Emergence of an Antigenically Drifted and Reassorted Influenza B Virus at the end of the 2024-25 Influenza Season

Preprint Akin et al., 2026

Published

May 24, 2026

Elgin Akin, David A. Villafuertea, Anne P. Werner, Matthew Pinsley, Corinne Pierce, Amary Fall, Omar Abdullah, Julie M. Norton, Richard E. Rothman, Katherine Z.J. Fenstermacher, Yu-Nong Gong Eili Klein, Heba H. Mostafa, Andrew Pekosz

Preprint Link : updated biorxiv

Preprint PDF Version 1 : PDF

Preprint PDF Version 2: PDF

Github : influenzabc3

Abstract

Influenza B virus (IBV) is a significant contributor to annual and severe cases of influenza, particularly in the young and elderly. Late in the 2024-25 Northern Hemisphere influenza season, a surge of IBV cases were identified in the Johns Hopkins Hospital Systems. The IBV responsible for the surge, C.3.1/re, was a clade C.3 virus that had reassorted with clade C.5.1 viruses and acquired the D197N mutation in hemagglutinin restoring a putative N-linked glycan predicted to mask a key neutralizing antibody epitope. The C.3.1/re viruses preferentially infected children but showed no significant change in disease severity. C.3.1/re viruses were poorly neutralized by pre- and post- influenza vaccination serum in a human cohort. Removal of the glycan at residue 197 restored neutralizing antibody recognition. The C.3.1/re IBV genotype that emerged late in the 2024-25 influenza season was antigenically mismatched with IBV vaccine strains for the 2025 and 2026 Southern hemisphere, as well as the 2025-26 Northern Hemisphere influenza seasons. While the 2026-27 Northern Hemisphere vaccine strain is a C.3.1/re, the egg adapted isolate selected (B/Tokyo/EIS13-175/2025) lacks the 197 glycosylation which is predicted to have poor recognition with circulating IBV clades. Phylogenetic analysis of currently circulating IBVs shows a diversification of circulating C.3 clades with multiple reassortment events between C.3 and C.5 clades in addition to independent acquisitions of D197N mutations, suggesting IBV is going through a period of significant antigenic and genetic expansion.