Campus-based genomic surveillance uncovers early emergence of a future dominant A(H3N2) influenza clade.

We conducted genomic surveillance of seasonal influenza during the 2022-2023 northern hemisphere flu season on a large university setting in Southwest Arizona USA to understand the diversity, evolution, and spread within a local environment and how it relates to national data. Through high-throughput sequencing and bioinformatics, we identified 100 positive samples (19%) from 516 clinical swabs collected at the student health clinic. We observed a dominance of subtype A(H3N2) which was consistent nationally for the 2022-2023 season. However, we found stark differences when examining subtype-specific H3 clades, which included an early dominance of clade 2a.3a.1 variants contrasting from country-level data in which 2b variants were most abundant. These variants might have contributed to the early seasonal peak on campus which lagged national trends by one month. We used phylodynamics to understand the timing, source, and impact of clade-specific introductions on campus and observed introductions of 2b variants from North America, Europe, and Asia in early 2022 which possibly contributed to its later-season dominance on campus towards the end of 2022. We also observed the impact of 2b variants in our Bayesian epidemiological model, as its its emergence and rapid rise coincided with the peak of infection on campus. We found several highly prevalent H3 mutations in known epitope sites that have been observed in multiple 3c.2a clades. In particular, we note the presence of N96S (N=57, 63%) which is a defining mutation of 2a.3 and 2a.3a.1 variants and has been shown to create a new potential N-glycosylation site in the globular head. We estimated vaccine effectiveness via an H3 epitope model with a range of 0.13-0.48 which overlaps with estimates for that year. Taken together, the abundance of antigenic drift mutations, in addition to our identification of numerous sequons found within HA1 (globular head) with high glycosylation potential likely contributed to moderate vaccine effectiveness on campus for that season. As 2a.3a.1 variants became nearly the exclusive H3 clade nationally in 2023-2024 as well as 2024-2025, our identification of their dominance on campus highlights the importance of monitoring local settings as potential early examples for national and influenza trajectories. By using high-throughput sequencing and multiple bioinformatics methods, we show the importance of genomic epidemiology in semi-closed, highly-dense university settings and its potential for early insight of seasonal influenza diversity at a national scale.