IMMU Subgroup Contributed Talks

Daniel B Reeves

Fred Hutchinson Cancer Center

"Modeling antibody mediated prevention of HIV to derive in vivo potency of VRC01"

The Antibody Mediated Prevention (AMP) trials demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV acquisition events. Here we used mathematical modeling 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, had a dose-response relationship with first positive viral load (p=0.03), which was particularly strong above a threshold of IIP=1.6 (r=-0.6, p=2e-4). Next, combined pharmacokinetic, pharmacodynamic and viral load kinetic modeling revealed that VRC01 neutralization predicted from in vitro IC80s and serum VRC01 concentrations overestimated in vivo neutralization by 600-fold (95% CI: 300-1200). We show how the trained model can be naturally conducive for informing design and projecting efficacy in coming preventive and therapeutic HIV trials of combination monoclonal antibodies.
Additional authors: Bryan T. Mayer 1; Allan C. deCamp 1; Yunda Huang 1,2; Bo Zhang 1; Lindsay N. Carpp 1; Craig A. Magaret 1; Michal Juraska 1; Peter B. Gilbert 1,3,4; David C. Montefiori 5; Katharine J. Bar6; E. Fabian Cardozo-Ojeda1; Joshua T. Schiffer 1,12; Raabya Rossenkhan 1; Paul Edlefsen 1; Lynn Morris 7,8,9; Nonhlanhla N. Mkhize 7,8; Carolyn Williamson 10; James I. Mullins 2,11,12; Kelly E. Seaton 13,14; Georgia D. Tomaras 13,14; Philip Andrew 15; Nyaradzo Mgodi 16; Julie E. Ledgerwood 17; Myron S. Cohen 18; Lawrence Corey 1,19; Logashvari Naidoo 20; Catherine Orrell 21; Paul A. Goepfert 22; Martin Casapia 23; Magdalena E. Sobieszczyk 24; Shelly T. Karuna 1,25; Srilatha Edupuganti 26 Affiliations: 1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. 2Department of Global Health, University of Washington, Seattle, WA, USA. 3Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. 4Department of Biostatistics, University of Washington, Seattle, WA, USA. 5Department of Surgery, Duke University Medical Center, Durham, NC, USA. 6Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa. 8Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. 9Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa. 10Division of Medical Virology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, South Africa 11Department of Microbiology, University of Washington, Seattle, WA, USA. 12Department of Medicine, University of Washington, Seattle, WA, USA. 13Center for Human Systems Immunology, Duke University, Durham, NC, USA. 14Departments of Surgery, Immunology, and Molecular Genetics and Microbiology, Duke University, Durham, NC, USA. 15Family Health International, Durham, NC, USA. 16Clinical Trials Research Centre, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe. 17Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 18Institute for Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 19Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. 20South African Medical Research Council, HPRU, Durban, South Africa. 21Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town. 22Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. 23Asociación Civil Selva Amazónica, Iquitos, Peru. 24Division of Infectious Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, New York-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA. 25GreenLight Biosciences, Medford, MA, USA. 26Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.

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David W. Dick

York University

"HIV-1 neutralization potential of red blood cells viral traps"

Management of human immunodeficiency virus (HIV) infection requires strict adherence to a daily drug regiment to prevent viral rebound. Red blood cells (RBCs) that lack nuclei and other organelles required for viral replication have been proposed as viral traps for HIV-1 as an alternative treatment for HIV-1. RBCs persistence in-host would require less frequent treatment offering a promising long-lasting augmentation to the existing highly active antiretroviral therapy (HAART). We develop an in-vitro model to assess the neutralization potential of RBCs targeting HIV-1 by expressing CD4, CCR5, or a CD4-glycophorin A (CD4-GpA) fusion protein and seek to elucidate the requirements for successful use of red blood cell viral traps for both treatment of HIV-1 and prophylaxis against both HIV-1 and SARS-CoV-2 infection.
Additional authors: Iain Moyles; York University, Department of Mathematics and Statistics, Centre for Disease Modelling; Jane M Heffernan; York University, Department of Mathematics and Statistics, Centre for Disease Modelling

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Katherine Owens

Fred Hutchinson Cancer Center

"Heterogeneous SARS-CoV-2 kinetics and in vitro overestimates of nirmatrelvir potency in humans"

SARS-CoV-2 viral loads have been linked with COVID-19 severity and transmission risk, and their kinetics vary across individuals. We clustered data from 1355 infections in the National Basketball Association cohort to identify six distinct patterns of viral shedding, which differ according to peak, duration, expansion rate and clearance rate. We then developed a mechanistic mathematical model that recapitulated observed viral trajectories, including viral rebound. Our results suggest that more rapid viral elimination occurs following vaccination and during omicron infection due to enhanced innate and acquired immune responses. We extended this model to include nirmatrelvir pharmacokinetics. In a published randomized double-blinded clinical trial, ritonavir-boosted nirmatrelvir decreased hospitalization and death by 95% and decreased nasal viral load by 0.5 log relative to placebo when given early during symptomatic infection to high-risk individuals. Our results from simulating this trial demonstrate niramtrelvir IC50 (50% inhibitory concentrations) estimates from in vitro assays are 100-fold less than plasma concentration required to reduce viral infection by 50% in humans. A maximally potent agent would reduce viral load by 3 orders of magnitude. We also project modifications to the treatment regimen that can reduce the frequency of viral rebound.
Additional authors: Shadi S. Esmaeili-Wellman, Fred Hutchinson Cancer Center; Joshua Schiffer, Fred Hutchinson Cancer Center

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Mohammad Aminul Islam

University at Buffalo, The State University of New York, Buffalo, NY

"Mathematical Modeling of Impacts of Patient Differences on COVID-19 Lung Fibrosis Outcomes"

Patient-specific premorbidity, age, and sex are significant heterogeneous factors that influence the severe manifestation of lung diseases, including COVID-19 fibrosis. The renin-angiotensin system (RAS) plays a prominent role in regulating effects of these factors. Recent evidence suggests that patient-specific alteration of RAS homeostasis with premorbidity and the expression level of angiotensin converting enzyme 2 (ACE2), depending on age and sex, is correlated with lung fibrosis. However, conflicting evidence suggests decreases, increases, or no changes in RAS after SARS-CoV-2 infection. In addition, detailed mechanisms connecting the patient-specific conditions before infection to infection-induced fibrosis are still unknown. Here, a mathematical model is developed to quantify the systemic contribution of heterogeneous factors of RAS in the progression of lung fibrosis. Three submodels are connected—a RAS model, an agent-based COVID-19 in-host immune response model, and a fibrosis model—to investigate the effects of patient-group-specific factors in the systemic alteration of RAS and collagen deposition in the lung. The model results indicate cell death due to inflammatory response as a major contributor to the reduction of ACE and ACE2, whereas there are no significant changes in ACE2 dynamics due to viral-bound internalization of ACE2. Reduction of ACE reduces the homeostasis of RAS including angiotensin II (ANGII), while the decrease in ACE2 increases ANGII and results in severe lung injury and fibrosis. The model explains possible mechanisms for conflicting evidence of RAS alterations in previously published studies. Also, the results show that ACE2 variations with age and sex significantly alter RAS peptides and lead to fibrosis with around 20% additional collagen deposition from systemic RAS with slight variations depending on age and sex. This model may find further applications in patient-specific calibrations of tissue models for acute and chronic lung diseases to develop personalized treatments.
Additional authors: Ashlee N. Ford Versypt; Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY

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