Journal Article

Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials

Corey, Lawrence, Mayer, Bryan T., Robb, Merlin L., Mascola, John R., Gilbert, Peter B., Reeves, Daniel B., Swan, David A., Boshier, Florencia A., Rolland, Morgane, Cohen, Myron S., Huang, Yunda, Cardozo-Ojeda, E. Fabian, Schiffer, Joshua T., Duke, Elizabeth R.

2020

Overview

The ongoing Antibody Mediated Prevention (AMP) trials will uncover whether passive infusion of the broadly neutralizing antibody (bNAb) VRC01 can protect against HIV acquisition. Previous statistical simulations indicate these trials may be partially protective. In that case, it will be crucial to identify the mechanism of breakthrough infections. To that end, we developed a mathematical modeling framework to simulate the AMP trials and infer the breakthrough mechanisms using measurable trial outcomes. This framework combines viral dynamics with antibody pharmacokinetics and pharmacodynamics, and will be generally applicable to forthcoming bNAb prevention trials. We fit our model to human viral load data (RV217). Then, we incorporated VRC01 neutralization using serum pharmacokinetics (HVTN 104) and in vitro pharmacodynamics (LANL CATNAP database). We systematically explored trial outcomes by reducing in vivo potency and varying the distribution of sensitivity to VRC01 in circulating strains. We found trial outcomes could be used in a clinical trial regression model (CTRM) to reveal whether partially protective trials were caused by large fractions of VRC01-resistant (IC50>50 μg/mL) circulating strains or rather a global reduction in VRC01 potency against all strains. The former mechanism suggests the need to enhance neutralizing antibody breadth; the latter suggests the need to enhance VRC01 delivery and/or in vivo binding. We will apply the clinical trial regression model to data from the completed trials to help optimize future approaches for passive delivery of anti-HIV neutralizing antibodies.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: AMP / Analysis / Antibodies / Armed forces / Biology and Life Sciences / Broadly Neutralizing Antibodies - immunology / Cancer / Cell death / Clinical trials / Clinical Trials as Topic / Computer simulation / Disease prevention / Drug dosages / Funding / Health aspects / Health sciences / HIV / HIV antibodies / HIV Antibodies - immunology / HIV Infections - immunology / HIV Infections - prevention & control / Human immunodeficiency virus / Humans / Infection / Infections / Infectious diseases / Mathematical analysis / Mathematical models / Medical research / Medical tests / Medicine / Medicine and Health Sciences / Military medicine / Models, Theoretical / Neutralization / Neutralizing / Pharmacodynamics / Pharmacokinetics / Pharmacology / Prevention / Public health / Regression models / Research and Analysis Methods / Statistical analysis / Supervision / Vaccines / Viruses