Introduction: Seasonal influenza A H3N2 viruses are constantly changing, reducing the effectiveness of existing vaccines. As a result, the World Health Organization (WHO) needs to frequently update the vaccine strains to match the antigenicity of emerged H3N2 variants. Traditional assessments of antigenicity rely on serological methods, which are both labor-intensive and time-consuming. Although numerous computational models aim to simplify antigenicity determination, they either lack a robust quantitative linkage between antigenicity and viral sequences or focus restrictively on selected features.

Methods: Here, we propose a novel computational method to predict antigenic distances using multiple features, including not only viral sequence attributes but also integrating four distinct categories of features that significantly affect viral antigenicity in sequences.

Results: This method exhibits low error in virus antigenicity prediction and achieves superior accuracy in discerning antigenic drift. Utilizing this method, we investigated the evolution process of the H3N2 influenza viruses and identified a total of 21 major antigenic clusters from 1968 to 2022.

Discussion: Interestingly, our predicted antigenic map aligns closely with the antigenic map generated with serological data. Thus, our method is a promising tool for detecting antigenic variants and guiding the selection of vaccine candidates.