Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition

• Type of Material: Article
• Authors: Kelly E Seaton, Molecular Genetics and Microbiology, Durham; Yunda Huang, University of Washington; Shelly Karuna, Fred Hutchinson Cancer Center, Seattle; Jack R Heptinstall, Molecular Genetics and Microbiology, Durham; Caroline Brackett, Molecular Genetics and Microbiology, Durham; Kelvin Chiong, Molecular Genetics and Microbiology, Durham; Lily Zhang, Fred Hutchinson Cancer Center, Seattle; Nicole L Yates, Molecular Genetics and Microbiology, Durham; Mark Sampson, Molecular Genetics and Microbiology; Erika Rudnicki, Fred Hutchinson Cancer Center, Seattle; Michal Juraska, Fred Hutchinson Cancer Center, Seattle; Allan C deCamp, Fred Hutchinson Cancer Center, Seattle; Paul T Edlefsen, Fred Hutchinson Cancer Center, Seattle; James I Mullins, University of Washington; Carolyn Williamson, University of Cape Town; Raabya Rossenkhan, Fred Hutchinson Cancer Center, Seattle; Elena E Giorgi, Fred Hutchinson Cancer Center, Seattle; Avi Kenny, University of Washington; Heather Angier, Fred Hutchinson Cancer Center, Seattle; April Randhawa, Fred Hutchinson Cancer Center, Seattle; Joshua A Weiner, Thayer School of Engineering at Dartmouth; Michelle Rojas, Molecular Genetics and Microbiology, Durham; Marcella Sarzotti-Kelsoe, Molecular Genetics and Microbiology, Durham; Lu Zhang, Molecular Genetics and Microbiology, Durham; Sheetal Sawant, Molecular Genetics and Microbiology, Durham; Margaret E Ackerman, Thayer School of Engineering at Dartmouth; Adrian B McDermott, Vaccine Research Center, Bethesda; John R Mascola, Vaccine Research Center, Bethesda; John Hural, Fred Hutchinson Cancer Center, Seattle; M. Julianna McElrath, Fred Hutchinson Cancer Center, Seattle; Philip Andrew, Family Health International, Durham NC; Jose A Hidalgo, Via Libre CRS, Lima, Peru; Jesse Clark, David Geffen School of Medicine at UCLA; Fatima Laher, Wits Health Consortium, Soweto; Catherine Orrell, University of Cape Town; Ian Frank, University of Pennsylvania; Pedro Gonzales, San Miguel Clinical Research Center, Lima; Srilatha Edupuganti, Emory University; Nyaradzo Mgodi, University of Zimbabwe; Lawrence Corey, University of Washington; Lynn Morris, University of the Witwatersrand; David Montefiori, Molecular Genetics and Microbiology, Durham; Myron S Cohen, University of North Carolina at Chapel Hill; Peter B Gilbert, University of Washington; Georgia D Tomaras, Molecular Genetics and Microbiology, Durham
• Language: English
• Date: 2023-07-01
• Publisher: Elsevier Ltd
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ebiom.2023.104590
• Title of Journal or Parent Work: eBioMedicine
• Volume: 93
• Start Page: 104590
• End Page: 104590
• Grant/Funding Information: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.
• Keywords: HIV-1; AIDS Vaccines; Humans; Broadly neutralising antibodies; Acquired Immunodeficiency Syndrome; Antibodies, Neutralizing; HIV Seropositivity; Broadly Neutralizing Antibodies; Prevention; Body weight-based dosing; HIV Antibodies; HIV Infections; HIV
• Research Categories: Health Sciences, Public Health; Biology, Molecular; Health Sciences, Immunology; Health Sciences, Oncology

Abstract

Background: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. Methods: The case–control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. Findings: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. Interpretation: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. Funding: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.