Near real-time tracking of the human neutralizing antibody landscape to influenza virus

Jesse Bloom

Fred Hutch Cancer Center / HHMI

These slides at https://slides.com/jbloom/flu-seqneut-2025

Panum (1847)

The Faroe Islands

"Measles had not prevailed on the Faroes since 1781, then it broke out early in April 1846."

Panum (1847)

"Of the 7782 inhabitants, about 6000 were taken with measles."

Panum (1847)

Panum (1847)

Panum was describing immune memory, which provides lifelong protection from measles

But we are repeatedly infected by some other viruses. Typical person infected by influenza ~5 years. Why?

History offers scenario with influenza like Panum's study of measles

In 1977, old H1N1 strain from ~1954 was inadvertently re-released and caused a global pandemic.

History offers scenario with influenza like Panum's study of measles

British Medical Journal (1978)

British Medical Journal (1978)

"One boy from Hong Kong had a transient febrile illness from 15 to 18 January. On Sunday 22 January, three boys were in the college infirmary… 512 boys (67%) spent between three and seven days away from class."

British Medical Journal (1978)

"Of about 130 adults who had some contact with the boys, only one, a house matron, developed similar symptoms."

Influenza infection also elicits durable immunity - but only if virus is evolutionarily frozen

Human neutralizing antibody landscape shapes influenza evolution and disease

Viral strains selected by evolution tend to be ones that are less neutralized by human antibodies.

People are more likely to be infected when they have low neutralizing titers to a strain to which they are exposed.

Immunity is heterogeneous across people: the median person never infected in a given year.

Vaccine is updated to try to track viral evolution.

How can we characterize human neutralizing antibody landscape at scale?

Assays measure just one virus against one serum in each row (or column) of a 96-well plate

Loes et al (2024)

Loes et al (2024)

Loes et al (2024)

Loes et al (2024)

Full viral library assayed in each row of plate

Loes et al (2024)

Full viral library assayed in each row of plate

Loes et al (2024)

Full viral library assayed in each row of plate

Loes et al (2024)

Neutralization of all the different viruses is read out simultaneously be sequencing

Loes et al (2024)

Neutralization of all the different viruses is read out simultaneously be sequencing

Loes et al (2024)

Neutralization of all the different viruses is read out simultaneously be sequencing

Loes et al (2024)

Neutralization of all the different viruses is read out simultaneously be sequencing

Loes et al (2024)

Neutralization of all the different viruses is read out simultaneously be sequencing

Loes et al (2024)

Neutralization of all the different viruses is read out simultaneously be sequencing

different recent H3N2 viral strains

Each row of plate measures titers to many viruses. Below are titers for one child serum.

this child has low titers to these viral strains

Kikawa et al, eLife (2025)

Person-to-person variation in per-strain titers

Kikawa et al, eLife (2025)

Heterogeneity within and between age groups

Kikawa et al, eLife (2025)

How do these heterogeneous neutralization titers for different humans shape viral evolution?

We measured neutralization for a large set of sera in two ways

sera from 95 individuals of different ages

Measured neutralization by each individual serum

Kikawa et al, eLife (2025)

sera from 95 individuals of different ages

Measured neutralization by pool of all sera

We measured neutralization for a large set of sera in two ways

Kikawa et al, eLife (2025)

Kikawa et al, eLife (2025)

We calculated actual growth rates of different strains in human population

But viral growth rates do not correlate with titers of a pool of all serum

Kikawa et al (2025)

Can we measure human neutralizing antibody landscape in near real-time?

Kikawa et al, bioRxiv (2025)

Timeline relative to Southern Hemisphere influenza vaccine strain selection

H3N2 strains in library vs global diversity

Kikawa et al, bioRxiv (2025)

Strains in library mostly cover current diversity of human seasonal influenza

Kikawa et al, bioRxiv (2025)

We measured neutralization titers of 188 human sera to 140 strains (~26,000 titers total)

We're still analyzing data to figure out how to best use them to inform evolutionary forecasts...

Exciting it is now possible to measure human influenza neutralizing antibody landscape in near real-time.

We're working to do the same for other viruses...

Lots of exciting experiments and analyses to come...

Data: https://github.com/jbloomlab/flu-seqneut-2025 

These slides: https://slides.com/jbloom/flu-seqneut-2025

Thanks