Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.

Abstract

Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRC07 (AAV8-VRC07) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial ( NCT03374202 ). AAV8-VRC07 was given at doses of 5 × 1010, 5 × 1011 and 2.5 × 1012 vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRC07; to determine the pharmacokinetics and immunogenicity of in vivo VRC07 production; and to describe the immune response directed against AAV8-VRC07 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRC07 on CD4 T cell count and VL and to assess the persistence of VRC07 produced in participants. In this cohort, IM injection of AAV8-VRC07 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1-3 years of follow-up reported here. In participants who received AAV8-VRC07, concentrations of VRC07 were increased 6 weeks (P = 0.008) and 52 weeks (P = 0.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRC07, with maximal VRC07 concentrations >1 µg ml-1 in three individuals. In four individuals, VRC07 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRC07 was similar to that of in vitro produced VRC07. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRC07. This ADA response appeared to decrease the production of serum VRC07 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases.

• Authors: Joseph P Casazza, Evan M Cale, Sandeep Narpala, Galina V Yamshchikov, Emily E Coates, Cynthia S Hendel, Laura Novik, LaSonji A Holman, Alicia T Widge, Preeti Apte, Ingelise Gordon, Martin R Gaudinski, Michelle Conan-Cibotti, Bob C Lin, Martha C Nason, Olga Trofymenko, Shinyi Telscher, Sarah H Plummer, Diane Wycuff, William C Adams, Janardan P Pandey, Adrian McDermott, Mario Roederer, Avery N Sukienik, Sijy O'Dell, Jason G Gall, Britta Flach, Travis L Terry, Misook Choe, Wei Shi, Xuejun Chen, Florence Kaltovich, Kevin O Saunders, Judy A Stein, Nicole A Doria-Rose, Richard M Schwartz, Alejandro B Balazs, David Baltimore, Gary J Nabel, Richard A Koup, Barney S Graham, Julie E Ledgerwood, John R Mascola, VRC 603 Study Team
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 5 Pg. 1022-1030 (05 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35411076 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Chemical References

• Antibodies, Neutralizing
• Broadly Neutralizing Antibodies
• HIV Antibodies

Topics

• Adult
• Antibodies, Neutralizing
• Broadly Neutralizing Antibodies
• Dependovirus (genetics)
• HIV Antibodies
• HIV Infections (drug therapy)
• HIV-1
• Humans