Gene transfer protocols offer an alternative to repeated injections of HIV broadly neutralizing antibodies (bNAb) as a means of maintaining effective immunoprophylaxis. VRC07 is a bNAb targeting the CD4 binding site of the HIV-1 envelope glycoprotein.
Eight HIV-infected volunteers on effective ARV therapy, age 30-60 yr, were enrolled in a phase I, open-label dose escalation trial of an AAV8 vector encoding the HIV bNAb VRC07 at doses of 5×10[sup]10[/sup] (N=3), 5×10[sup]11[/sup] (N=2), and 2.5×10[sup]12[/sup] (N=3) viral genomes per kilogram (vg/kg) by IM injection. All volunteers in the 5×10[sup]10[/sup] and 5×10[sup]11[/sup] vg/kg doses were followed for >2 yr. Three volunteers in the 2.5×10[sup]12[/sup] dose group have been followed for 1yr or longer.
Product administration was well tolerated. No serious adverse events were attributed to product. Peak VRC07 concentrations were 0.17-0.43 ?g/ml in the 5×1010 dose group, 0.23-0.74 ?g/ml in the 5×1011 dose group and 1.1-1.2 ?g/ml in the 2.5×1012 dose group. The data from 5 of the 8 volunteers suggest a pattern of antibody production defined by an early peak in VRC07 concentration followed by a decrease in concentration and then a slow secondary increase in concentration after 16 wks. In 4 of these 5 volunteers VRC07 concentration either increased or remained stable for >1y. In the 3 volunteers who did not show a secondary increase in VRC07 production, anti-VRC07 antibodies (ADA) were detected. In each case anti-VRC07 antibodies bound both VRC07 and the VRC07 Fab fragment. No correlation between the subject heavy chain IgG1 allotype and presence of ADA was found. After protein A IgG purification, in vitro IgG containing VRC07 was characterized. Measured VRC07 closely correlated with neutralization activity. In the 7 individuals where IgG containing VRC07 was characterized, pseudovirus neutralization IC 80s for 5 tier 2 pseudovirus were similar to reported IC80s for ex vivo produced VRC07. Neutralization of pseudovirus infections by purified IgG containing in vivo produced VRC07 was inhibited by the VRC07 paratope binding antibody 5C9.
AAV vectors can safely be used to stably produce biologically active HIV-1 specific bNAbs in humans for over 1-year. AAV8 mediated gene transfer offers a means of generating vectored immunoprophylaxis in humans but the reasons for the induced ADA responses need to be understood to optimize future gene transfer protocols.