Several factors have contributed to the higher impact of A(H3N2) viruses over the last 50 years. First, A(H3N2) viruses have undergone antigenic change at a much higher rate than influenza A(H1N1) viruses.73 Frequent changes to the hemagglutinin protein have allowed A(H3N2) viruses to evade human immune responses both through (1) conformational changes around important antigenic sites, notably the receptor binding pocket, and (2) increased glycosylation of the hemagglutinin protein shielding the antigenic sites of the virus from antibody binding.74
Secondly, A(H3N2) virus has had a disproportionate impact on older adults. Persons aged 65 years and older have a higher rate of comorbidities that increase their risk for influenza complications, and this group experiences higher mean hospitalization rates during influenza seasons in which H3 viruses predominate than in seasons in which H1 viruses predominate.75 Contributing factors may include waning immunity and decline in vaccine-derived immune protection.76 In addition, older adults may respond less effectively to A(H3N2) virus infections because of immunological imprinting, also referred to as “original antigenic sin.”77 This suggests that persons first infected by A(H1N1) virus (i.e., 1918–1957) are protected from severe H1N1 disease but are less protected against severe illness with A(H3N2) virus infection.
Third, when A(H3N2) viruses are propagated in eggs, they change conformation and can lose sites of glycosylation, causing them to differ from the circulating A(H3N2) viruses. This likely contributes to the lower vaccine effectiveness observed for A(H3N2) viruses, especially in older adults,78 highlighting the need for improving the effectiveness of seasonal influenza vaccines through increased antigen content, addition of adjuvants, and ultimately through development of more broadly protective and longer lasting “universal” vaccines.
Since their emergence, influenza A(H3N2) viruses have caused substantial cumulative morbidity and mortality worldwide during seasonal influenza epidemics, greatly exceeding their impact in the first years of the pandemic beginning in 1968. More than 50 years later, A(H3N2) continues to adapt to evade host immunity and cause higher numbers of hospitalizations and deaths than influenza A(H1N1) and B viruses. New therapies and vaccine technologies have been developed, but further improvements in the prevention and control of influenza are still needed and will be critical in preparing for the next influenza pandemic.
