Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial

Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRCO7 (AAV8-VRCO7) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial (NCT03374202). AAV8-VRCO7 was given at doses of 5 x 10(10), 5 x 10(11) and 2.5 x 10(12) vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRCO7; to determine the pharmacokinetics and immunogenicity of in vivo VRCO7 production; and to describe the immune response directed against AAV8-VRCO7 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRCO7 on CD4 T cell count and VL and to assess the persistence of VRCO7 produced in participants. In this cohort, IM injection of AAV8-VRCO7 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1-3 years of follow-up reported here. In participants who received AAV8-VRCO7, concentrations of VRCO7 were increased 6 weeks (P = 0.008) and 52 weeks (P = 0.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRCO7, with maximal VRCO7 concentrations >1 mu g ml(-1) in three individuals. In four individuals, VRCO7 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRCO7 was similar to that of in vitro produced VRCO7. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRCO7. This ADA response appeared to decrease the production of serum VRCO7 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases.