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; Srilatha Edupuganti

doi:10.1038/s41467-023-43384-y

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

Nat Commun. 2023 Dec 14;14(1):8299. doi: 10.1038/s41467-023-43384-y.

Authors

Daniel B Reeves^#^{1

2}, Bryan T Mayer^#³, Allan C deCamp³, Yunda Huang^{3

4}, Bo Zhang³, Lindsay N Carpp³, Craig A Magaret³, Michal Juraska³, Peter B Gilbert^{3

5

6}, David C Montefiori⁷, Katharine J Bar⁸, E Fabian Cardozo-Ojeda³, Joshua T Schiffer^{3

9}, Raabya Rossenkhan³, Paul Edlefsen³, Lynn Morris^{10

11

12}, Nonhlanhla N Mkhize^{10

11}, Carolyn Williamson¹³, James I Mullins^{4

9

14}, Kelly E Seaton^{15

16}, Georgia D Tomaras^{15

16}, Philip Andrew¹⁷, Nyaradzo Mgodi¹⁸, Julie E Ledgerwood¹⁹, Myron S Cohen²⁰, Lawrence Corey^{3

21}, Logashvari Naidoo²², Catherine Orrell²³, Paul A Goepfert²⁴, Martin Casapia²⁵, Magdalena E Sobieszczyk²⁶, Shelly T Karuna^{3

27}, Srilatha Edupuganti²⁸

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. dreeves@fredhutch.org.
² Department of Global Health, University of Washington, Seattle, WA, USA. dreeves@fredhutch.org.
³ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁴ Department of Global Health, University of Washington, Seattle, WA, USA.
⁵ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁶ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁷ Department of Surgery, Duke University Medical Center, Durham, NC, USA.
⁸ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁰ National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
¹¹ Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
¹² Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.
¹³ Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, South Africa.
¹⁴ Department of Microbiology, University of Washington, Seattle, WA, USA.
¹⁵ Center for Human Systems Immunology, Duke University, Durham, NC, USA.
¹⁶ Departments of Surgery, Immunology, and Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
¹⁷ Family Health International, Durham, NC, USA.
¹⁸ Clinical Trials Research Centre, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.
¹⁹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
²⁰ Institute for Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
²² South African Medical Research Council, HPRU, Durban, South Africa.
²³ Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa.
²⁴ Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁵ Facultad de Medicina Humana, Universidad Nacional de la Amazonia Peru, Iquitos, Peru.
²⁶ Division of Infectious Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, New York-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA.
²⁷ GreenLight Biosciences, Medford, MA, USA.
²⁸ Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.

^# Contributed equally.

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.

MeSH terms

Antibodies, Neutralizing
HIV Antibodies
HIV Infections*
HIV-1*
Humans
Models, Theoretical
Viral Load

Substances

Antibodies, Neutralizing
HIV Antibodies

Abstract

MeSH terms

Substances

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