Keywords
Effectiveness
Immunogenicity.
How to Cite
Abstract
Introduction: Influenza is a highly transmissible respiratory disease for which vaccination remains the primary preventive strategy [1–3]. This study provides a comprehensive evaluation of influenza vaccine effectiveness by comparing evidence from randomized controlled trials (RCTs) and test-negative design (TND) observational studies, while also quantifying the relationship between immunogenicity and clinical protection using hemagglutination inhibition (HAI) antibody titers, as originally characterized by Hobson in 1973 [4].
Methods: A systematic electronic search identified studies assessing vaccine effectiveness, with methodological quality evaluated using standardized risk-of-bias instruments [5,6]. For immunogenicity analyses, studies indexed in PubMed and Scopus were screened to examine associations between HAI titers and vaccine efficacy. Meta-regression models were constructed to estimate functional relationships between antibody levels and protective efficacy, stratified by influenza strain and vaccine platform.
Results: Seventy-three studies met inclusion criteria for effectiveness meta-analysis from 2,993 screened records. The pooled vaccine effectiveness in RCTs was 48% (95% CI: 42–54), whereas adjusted effectiveness in TND studies was 39.9% (95% CI: 31–48), demonstrating consistent protection estimates across methodological frameworks. In the immunogenicity review, 7 studies were included following screening of 550 records. Vaccine efficacy depending on HAI ranged from 26% to 96%, varying according to vaccine type, circulating strain, and population characteristics, with higher HAI titers strongly associated with increased clinical protection.
Discussion and Conclusion: These findings support TND studies as a valid, efficient, and cost-effective approach for monitoring seasonal influenza vaccine effectiveness relative to RCTs. Furthermore, HAI titers ≥40 correspond to protective efficacy thresholds, reinforcing their utility as an immunological correlate of protection. Collectively, the results highlight the predictive value of quantitative immunogenicity models for estimating vaccine performance and informing evidence-based public health strategies.
References
1. European Centre for Disease Prevention and Control. Systematic review of the efficacy, effectiveness and safety of newer and enhanced seasonal influenza vaccines for the prevention of laboratory-confirmed influenza in individuals aged 18 years and over. [Internet]. LU: Publications Office; 2020 [cited 2023 Apr 30]. Available from: https://data.europa.eu/doi/10.2900/751620
2. Buchy P, Badur S. Who and when to vaccinate against influenza. International Journal of Infectious Diseases. 2020 Apr;93:375–87. doi:10.1016/j.ijid.2020.02.040
3. WHO Regional Office for Europe. WHO Regional Office for Europe recommendations on influenza vaccination for the 2020/2021 season during the ongoing COVID-19 pandemic. [Internet]. Copenhagen; 2020. Report. Available from: https://shorturl.at/yQSU9
4. Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. Epidemiol Infect. 1972 Dec;70(4):767–77. doi:10.1017/S0022172400022610
5. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016 Oct 12;i4919. doi:10.1136/bmj.i4919
6. Shi L, Lin L. The trim-and-fill method for publication bias: practical guidelines and recommendations based on a large database of meta-analyses. Medicine. 2019 Jun;98(23):e15987. doi:10.1097/MD.0000000000015987
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright (c) 2026 André Martins