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

Creators: Casazza, Joseph P.; Cale, Evan M.; Narpala, Sandeep; Yamshchikov, Galina V.; Coates, Emily E.; Hendel, Cynthia S.; Novik, Laura; Holman, LaSonji A.; Widge, Alicia T.; Apte, Preeti; Gordon, Ingelise; Gaudinski, Martin R.; Conan-Cibotti, Michelle; Lin, Bob C.; Nason, Martha C.; Trofymenko, Olga; Telscher, Shinyi; Plummer, Sarah H.; Wycuff, Diane; Adams, William C.; Pandey, Janardan P.; McDermott, Adrian; Roederer, Mario; Sukienik, Avery N.; O'Dell, Sijy; Gall, Jason G.; Flach, Britta; Terry, Travis L.; Choe, Misook; Shi, Wei; Chen, Xuejun; Kaltovich, Florence; Saunders, Kevin O.; Stein, Judy A.; Doria-Rose, Nicole A.; Schwartz, Richard M.; Balazs, Alejandro B.; Baltimore, David; Nabel, Gary J.; Koup, Richard A.; Graham, Barney S.; Ledgerwood, Julie E.; Mascola, John R.; Andrews, Charla; Arthur, Anita; Awan, Seemal F.; Beck, Allison; Burch, Eugeania; Burgos Florez, Maria C.; Berkowitz, Nina M.; Boritz, Eli A.; Carlton, Kevin; Cartagena, Cora T.; Carter, Christina; Chen, Grace L.; Costner, Pamela; Cunningham, Jennifer; Douek, Daniel C.; Eshun, Aba M.; Evans, Catina; Hicks, Renunda; Houser, Katherine V.; Jones, Justine; Larkin, Brenda; Le, Lam; Mendoza, Floreliz; Migueles, Stephen; Misasi, John; Nguyen, Thuy A.; Ola, Abidemi; Parker, Karen; Pittman, Iris; Requilman, La' Shawn; Rothwell, Ro Shauna; Schieber, Gretchen L.; Saunders, Jamie; Sitar, Sandra; Tran, Colin; Trofymenko, Olga; Vasilenko, Olga; Waheed, Sana; Wang, Lingshu; Wang, Xiaolin; Whalen, William; Williams, Pernell; Wu, Richard L.; Zephir, Kathy; VRC 603 Study Team

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.

Additional Information

© 2022 Nature Publishing Group. Received 30 June 2021; Accepted 28 February 2022; Published 11 April 2022. We would like to acknowledge J. Gilly and C. Case of Science Applications International Corporation for their contributions to study product manufacturing as well as P. Johnson and F. Wright of Children's Hospital of Philadelphia for providing critical AAV expertise. We thank R. Kothera for technical assistance in GM allotyping. We would like to thank our trial volunteers for their contribution and commitment to developing an effective clinical intervention for the prevention and control of HIV. This work was supported by intramural funding from the National Institute of Allergy and Infectious Diseases through the National Institutes of Health Intramural Research Program. A.B.B. is supported by National Institutes for Drug Abuse Avenir New Innovator Award DP2DA040254, the MGH Transformative Scholars Program as well as funding from the Charles H. Hood Foundation. J.P.P. received funding from Leidos Biomedical Research, Inc. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Data availability: Data generated in this study, including the study protocol, statistical analysis plan and informed consent form, will be available as de-identified data on ClinicalTrials.gov (NCT03186781) within 1 year from the primary completion date of the study. Individual de-identified participant data that underlie the results reported in this article are available, after de-identification, in the Supplementary Information section immediately after publication with no end date. Requests for additional data or materials will be promptly reviewed by the corresponding author (J.C.) to determine if these are subject to intellectual property, confidentiality or ethical obligations. Any data and materials that can be shared will be released via a material transfer agreement. Personal data underlying this article cannot be shared publicly as they are sensitive. Inquiries regarding data or material availability should be directed to jcasazza@mail.nih.gov. Contributions: J.P.C. had full access to all data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: J.R.M., J.E.L., G.J.N., B.S.G., R.A.K., M.R., G.V.Y., K.O.S., J.G.G., J.P.C., D.B. and A.B.B. Regulatory affairs: A.B.B. and D.B. Clinical oversight: J.E.L., M.R.G., I.G. and A.T.W. Volunteer recruitment, product administration, volunteer safety and sample acquisition: P.A., L.N., A.T.W., L.A.H., S.T. and C.S.H. Acquisition, analysis or interpretation of data: A.B.M., S.N., B.C.L., E.M.C., B.F., J.P.C., A.N.S., S.O., N.A.D.-R., J.P.P., E.E.C., T.L.T. and M.C.N. Administrative, technical, or material support: G.V.Y., R.M.S., O.T., S.H.P., M.C.-C., W.S., X.C. and W.C.A. Drafting of the manuscript: J.P.C. and E.E.C. Competing interests: A.B. and D.B. are named inventors on patent US9527904B2 held by the California Institute of Technology describing the vector used in this study. J.M. and G.N. are named inventors on patents US 61/568,520, 14/363,740 and 15/612,846 held by the National Institutes of Health describing the ex vivo production of VRC07. The remaining authors declare no competing interests. Peer review information: Nature Medicine thanks Keith Jerome, Jialu Li, Jean-Pierre Routy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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