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

Presented During:

Wednesday, Mar 10, 2021: 12:35 PM  - 12:45 PM 
Virtual CROI 2021  

Abstract Number:

160 

Abstract Type:

General Abstract  

Authors:

Joseph P. Casazza1, Evan M. Cale1, Sandeep Narpala1, Laura Novik1, Galina V. Yamshchikov1, Bob C. Lin1, Janardan P. Pandey2, Adrian McDermott1, Mario R. Roederer1, Alejandro Balazs3, David Baltimore4, Richard A. Koup1, Julie E. Ledgerwood1, John R. Mascola1, for the VRC603 Team

Institutions:

1National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 2Medical University of South Carolina, Charleston, SC, USA, 3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 4California Institute of Technology, Pasadena, CA, USA

Presenting Author:

Dr Joseph Casazza, MD, PhD  

Background:

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.

Methods:

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 5x1010 (N=3), 5x1011 (N=2), and 2.5x1012 (N=3) viral genomes per kilogram (vg/kg) by IM injection. All volunteers in the 5x1010 and 5x1011 vg/kg doses were followed for >2 yr. Three volunteers in the 2.5x1012 dose group have been followed for 1yr or longer.

Results:

Product administration was well tolerated. No serious adverse events were attributed to product. Peak VRC07 concentrations were 0.17-0.43 μg/ml in the 5x1010 dose group, 0.23-0.74 μg/ml in the 5x1011 dose group and 1.1-1.2 μg/ml in the 2.5x1012 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.

Conclusion:

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.

Basic Science:

(E) HIV Reservoirs, Latency, and Curative Strategies Including Therapeutic Vaccines and Gene Therapy 

Keywords:

broadly neutralizing antibodies
clinical trial
Gene transfer
HIV infection
Human

Does this abstract include any aspects of research on SARS-CoV-2 or COVID-19?

No

Prior Presentation or Publication: In general, CROI does not accept work that has been previously published or publicly presented. Abstract text that is under copyright by a publication or another conference should not be submitted verbatim to CROI. Consideration may be given to a previously presented submission if meaningful newer data or different analyses are included or if the prior presentation was to a conference not focused on HIV- or SARS-CoV-2-related topics. Have your study data or abstract information been published, submitted for publication where publication is anticipated on or before the start of the CROI where you will present, or presented at any other major national or international scientific or medical HIV-related conferences (ie, generally 400 or more attendees)?

Yes

Prior Publication or Presentation Detail: If you responded yes above, please provide the name and year of prior or upcoming conference, publication information or submission for publication, and whether the prior abstract is copyrighted. In addition, describe what data have been updated for presentation at CROI.

A preliminary report was presented at CROI 2020. It was not copyrighted. In these data we show that in vivo produced Ab neutralizes 5 different tier 2 virus and has the same IC 80s for these pseudoviruses as reported for in vitro produced VRC07 and that neutralization of these viruses is inhibited by a VRC07 paratope binding Ab. We further describe the induced ADAs as binding the Fab fragment. We also show no correlation between IgG heavy chain allotype and measured ADA response. All new data.