High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

• Type of Material: Article
• Authors: Daniel B. Reeves, University of Washington, Seattle; Bryan T. Mayer, Fred Hutchinson Cancer Center; Allan C. deCamp, Fred Hutchinson Cancer Center; Yunda Huang, University of Washing, Seattle; Bo Zhang, Fred Hutchinson Cancer Center; Lindsay N. Carpp, Fred Hutchinson Cancer Center; Craig A. Magaret, Fred Hutchinson Cancer Center; Michal Juraska, Fred Hutchinson Cancer Center; Peter B. Gilbert, University of Washington, Seattle; David C. Montefiori, Duke University; Katharine J. Bar, University of Pennsylvania; E. Fabian Cardozo-Ojeda, Fred Hutchinson Cancer Center; Joshua T. Schiffer, University of Washington, Seattle; Raabya Rossenkhan, Fred Hutchinson Cancer Center; Paul Edlefsen, Fred Hutchinson Cancer Center; Lynn Morris, University of the Witwatersrand; Nonhlanhla Mkhize, University of the Witwatersrand; Carolyn Williamson, University of Cape Town; James I. Mullins, University of Washington, Seattle; Kelly E. Seaton, Duke University; georgia D. Tomaras, Duke University; Philip Andrew, Family Health International; Nyaradzo Mgodi, University of Zimbabwe; Julie E. Ledgerwood, National Institutes of Health; Myron S. Cohen, University of North Carolina, Chapel Hill; Lawrence Corey, University of Washington, Seattle; Logashvari Naidoo, South African Medical Research Council; Catherine Orrell, University of Cape Town; Paul A. Goepfert, University of Alabama, Birmingham; Martin Casapia, Universidad Nacional de la Amazonia Peru; Magdalena E. Sobieszczyk, Columbia University; Shelly T. Karuna, Fred Hutchinson Cancer Center; Sri Edupuganti, Emory University
• Language: English
• Date: 2023-12-14
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023, corrected publication 2024
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038/s41467-023-43384-y; https://doi.org/10.1038/s41467-024-46805-8
• Title of Journal or Parent Work: Nature Communications
• Volume: 14
• Start Page: 8299
• Grant/Funding Information: This work was supported by the National Institutes of Health through award numbers R01 AI150500 (E.F. C-O.), UM1 AI068614 (G.D.T., L.C.), UM1 AI068635 (Y.H., P.B.G.), 4 R37 AI054165-21 (P.B.G.), UM1 AI068618, UM1 AI068619 (M.S.C), UM1 AI068613, UM1 AI068617, P30 AI027757, P30 AI064518, K25 AI155224 (D.B.R.), the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, and the South African Medical Research Council (SAMRC).
• Keywords: HIV infections; Antibodies; Applied mathematics; Scientific data

Abstract

The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300–1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.