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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

Casazza, Joseph P. and Cale, Evan M. and Narpala, Sandeep and Yamshchikov, Galina V. and Coates, Emily E. and Hendel, Cynthia S. and Novik, Laura and Holman, LaSonji A. and Widge, Alicia T. and Apte, Preeti and Gordon, Ingelise and Gaudinski, Martin R. and Conan-Cibotti, Michelle and Lin, Bob C. and Nason, Martha C. and Trofymenko, Olga and Telscher, Shinyi and Plummer, Sarah H. and Wycuff, Diane and Adams, William C. and Pandey, Janardan P. and McDermott, Adrian and Roederer, Mario and Sukienik, Avery N. and O’Dell, Sijy and Gall, Jason G. and Flach, Britta and Terry, Travis L. and Choe, Misook and Shi, Wei and Chen, Xuejun and Kaltovich, Florence and Saunders, Kevin O. and Stein, Judy A. and Doria-Rose, Nicole A. and Schwartz, Richard M. and Balazs, Alejandro B. and Baltimore, David and Nabel, Gary J. and Koup, Richard A. and Graham, Barney S. and Ledgerwood, Julie E. and Mascola, John R. and Andrews, Charla and Arthur, Anita and Awan, Seemal F. and Beck, Allison and Burch, Eugeania and Burgos Florez, Maria C. and Berkowitz, Nina M. and Boritz, Eli A. and Carlton, Kevin and Cartagena, Cora T. and Carter, Christina and Chen, Grace L. and Costner, Pamela and Cunningham, Jennifer and Douek, Daniel C. and Eshun, Aba M. and Evans, Catina and Hicks, Renunda and Houser, Katherine V. and Jones, Justine and Larkin, Brenda and Le, Lam and Mendoza, Floreliz and Migueles, Stephen and Misasi, John and Nguyen, Thuy A. and Ola, Abidemi and Parker, Karen and Pittman, Iris and Requilman, La’ Shawn and Rothwell, Ro Shauna and Schieber, Gretchen L. and Saunders, Jamie and Sitar, Sandra and Tran, Colin and Trofymenko, Olga and Vasilenko, Olga and Waheed, Sana and Wang, Lingshu and Wang, Xiaolin and Whalen, William and Williams, Pernell and Wu, Richard L. and Zephir, Kathy (2022) Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial. Nature Medicine, 28 (5). pp. 1022-1030. ISSN 1078-8956. doi:10.1038/s41591-022-01762-x.

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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.

Item Type:Article
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URLURL TypeDescription ReadCube access ItemData
Casazza, Joseph P.0000-0001-5648-4639
Widge, Alicia T.0000-0001-7615-8320
McDermott, Adrian0000-0003-0616-9117
Chen, Xuejun0000-0001-9192-0440
Saunders, Kevin O.0000-0001-7399-7954
Balazs, Alejandro B.0000-0002-1767-3944
Baltimore, David0000-0001-8723-8190
Nabel, Gary J.0000-0003-0619-4419
Alternate Title:Durable VRC07 Production by Adeno-Associated Virus-8 Mediated Gene Transfer
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 (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 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.
Funding AgencyGrant Number
MGH Transformative Scholars ProgramUNSPECIFIED
Charles H. Hood FoundationUNSPECIFIED
Leidos Biomedical Research, Inc.UNSPECIFIED
Subject Keywords:Applied immunology; Genetic vectors; Phase I trials; Translational research
Issue or Number:5
Record Number:CaltechAUTHORS:20220411-915265900
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Official Citation:Casazza, J.P., Cale, E.M., Narpala, S. 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, 1022–1030 (2022).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114214
Deposited By: Tony Diaz
Deposited On:11 Apr 2022 22:07
Last Modified:23 May 2022 17:41

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