EBioMedicine (Jul 2023)
Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context
- Kelly E. Seaton,
- Yunda Huang,
- Shelly Karuna,
- Jack R. Heptinstall,
- Caroline Brackett,
- Kelvin Chiong,
- Lily Zhang,
- Nicole L. Yates,
- Mark Sampson,
- Erika Rudnicki,
- Michal Juraska,
- Allan C. deCamp,
- Paul T. Edlefsen,
- James I. Mullins,
- Carolyn Williamson,
- Raabya Rossenkhan,
- Elena E. Giorgi,
- Avi Kenny,
- Heather Angier,
- April Randhawa,
- Joshua A. Weiner,
- Michelle Rojas,
- Marcella Sarzotti-Kelsoe,
- Lu Zhang,
- Sheetal Sawant,
- Margaret E. Ackerman,
- Adrian B. McDermott,
- John R. Mascola,
- John Hural,
- M. Julianna McElrath,
- Philip Andrew,
- Jose A. Hidalgo,
- Jesse Clark,
- Fatima Laher,
- Catherine Orrell,
- Ian Frank,
- Pedro Gonzales,
- Srilatha Edupuganti,
- Nyaradzo Mgodi,
- Lawrence Corey,
- Lynn Morris,
- David Montefiori,
- Myron S. Cohen,
- Peter B. Gilbert,
- Georgia D. Tomaras
Affiliations
- Kelly E. Seaton
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA; Corresponding author.
- Yunda Huang
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA; Department of Global Health, University of Washington, Seattle, WA, 98195, USA; Corresponding author.
- Shelly Karuna
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Jack R. Heptinstall
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Caroline Brackett
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Kelvin Chiong
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Lily Zhang
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Nicole L. Yates
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Mark Sampson
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Erika Rudnicki
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Michal Juraska
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Allan C. deCamp
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Paul T. Edlefsen
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- James I. Mullins
- Department of Global Health, University of Washington, Seattle, WA, 98195, USA; Departments of Microbiology and Medicine, University of Washington, Seattle, WA, 98195, USA
- Carolyn Williamson
- Division of Medical Virology, Institute of Infectious Disease & Molecular Medicine, University of Cape Town and National Health Laboratory Service, South Africa
- Raabya Rossenkhan
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Elena E. Giorgi
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Avi Kenny
- Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA
- Heather Angier
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- April Randhawa
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Joshua A. Weiner
- Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA
- Michelle Rojas
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Marcella Sarzotti-Kelsoe
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Lu Zhang
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Sheetal Sawant
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Margaret E. Ackerman
- Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA
- Adrian B. McDermott
- Vaccine Research Center, Bethesda, MD, USA
- John R. Mascola
- Vaccine Research Center, Bethesda, MD, USA
- John Hural
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- M. Julianna McElrath
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- Philip Andrew
- Family Health International, Durham, NC, 27710, USA
- Jose A. Hidalgo
- Via Libre CRS, Lima, Peru
- Jesse Clark
- Department of Medicine, Division of Infectious Disease and Department of Family Medicine in the David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Fatima Laher
- Perinatal HIV Research Unit (PHRU), Wits Health Consortium, Soweto, Johannesburg, South Africa
- Catherine Orrell
- Desmond Tutu Health Foundation, University of Cape Town (Institute of Infectious Disease and Molecular Medicine, and Department of Medicine), Observatory, 7925, Cape Town, South Africa
- Ian Frank
- Penn Center for AIDS Research, Infectious Disease Division, University of Pennsylvania, 3400 Civic Center Boulevard Building 421, Philadelphia, PA, 19104, USA
- Pedro Gonzales
- Asociacion Civil Impacta Salud y Educación, San Miguel Clinical Research Center, Lima, Peru
- Srilatha Edupuganti
- Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA
- Nyaradzo Mgodi
- University of Zimbabwe-University of California San Francisco (UZ-UCSF) Collaborative Research Programme, Harare, Zimbabwe, South Africa
- Lawrence Corey
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA; Departments of Medicine and Laboratory Medicine, University of Washington, Seattle, WA, 98195, USA; Division of Medical Virology, University of Cape Town, Anzio Road, Observatory, 7925, Cape Town, South Africa
- Lynn Morris
- National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, 2192, South Africa; Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2000, South Africa; Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, 4041, South Africa
- David Montefiori
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA
- Myron S. Cohen
- Institute of Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Peter B. Gilbert
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA; Departments of Microbiology and Medicine, University of Washington, Seattle, WA, 98195, USA
- Georgia D. Tomaras
- Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA; Corresponding author.
- Journal volume & issue
-
Vol. 93
p. 104590
Abstract
Summary: 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.
