exacerbate subsequent infections with related flaviviruses. To overcome this challenge, we explore vectored immunoprophylaxis (VIP), which involves the passive transfer of protective antibody genes via viral vectors for in vivo expression. We utilized a recombinant adeno-associated virus (rAAV) to express a broad anti-flavivirus neutralizing human monoclonal antibody, bnAb 752-2C8, and tested its protection against four serotypes of DENV and ZIKV. The bnAb 752-2C8 antibody gene was cloned into an AAV plasmid and the rAAV was successfully generated to express bnAb 752-2C8. After a single dose of rAAV administration into AGB6 mice, the human antibody concentrations increased to ∼1,000 μg/mL and remained elevated for at least 48 weeks. VIP-treated mice were completely protected from a lethal challenge of DENVs and ZIKV, while control mice without bnAb 752-2C8 succumbed to infection. Our results demonstrate the effectiveness of rAAV in delivering bnAb 752-2C8 for long-term protection against multiple flaviviruses, providing a potential strategy to control flavivirus infections and possibly other viral diseases.

Keywords: ADE; VIP; Zika virus; antibody-dependent enhancement; broadly neutralizing antibody; dengue virus; flavivirus; long-term immunity; rAAV; recombinant adeno-associated virus; vectored immunoprophylaxis.