Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context
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 in...
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-07-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239642300155X |
| _version_ | 1797807158854680576 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kelly E. Seaton |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T06:18:22Z |
| format | Article |
| id | doaj.art-1fb6811de76c4d6b9e00985ef3384be8 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-13T06:18:22Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-1fb6811de76c4d6b9e00985ef3384be82023-06-10T04:27:54ZengElsevierEBioMedicine2352-39642023-07-0193104590Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in contextKelly E. Seaton0Yunda Huang1Shelly Karuna2Jack R. Heptinstall3Caroline Brackett4Kelvin Chiong5Lily Zhang6Nicole L. Yates7Mark Sampson8Erika Rudnicki9Michal Juraska10Allan C. deCamp11Paul T. Edlefsen12James I. Mullins13Carolyn Williamson14Raabya Rossenkhan15Elena E. Giorgi16Avi Kenny17Heather Angier18April Randhawa19Joshua A. Weiner20Michelle Rojas21Marcella Sarzotti-Kelsoe22Lu Zhang23Sheetal Sawant24Margaret E. Ackerman25Adrian B. McDermott26John R. Mascola27John Hural28M. Julianna McElrath29Philip Andrew30Jose A. Hidalgo31Jesse Clark32Fatima Laher33Catherine Orrell34Ian Frank35Pedro Gonzales36Srilatha Edupuganti37Nyaradzo Mgodi38Lawrence Corey39Lynn Morris40David Montefiori41Myron S. Cohen42Peter B. Gilbert43Georgia D. Tomaras44Duke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA; Corresponding author.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.Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USADepartment of Global Health, University of Washington, Seattle, WA, 98195, USA; Departments of Microbiology and Medicine, University of Washington, Seattle, WA, 98195, USADivision of Medical Virology, Institute of Infectious Disease & Molecular Medicine, University of Cape Town and National Health Laboratory Service, South AfricaVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USADepartment of Biostatistics, University of Washington, Seattle, WA, 98195, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAThayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USAThayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USAVaccine Research Center, Bethesda, MD, USAVaccine Research Center, Bethesda, MD, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAFamily Health International, Durham, NC, 27710, USAVia Libre CRS, Lima, PeruDepartment of Medicine, Division of Infectious Disease and Department of Family Medicine in the David Geffen School of Medicine at UCLA, Los Angeles, CA, USAPerinatal HIV Research Unit (PHRU), Wits Health Consortium, Soweto, Johannesburg, South AfricaDesmond Tutu Health Foundation, University of Cape Town (Institute of Infectious Disease and Molecular Medicine, and Department of Medicine), Observatory, 7925, Cape Town, South AfricaPenn Center for AIDS Research, Infectious Disease Division, University of Pennsylvania, 3400 Civic Center Boulevard Building 421, Philadelphia, PA, 19104, USAAsociacion Civil Impacta Salud y Educación, San Miguel Clinical Research Center, Lima, PeruDivision of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USAUniversity of Zimbabwe-University of California San Francisco (UZ-UCSF) Collaborative Research Programme, Harare, Zimbabwe, South AfricaVaccine 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 AfricaNational 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 AfricaDuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USAInstitute of Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USAVaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA; Departments of Microbiology and Medicine, University of Washington, Seattle, WA, 98195, USADuke Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Durham, NC, 27710, USA; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S235239642300155XBody weight-based dosingHIVPreventionBroadly neutralising antibodies |
| spellingShingle | 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 Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context EBioMedicine Body weight-based dosing HIV Prevention Broadly neutralising antibodies |
| title | Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context |
| title_full | Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context |
| title_fullStr | Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context |
| title_full_unstemmed | Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context |
| title_short | Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisitionResearch in context |
| title_sort | pharmacokinetic serum concentrations of vrc01 correlate with prevention of hiv 1 acquisitionresearch in context |
| topic | Body weight-based dosing HIV Prevention Broadly neutralising antibodies |
| url | http://www.sciencedirect.com/science/article/pii/S235239642300155X |
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