CONFERENCE ON RETROVIRUSES
AND OPPORTUNISTIC INFECTIONS

March 8–11, 2020

 

Conference Dates and Location: 
March 8–11, 2020 | Boston, Massachusetts
Abstract Number: 
41

DURABLE HIV-1 ANTIBODY PRODUCTION IN HUMANS AFTER AAV8-MEDIATED GENE TRANSFER

Author(s): 

Joseph P. Casazza1, Sandeep Narpala1, Laura Novik1, Galina Yamshchikov1, Evan Cale1, Nicole Doria-Rose1, Bob C. Lin1, Adrian B. McDermott1, Mario Roederer1,

1Vaccine Research Center, NIAID, Bethesda, MD, USA,2Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA,3California Institute of Technology, Pasadena, CA, USA

Abstract Body: 

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 5x1010 (N=3), 5x1011 (N=2), and 2.5x1012 (N=2) viral genomes per kilogram (vg/kg) by IM injection.   Volunteers were between 30 to 60 yr.  All volunteers in the 5x1010 and 5x1011 vg/kg doses were followed for 1yr or longer.    Two volunteers in the 2.5x1012 dose group have been followed for between 7-9 mo.

Product administration was well tolerated. Local reactogenicity was observed only in the 2.5x1012 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 g/ml in the 5x1010 dose group, 0.23-0.74 g/ml in the 5x1011 dose group and 1.1-1.2 g/ml in the 2.5x1012 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 5x1010, the other in the 5x1011 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.

Session Number: 
O-03
Session Title: 
THERAPEUTIC INTERVENTIONS FOR HIV TREATMENT AND ERADICATION
Presenting Author: 
Joseph Casazza
Presenter Institution: 
National Institutes of Health, USA