This November, Get Free Media with your purchase of Airway Cells! Order online by November 30th (US Customers only). Click here!
Immunization

Human Airway Microphysiological System Demonstrates Predictive Power for SARS-CoV-2 Drug Efficacy

November 13, 2025 / by Lifeline® Cell Technology

The Need for Better Preclinical Models

Developing effective antiviral therapies for respiratory infections such as COVID-19, influenza, and RSV remains a persistent challenge—largely due to the limitations of current preclinical models. Traditional systems based on immortalized cell lines and animal models often fail to capture the complexity of the human airway. For example, commonly used cell lines such as Calu-3, A549, and Vero E6 lack key physiological features of human lung and airway tissues, including mucus production and ciliary motion. As a result, they do not fully recapitulate the microenvironmental mechanisms that drive viral infection and host response, limiting their predictive value for human outcomes. To bridge this translational gap, researchers are increasingly turning to advanced microphysiological systems (MPS) that more accurately mimic airway biology and disease pathology for therapeutic testing.

Evaluating PREDICT96-ALI as a Predictive Antiviral Screening Platform

A recent study by Quezada and colleagues evaluated PREDICT96-ALI, a high-throughput MPS that models primary human tracheobronchial tissue, as a predictive platform for antiviral drug screening. The model was established using primary normal human bronchial/tracheal epithelial cells (NHBE) and BronchiaLife™ Epithelial Airway Medium from Lifeline® Cell Technology, generating differentiated airway microtissues with ciliated epithelial cells exhibiting active motion, mucus-producing goblet cells, basal cells, and club cells. PREDICT96-ALI applies fluid flow during tissue maturation to promote physiological differentiation and functional airway architecture.

Previously validated for modeling responses to influenza A viruses and common cold coronaviruses, PREDICT96-ALI also supports infection and replication of SARS-CoV-2, with confirmed expression of viral entry factors ACE2 and TMPRSS2. Infection with the original USA-WA1/2020 strain produced robust viral replication across multiple tissue donors, and similar replication kinetics were observed with the Delta (B.1.617.2) and Omicron (B.1.1.529) variants of concern, demonstrating the model’s ability to capture variant-specific infection dynamics.

After establishing viral kinetics, the team tested five antiviral compounds against the SARS-CoV-2 USA-WA1/2020 strain, including approved COVID-19 therapeutics—Paxlovid (nirmatrelvir), Lagevrio (molnupiravir), and Veklury (remdesivir)—as well as PF-00835231 and calpeptin, across multiple doses (10, 1, and 0.1 µM). Tissues were treated at 2 hours post-infection and again at 2- and 4-days post-infection. Four of the five antivirals demonstrated significant reductions in viral titers, as measured by RT-qPCR, while calpeptin showed no measurable effect. Nirmatrelvir exhibited the strongest and most consistent antiviral activity across all concentrations and time points.

Building on the initial antiviral screen, the researchers evaluated the SARS-CoV-2 Omicron (B.1.1.529) variant and included two additional compounds—fluvoxamine and amodiaquine—that had shown promise in earlier in vitro models but failed in clinical trials. Consistent with clinical data, these agents showed no antiviral activity in PREDICT96-ALI, while nirmatrelvir, molnupiravir, and remdesivir maintained potent efficacy.

This proof-of-concept study demonstrates the potential of PREDICT96-ALI as a human-relevant platform capable of distinguishing clinically effective antivirals from those that fail in translation based on testing with other in vitro models. This system provides a powerful tool to improve preclinical prediction, accelerate antiviral discovery, and reduce the attrition rate of drug candidates.

Lifeline® Lung & Airway Products  

Lifeline® Cell Technology offers a comprehensive portfolio of normal and diseased human lung and airway cells and culture media optimized for their growth, providing researchers with the tools they need for drug discovery, disease research, and translational studies.

Join us next month for another installment of the Lifeline® blog to see how our cells and culture media are advancing biomedical research worldwide. If you have used our products in your publication, we’d love to feature your work here!

Main Menu