Gene transfer protocols offer an alternative to repeated injections of bNAbs as a means of maintaining effective immunoprophylaxis. VRC07 is a bNAb targeting the CD4 binding site of the HIV-1 envelope glycoprotein.
Ten HIV-infected volunteers on effective ARV therapy were enrolled in a phase I dose escalation trial of an AAV8 vectored VRC07 gene transfer at doses of 5×1010 (N=3), 5×1011 (N=3), and 2.5×1012 (N=4) viral genomes per kilogram (vg/kg) given by IM injection. Volunteers were between ages 22 and 60 years at enrollment and have been followed for 3 months – 3.75 years.
Product administration was well tolerated. No product related serious events occurred during this time. Vector-based VRC07 production was found in serum from all volunteers given AAV8-VRC07. Data from the long-term follow-up of 8 individuals followed for 1-1.5 years suggest a characteristic pattern of bNAb production defined by an early peak in VRC07 concentration 4-6 weeks after product administration, a decrease in VRC07 concentration from 7-14 weeks after product administration and then a slow increase in VRC07 concentration from 16 weeks onward resulting in stable or continually increasing Ab concentration. In 3 of the 8 individuals the secondary increase in VRC07 was either blunted or eliminated by a product-induced non-idiotypic anti-drug antibody (ADA) response. In the 5 individuals without significant ADA, peak VRC07 concentrations were 0.15-0.48 ?g/ml in the 5×1010 dose group, 0.59 ?g/ml in the 5×1011 dose group and 1.2-3.1 ?g/ml in the 2.5×1012 dose group. At 1.5 years after product administration VRC07 concentration were 0.34-0.48 ?g/ml in the 5×1010 dose group, 0.45 ?g/ml in the 5×1011 dose group and 0.31-3.1 ?g/ml in the 2.5×1012 dose group. Data from the low dose group show stable VRC07 expression through 2.5-3 years after product administration. After protein A IgG purification, IgG containing VRC07 was characterized in the 7 individuals. Pseudovirus neutralization IC80s for 5 tier 2 pseudovirus for in vivo and ex vivo produced VRC07 were similar.
These data suggest that adeno-associated viral vectors can safely be used to stably produce biologically active bNAbs in the majority of humans given product for over a 1.5 year period. AAV8 mediated gene transfer may offer a means to generate effective immunoprophylaxis. Identifying the cause of the ADA response may allow further increases in bNAb concentrations.