DOES REPEATED INFLUENZA VACCINATION ATTENUATE IMMUNOPROTECTION? A SYSTEMATIC REVIEW

Background: Annual influenza vaccination is recommended in many countries due to the rapid antigenic drift of circulating strains, particularly influenza A (H3N2). Evidence indicates that vaccine effectiveness may decline after repeated administrations, partly due to antigenic imprinting, although cellular immunity often remains stable or improves. Understanding the long-term immunological impact of repeated vaccination across age groups is essential for optimizing public health strategies. Aim of the study: To evaluate the effect of repeated influenza vaccination on vaccine effectiveness and immunological outcomes in the general population. Material and Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. Studies published between January 2020 and March 2025 were identified through PubMed, Google Scholar, and ResearchGate using predefined search strings. Eligible studies reported on repeated or annual influenza vaccination in humans and measured humoral or cellular immune outcomes. Risk of bias and methodological quality were assessed using validated tools. Twenty-eight studies met the inclusion criteria. Results: The studies varied in population characteristics, design, and vaccine type, with most using inactivated formulations. Immune responses were assessed mainly through antibody titers, seroconversion rates, and in some cases, cellular immunity markers. Findings were heterogeneous: 10 studies reported a negative effect of repeated vaccination, 11 showed a beneficial effect, and 7 found no significant impact. When reported, effect sizes were generally small to moderate. Statistical significance was inconsistent, and clinical relevance was frequently unclear. Observed effects were influenced by age, immune status, prior vaccination history, and vaccine formulation. Conclusions: While repeated vaccination may attenuate humoral responses in some populations, particularly older adults, cellular immunity tends to remain stable or improve, contributing to sustained protection. Personalized strategies, such as high-dose or adjuvanted vaccines for the elderly, may help offset reduced antibody responses. Limitations of the current evidence include heterogeneity in study design, absence of standardized outcome definitions, inconsistent statistical reporting, and limited long-term follow-up. Future research should incorporate robust bias assessment, standardized immunological endpoints, and age-stratified analyses to clarify mechanisms and optimize vaccination strategies.