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

Publication ,  Journal Article
Casazza, JP; Cale, EM; Narpala, S; Yamshchikov, GV; Coates, EE; Hendel, CS; Novik, L; Holman, LA; Widge, AT; Apte, P; Gordon, I; Gaudinski, MR ...
Published in: Nat Med
May 2022

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

May 2022

Volume

28

Issue

5

Start / End Page

1022 / 1030

Location

United States

Related Subject Headings

  • Immunology
  • Humans
  • HIV-1
  • HIV Infections
  • HIV Antibodies
  • Dependovirus
  • Broadly Neutralizing Antibodies
  • Antibodies, Neutralizing
  • Adult
  • 42 Health sciences
 

Citation

APA
Chicago
ICMJE
MLA
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Casazza, J. P., Cale, E. M., Narpala, S., Yamshchikov, G. V., Coates, E. E., Hendel, C. S., … VRC 603 Study Team, . (2022). Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial. Nat Med, 28(5), 1022–1030. https://doi.org/10.1038/s41591-022-01762-x
Casazza, Joseph P., Evan M. Cale, Sandeep Narpala, Galina V. Yamshchikov, Emily E. Coates, Cynthia S. Hendel, Laura Novik, et al. “Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.Nat Med 28, no. 5 (May 2022): 1022–30. https://doi.org/10.1038/s41591-022-01762-x.
Casazza JP, Cale EM, Narpala S, Yamshchikov GV, Coates EE, Hendel CS, et al. Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial. Nat Med. 2022 May;28(5):1022–30.
Casazza, Joseph P., et al. “Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.Nat Med, vol. 28, no. 5, May 2022, pp. 1022–30. Pubmed, doi:10.1038/s41591-022-01762-x.
Casazza JP, Cale EM, Narpala S, Yamshchikov GV, Coates EE, Hendel CS, Novik L, Holman LA, Widge AT, Apte P, Gordon I, Gaudinski MR, Conan-Cibotti M, Lin BC, Nason MC, Trofymenko O, Telscher S, Plummer SH, Wycuff D, Adams WC, Pandey JP, McDermott A, Roederer M, Sukienik AN, O’Dell S, Gall JG, Flach B, Terry TL, Choe M, Shi W, Chen X, Kaltovich F, Saunders KO, Stein JA, Doria-Rose NA, Schwartz RM, Balazs AB, Baltimore D, Nabel GJ, Koup RA, Graham BS, Ledgerwood JE, Mascola JR, VRC 603 Study Team. Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial. Nat Med. 2022 May;28(5):1022–1030.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

May 2022

Volume

28

Issue

5

Start / End Page

1022 / 1030

Location

United States

Related Subject Headings

  • Immunology
  • Humans
  • HIV-1
  • HIV Infections
  • HIV Antibodies
  • Dependovirus
  • Broadly Neutralizing Antibodies
  • Antibodies, Neutralizing
  • Adult
  • 42 Health sciences