Prediction of serum HIV-1 neutralization titers of VRC01 in HIV-uninfected Antibody Mediated Prevention (AMP) trial participants

• Type of Material: Article
• Authors: Yunda Huang, Fred Hutchinson Cancer Research Center; Lily Zhang, Fred Hutchinson Cancer Research Center; Amanda Eaton, Duke University; Nonhlanhla N. Mkhuze, Fred Hutchinson Cancer Research Center; Lindsay N. Carpp, Fred Hutchinson Cancer Research Center; Erika Rudnicki, Fred Hutchinson Cancer Research Center; Allan DeCamp, Fred Hutchinson Cancer Research Center; Michal Juraska, Fred Hutchinson Cancer Research Center; April Randhawa, Fred Hutchinson Cancer Research Center; Adrian McDermott, National Institutes of Health; Julie Ledgerwood, National Institutes of Health; Philip Andrew, Family Health International; Shelly Karuna, Fred Hutchinson Cancer Research Center; Srilatha Edupuganti, Emory University; Nyaradzo Mgodi, University of Zimbabwe; Myron Cohen, University of North Carolina; Lawrence Corey, Fred Hutchinson Cancer Research Center; John Mascola, National Institutes of Health; Peter B. Gilbert, Fred Hutchinson Cancer Research Center; Lynn Morris, National Institute for Communicable Diseases; David C. Montefiori, Duke University
• Language: English
• Date: 2021-06-02
• Publisher: Taylor & Francis
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Fred Hutchinson Cancer Research Center. Published with license by Taylor & Francis Group, LLC.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1080/21645515.2021.1908030
• Title of Journal or Parent Work: Human Vaccines & Immunotherapeutics
• Volume: 18
• Issue: 1
• Grant/Funding Information: This work was supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health under Grants UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068619 [LOC: HIV Prevention Trials Network], UM1 AI068635 [HVTN SDMC FHCRC], UM1AI068617 [HPTN SDMC], UM1 AI068618 [HVTN Laboratory Center FHCRC], and UM1AI068613 [HPTN Laboratory Center]. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: broadly neutralizing antibody; Population pharmacokinetic modeling; HIV-1 prevention; monoclonal antibodies; breakthrough viruses; pharmacokinetics/pharmacodynamics joint modeling; correlates analysis
• Research Categories: Biology, Virology; Health Sciences, Immunology; Health Sciences, Public Health

Abstract

VRC01 is being evaluated in the AMP efficacy trials, the first assessment of a passively administered broadly neutralizing monoclonal antibody (bnAb) for HIV-1 prevention. A key analysis will assess serum VRC01-mediated neutralization as a potential correlate of protection. To prepare for this analysis, we conducted a pilot study where we measured longitudinal VRC01 serum concentrations and serum VRC01-mediated neutralization in 47 and 31 HIV-1 uninfected AMP participants, respectively. We applied four different statistical approaches to predict serum VRC01-mediated neutralization titer against Env-pseudotyped viruses, including breakthrough viruses isolated from AMP placebo recipients who became HIV-1 infected during the trial, using VRC01 serum concentration and neutralization potency (IC50 or IC80) of the VRC01 clinical lot against the same virus. Approaches 3 and 4, which utilized pharmacokinetics/pharmacodynamics joint modeling of concentration and neutralization titer, generally performed the best or comparably to Approaches 1 and 2, which, respectively, utilized only measured and model-predicted concentration. For prediction of ID80 titers against breakthrough viruses, Approaches 1 and 2 rendered comparable performance to Approaches 3 and 4, and could be reasonable approaches to adopt in practice as they entail reduced assay cost and less complicated statistical analysis. Our results may be applied to future studies of other bnAbs and bnAb combinations to maximize resource efficiency in serum neutralization titer measurement.