Complete definition of how mutations affect antibodies used to prevent RSV

Jesse Bloom

Fred Hutch Cancer Center / HHMI

Study led by Cassie Simonich

Pediatrics Medical Fellow

Seattle Childrens / Fred Hutch

These slides: https://slides.com/jbloom/grc-2026

Antibodies can bind to RSV F and neutralize viral infection of cells

https://pdb101.rcsb.org/motm/286

the antibody nirsevimab bound to prefusion F at epitope that includes glycan

https://pdb101.rcsb.org/motm/286

the antibody nirsevimab bound to prefusion F at epitope that includes glycan

Simonich et al (2025)

Antibodies can bind to RSV F and neutralize viral infection of cells

Economic challenges of antibodies against respiratory viruses

Although population disease burden is substantial, annual risk to any individual is low, and impossible to prospectively identify who will become severely ill at any given time.

Monoclonal antibodies are expensive to produce, and repeated dosing is required for sustained protection.

Viruses can evolve to become resistant. 

Although population disease burden is substantial, annual risk to any individual is low, and impossible to prospectively identify who will become severely ill at any given time.

Monoclonal antibodies are expensive to produce, and repeated dosing is required for sustained protection.

Viruses can evolve to become resistant.

Why anti-RSV antibody prophylaxis for infants is economically feasible

Severe disease concentrated in an easily identifiable population (infants).

Although population disease burden is substantial, annual risk to any individual is low, and impossible to prospectively identify who will become severely ill at any given time.

Monoclonal antibodies are expensive to produce, and repeated dosing is required for sustained protection.

Viruses can evolve to become resistant.

Severe disease concentrated in an easily identifiable population (infants).

Infants require lower dose, protection most needed only for first year, and antibodies have been engineered to be more potent and long lived.

Why anti-RSV antibody prophylaxis for infants is economically feasible

Although population disease burden is substantial, annual risk to any individual is low, and impossible to prospectively identify who will become severely ill at any given time.

Monoclonal antibodies are expensive to produce, and repeated dosing is required for sustained protection.

Viruses can evolve to become resistant.

Severe disease concentrated in an easily identifiable population (infants).

Topic of this talk.

Why anti-RSV antibody prophylaxis for infants is economically feasible

Infants require lower dose, protection most needed only for first year, and antibodies have been engineered to be more potent and long lived.

Brief history of anti-F antibodies for RSV prevention in infants

Palivizumab

Lower potency than subsequent antibodies.

Due in part to cost, recommendation only for infants born <29 weeks gestational age or <32 weeks with chronic lung disease

Neutralization curves from Simonich et al (2025)

Suptavumab

Much more potent against some strains than palivizumab.

Failed Phase 3 clinical trial from 2015-2017 due to lack of efficacy against subtype B; coincided with evolution of new variants with mutations at F sites 172 and 173.

Neutralization curves from Simonich et al (2025)

High potency and extended half life.

Recommended in United States in 2023 for all infants <8 months old entering their first RSV season.

~80% effectiveness in preventing RSV hospitalization.

Nirsevimab

Neutralization curves from Simonich et al (2025)

Clesrovimab

High potency and extended half life similar to nirsevimab but targets different region of F.

Approved in United States in 2025.

Neutralization curves from Simonich et al (2025)

Impact of RSV evolution on clinical antibodies so far

The clinical antibody nirsevimab neutralizes most RSV strains

plotted data from Simonich et al (2025)

Resistant strains have been identified in clinical and lab-passaging studies, plotted data from Simonich et al (2025)

But some (currently rare) natural RSV strains escape nirsevimab neutralization

The mysterious subtype-dependence of nirsevimab-escape mutations

Two subtypes of RSV: A & B. Their F proteins have ~90% sequence identity & similar structures

Joyce et al (2019)

RSV B F structure

RSV A F structure

The structures have a RMSD deviation of only 1.8 angstroms.

Nirsevimab IgG has similar neutralization of RSV A and RSV B

plotted data from Simonich et al (2025)

But resistance is more common for RSV B than A in nirsevimab-treated infants

Rates of resistance to nirsevimab neutralization in RSV breakthrough infections of infants who received nirsevimab.

Some F mutations reduce nirsevimab neutralization of subtype B but not A

Simonich et al (2026)

Why is RSV B more prone to nirsevimab resistance despite IgG neutralizing both subtypes similarly?

IgG antibodies are bivalent, with two connected Fabs

Apparent affinity (avidity) of bivalent IgG can be very high 

Klein and Bjorkman (2010)

Biophysical model: IgG neutralization buffered against viral mutations when Fab potency high

Simonich et al (2026)

See https://jbloomlab.github.io/IgG-vs-Fab-neutralization/notebook.html for full mathematical model

In real data, Fab potency higher to subtype A, thereby buffering IgG neutralization to mutations

Simonich et al (2026)

Measurement of mutation effects to inform surveillance for RSV antibody resistance

Previously, resistance mutations identified by viral passaging and characterizing clinical isolates

Example studies serial passaging RSV in presence of antibodies:

• Zhu et al (2018)
• Tang et al (2019)
• Terstappen et al (2026)

Example studies identifying resistance mutations in clinical infections:

• Hause et al (2017)
• Ahani et al (2023)
• Fourati et al (2025)

​These approaches identify just a fraction of mutations that affect antibody neutralization, and do not distinguish causal and hitchhiking mutations.

We can compare functional tolerance for escape from different antibodies

Simonich et al (2026)

Letter heights indicate reduction in antibody neutralization, color indicates impact on F's cell entry function. These visualizations help quantify how constraint limits escape from different antibodies.

Nirsevimab

Clesrovimab

site

cell entry function

Experimentally informed sequence surveillance

Conclusions

RSV antibodies are effective at preventing infant hospitalizations, but we need to be vigilant about potential resistance.

Difference in nirsevimab IgG resistance between RSV subtypes is explained by a biophysical model that accounts for different Fab potencies.

We have completely measured how RSV F mutations affect neutralization by antibodies in clinical use.

These data enable real-time surveillance for natural strains with resistance mutations.

Thanks

Cassie Simonich

Pediatrics Medical Fellow

Seattle Childrens / Fred Hutch

Teagan McMahon

Research Technician

Fred Hutch

Lucas Kampman (Grad Student, Fred Hutch)

Gavin Juviler (Research Tech, Fred Hutch)

Helen Chu (University of Washington)

Richard Neher (University of Basel)

These slides: https://slides.com/jbloom/grc-2026

Full data: https://dms-vep.org/RSV_Long_F_DMS/

Check out Lucas's poster about avidity based buffering of antibody escape