Biology subjects

McMahon, T. E.

Publications and source records attributed to McMahon, T. E..

2 recordsLinked to original sources

bioRxiv2026

Complete definition of how mutations affect antibodies used to prevent RSV

New antibodies targeting the F protein of RSV have substantially reduced infant hospitalizations. However, viral resistance is a concern: one antibody failed clinical trials due to a resistant strain, and sporadic resistance mutations to the most widely used antibody (nirsevimab) have been identified. Here we define how RSV F mutations affect antibody neutralization. We first provide a biophysical model of how the buffering of bivalent IgG binding combines with the lower Fab potency of nirsevimab to subtype B to make resistance to this antibody more common in subtype B than A strains. We then perform pseudovirus deep mutational scanning to safely measure how nearly all mutations to F affect its cell entry function and neutralization by IgG and Fab forms of nirsevimab, clesrovimab, and several other key antibodies. We use these measurements to enable real-time surveillance of RSV sequences for antibody resistance, and show that resistant strains have arisen sporadically but are currently rare. Overall, our work shows how Fab potency and epitope specificity combine to determine how viral mutations impact antibody neutralization, enables monitoring for natural RSV strains resistant to antibodies of public-health importance, and can help guide development of future antibodies with resilience to viral escape.

microbiology↗

bioRxiv2023

Full-spike deep mutational scanning helps predict the evolutionary success of SARS-CoV-2 clades

SARS-CoV-2 variants acquire mutations in spike that promote immune evasion and impact other properties that contribute to viral fitness such as ACE2 receptor binding and cell entry. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning to measure how >9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry, or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully impacted ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456, and 473--however, the antigenic impacts of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.

microbiology↗