AAV-vectored expression of Marburg virus-neutralizing antibody MR191 provides complete protection from challenge in a guinea pig model

Abstract

Marburg virus (MARV) is a highly pathogenic filovirus responsible for numerous outbreaks, including three in West Africa since 2021. Although there are no approved vaccines or therapeutics available to prevent or treat disease caused by MARV, potently neutralizing monoclonal antibodies (mAbs) derived from B cells of human survivors of infection have been identified. One such mAb, known as MR191, was shown to provide complete protection against MARV in nonhuman primates when administered on 4- and 7-days post-challenge. We previously demonstrated that prophylactic administration of an adeno-associated virus (AAV) expressing MR191 was able to protect mice from a lethal dose of MARV. In the present study, we rationally modified the AAV-MR191 coding sequence to enhance efficacy and re-evaluated protection in a guinea pig model. Remarkably, four different variants of MR191-expressing AAV vectors provided complete protection against MARV, even though the AAVs were administered 90 days prior to challenge. Based on superior expression kinetics, we chose one variant, AAV-MR191-io2, and evaluated its protective efficacy in a dose-reduction experiment. The highest dose proved 100% protection in guinea pigs challenged with MARV, while a lower dose provided ∼88% protection. These data confirm the efficacy of AAV-mediated expression of MR191 and support the further development of this promising MARV countermeasure.