Background/Objectives: Although several studies have shed light on the epidemiology of the influenza A/H3N2 subtype in Saudi Arabia, the knowledge regarding the molecular epidemiology and genetic diversity of the A/H3N2 subtype in the Riyadh region is still significantly restricted. Thus, the current research intends to investigate the molecular epidemiology and circulation patterns of the influenza A/H3N2 subtype in Riyadh, Saudi Arabia, over the past 9 years.
Methods: A total of 380 nasopharyngeal aspirate samples (NPAs) (winter seasons 2020–2023) were screened for the presence of A/H3N2 subtype.
Results: Sixty-five samples (17.11%) were found to be positive for the influenza A virus (IAV). A/H3N2 subtype 35 (9.21%) slightly predominated over A/H1N1 pdm09 30 (7.89%), the incidence rate was high in males (16.47%), and the most affected group was the 0–4 age group (14, 14.75%). The phylogenetic analysis revealed that the majority of Riyadh A/H3N2 samples were categorized into the sub-clades 3c.2a1b.1a and 3c.2a1b.1b, which did not exhibit any exclusive clustering with the vaccine strains. Out of the 20 amino acid substitutions detected in the HA1 domain of A/H3N2 strains, 9 were not found in any of the vaccine strains. The HA protein from the Riyadh samples has 8–11 N-glycosylation sites, some of which have been recorded in vaccine strains, yet are lacking in all strains analyzed in this study.
Conclusions: As a result, the flu vaccines administered in Saudi Arabia might need to be reevaluated to incorporate additional vaccine strains that are more pertinent to those currently circulating in the recent epidemic seasons in Saudi Arabia.