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

Daniel B. Reeves (), Bryan T. Mayer, Allan C. deCamp, Yunda Huang, Bo Zhang, Lindsay N. Carpp, Craig A. Magaret, Michal Juraska, Peter B. Gilbert, David C. Montefiori, Katharine J. Bar, E. Fabian Cardozo-Ojeda, Joshua T. Schiffer, Raabya Rossenkhan, Paul Edlefsen, Lynn Morris, Nonhlanhla N. Mkhize, Carolyn Williamson, James I. Mullins, Kelly E. Seaton, Georgia D. Tomaras, Philip Andrew, Nyaradzo Mgodi, Julie E. Ledgerwood, Myron S. Cohen, Lawrence Corey, Logashvari Naidoo, Catherine Orrell, Paul A. Goepfert, Martin Casapia, Magdalena E. Sobieszczyk, Shelly T. Karuna and Srilatha Edupuganti
Additional contact information
Daniel B. Reeves: Fred Hutchinson Cancer Center
Bryan T. Mayer: Fred Hutchinson Cancer Center
Allan C. deCamp: Fred Hutchinson Cancer Center
Yunda Huang: Fred Hutchinson Cancer Center
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: Fred Hutchinson Cancer Center
David C. Montefiori: Duke University Medical Center
Katharine J. Bar: University of Pennsylvania
E. Fabian Cardozo-Ojeda: Fred Hutchinson Cancer Center
Joshua T. Schiffer: Fred Hutchinson Cancer Center
Raabya Rossenkhan: Fred Hutchinson Cancer Center
Paul Edlefsen: Fred Hutchinson Cancer Center
Lynn Morris: National Health Laboratory Service
Nonhlanhla N. Mkhize: National Health Laboratory Service
Carolyn Williamson: University of Cape Town and National Health Laboratory Service
James I. Mullins: University of Washington
Kelly E. Seaton: Duke University
Georgia D. Tomaras: Duke University
Philip Andrew: Family Health International
Nyaradzo Mgodi: University of Zimbabwe College of Health Sciences
Julie E. Ledgerwood: National Institutes of Health
Myron S. Cohen: The University of North Carolina at Chapel Hill
Lawrence Corey: Fred Hutchinson Cancer Center
Logashvari Naidoo: South African Medical Research Council, HPRU
Catherine Orrell: University of Cape Town
Paul A. Goepfert: University of Alabama at Birmingham
Martin Casapia: Universidad Nacional de la Amazonia Peru
Magdalena E. Sobieszczyk: New York-Presbyterian/Columbia University Irving Medical Center
Shelly T. Karuna: Fred Hutchinson Cancer Center
Srilatha Edupuganti: Emory University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43384-y

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