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Influenza poses a significant global public health threat, with vaccination being the most effective and economical preventive measure. However, these punctuated antigenic changes, particularly in HA, result in escape from the immunity that was induced by prior infection or vaccination. Accurately predicting antigenic variation and understanding the antigenic dynamics of influenza viruses are crucial for selecting appropriate vaccine strains, but no established methods exist for influenza B viruses. Therefore, we present PREDAC-FluB, a hybrid deep learning framework that integrates spatial feature extraction via CNN to model interactions in HA1 sequences, multimodal sequence representation combining ESM-2 embeddings with six physicochemical descriptors and continuous encoding (ESM2–7-features), and UMAP-guided clustering for antigenic cluster identification. Using data from 9036 B/Victoria-lineage and 4520 B/Yamagata-lineage influenza virus pair. PREDAC-FluB demonstrates superior performance over traditional machine learning methods in predicting antigenic variation in influenza viruses, successfully identifying major antigenic clusters. Specifically, PREDAC-FluB classified the B/Victoria lineage into nine antigenic clusters and the B/Yamagata lineage into three antigenic clusters. In five-fold cross-validation for B/Victoria viruses, PREDAC-FluB with ESM2–7-features encoding achieved AUROC values of 0.9961 on the validation set and 0.9856 on the independent test set. In retrospective testing for B/Victoria viruses, PREDAC-FluB achieved AUROC values ranging from 0.83 to 0.97, demonstrating high prediction accuracy and effectively capturing antigenic variation information. In conclusion, PREDAC-FluB is a robust tool for antigenic computation, capable of accurately predicting antigenic variation in influenza B viruses. Its high prediction accuracy makes it a promising auxiliary method for recommending future influenza vaccine strains.

PREDAC-FluB: predicting antigenic clusters of seasonal influenza B viruses with protein language model embedding based convolutional neural network