Low Effectiveness of Influenza Vaccines vis-à-vis Mechanism of Protection by Vaccines – Potential Causes and Recommendations to Improve Control of Influenza

Rajesh K. Gupta*, Kishore Alugupalli§, James L. Cowell¶

*Biologics Quality & Regulatory Consultants, LLC, North Potomac, MD, USA, Corresponding author, [email protected]

§TurboVax Inc., Horsham, PA, USA

¶Cowell Vaccine Consulting, Holly Springs, NC, USA

Abstract

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 after strain selection and from egg-adaptation during production, 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. Published studies report that serial vaccination in young and older adults can increase regulatory T-cell activation, reducing vaccine-induced antibody titers. In older adults, this effect may be compounded by age-associated CD4+ T-cell memory populations with 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 expanding non-egg-based vaccine technologies, including cell-culture–derived vaccines, recombinant HA vaccines, and mRNA platforms. In parallel, the rational selection and development of adjuvants that minimize T-regulatory cell induction while enhancing durable memory B-cell formation 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 prophylactic monoclonal antibodies, especially those engineered for extended in vivo half-life, represent important adjuncts for protecting vulnerable populations such as the elderly, young children, and immunocompromised individuals. Strengthening and advancing these modalities should be prioritized as part of an integrated strategy to improve influenza control and reduce the global burden of disease.

https://www.researchgate.net/publication/405055788_Low_effectiveness_of_influenza_vaccines_vis-a-vis_mechanism_of_protection_by_vaccines_-_potential_causes_and_recommendations_to_improve_control_of_influenza