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.
Seven HIV-infected volunteers on effective ARV therapy were enrolled in a phase I, open-label dose escalation trial of an AAV8 vector encoding the HIV bNAb VRC07 at doses of 5×1010 (N=3), 5×1011 (N=2), and 2.5×1012 (N=2) viral genomes per kilogram (vg/kg) by IM injection. Volunteers were between 30 to 60 yr. All volunteers in the 5×1010 and 5×1011 vg/kg doses were followed for 1yr or longer. Two volunteers in the 2.5×1012 dose group have been followed for between 7-9 mo.
Product administration was well tolerated. Local reactogenicity was observed only in the 2.5×1012 vg/kg dose group where both volunteers reported mild pain and tenderness at the injection sites. One person in the intermediate dose group reported mild myalgia. All reactogenicities resolved within 1 week of product administration. No serious adverse events were attributed to product. Vector-based VRC07 production was found in all volunteers following injection. Peak VRC07 concentrations were 0.17-0.43 μg/ml in the 5×1010 dose group, 0.23-0.74 μg/ml in the 5×1011 dose group and 1.1-1.2 μg/ml in the 2.5×1012 dose group (Figure). The data suggest a pattern of antibody production defined by an early peak in VRC07 concentration 4-6 wks after product administration, a decrease in concentration 7-14 weeks after product administration and then a slow increase in concentration after 16 wks resulting in stable or continually increasing antibody concentration over the next 36 wks. In 3 of 5 individuals followed for one year or longer, antibody concentrations at 1 yr were higher than at the 4-6 wk peak. In the other 2 volunteers, one in the 5×1010, the other in the 5×1011 vg/kg dose group, anti-VRC07 antibodies were identified starting 6 and 14 wks after product administration. Anti-VRC07 antibodies were not detected in the other 5 volunteers.
These data suggest that adeno-associated viral vectors can safely be used to stably produce HIV-1 specific bNAbs in humans for over a 1-year period following a single administration of vector. AAV8 mediated gene transfer may offer a means to generate effective vectored immunoprophylaxis in humans.