Low effectiveness of influenza vaccines vis-à-vis mechanism of protection by vaccines - potential causes and recommendations to improve control of influenza.

Current licensed influenza vaccines primarily protect by eliciting antibodies against the viral hemagglutinin (HA) glycoprotein, thereby blocking viral attachment and fusion with host cells. Unlike most vaccines, influenza vaccines must be administered annually because circulating viruses undergo continuous antigenic drift and population antibody titers wane over time. Despite yearly reformulation, influenza vaccine effectiveness remains highly variable, often below 45%, largely due to antigenic mismatches. These mismatches arise from ongoing HA evolution following strain selection and from egg-adaptation during production or propagation in animal cell cultures, which can alter key HA epitopes relative to circulating strains. Even when an antigenic match is favorable, repeated annual vaccination may elicit immunological phenomena that attenuate protective responses. Serial vaccination in young and older adults can increase regulatory T-cell activation, reducing vaccine-induced antibody titers. In older adults, this may be compounded by age-associated CD4+ T-cell memory populations that have reduced capacity to activate HA-specific B cells. While natural influenza infection induces durable memory B cells, conventional vaccination does not reliably generate such long-lived memory, suggesting a fundamental limitation of current vaccine platforms. Collectively, these observations underscore the need to re-evaluate influenza vaccination strategies, particularly to improve protection in high-risk groups such as older adults. Reducing antigenic mismatch remains essential and can be facilitated by improving the vaccine selection process and expanding the use of recombinant protein and mRNA vaccine production platforms that do not rely on egg- or animal-cell culture technologies. In parallel, the rational selection and development of adjuvants that minimize T-regulatory cell induction while enhancing durable memory B-cell formation and long-lived plasma cells may help overcome the immunological constraints associated with repeated annual vaccination. Beyond active immunization, complementary countermeasures are critical for mitigating severe outcomes, including hospitalizations and deaths. Antiviral drugs and monoclonal antibodies, especially those engineered for extended