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Cite as: Archiv EuroMedica. 2025. 15; 4. DOI 10.35630/2025/15/4.001

Received 31 July 2025;
Accepted 25 August 2025;
Published 26 August 2025

DOES REPEATED INFLUENZA VACCINATION ATTENUATE IMMUNOPROTECTION? A SYSTEMATIC REVIEW

Łukasz Skowron¹ , Bartłomiej Bobrowski² ,
Honorata Derlatka¹ , Jan Drugacz³ ,
Olaf Helbig⁴ , Klaudia Kontek⁵ ,
Anna Kukhtiak⁶ , Julia Marcinkowska⁷ ,
Martyna Radelczuk⁸

¹ Collegium Medicum, Jan Kochanowski University, Kielce, Poland
² Dr. Bartosz Bobrowski Medical Practice, Cieszyn, Poland
³ Dr. Jan Drugacz Medical Practice, Bielsko-Biała, Poland
⁴ Poznan University of Medical Sciences, Poznan, Poland
⁵ John Paul II District Hospital in Kolbuszowa, Poland
⁶ Faculty of Medicine, Medical University of Lodz, Poland
⁷ Pomeranian Medical University in Szczecin, Poland
⁸ Military Institute of Medicine, Warsaw, Poland

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ABSTRACT

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.

Keywords: influenza vaccine, repeated vaccination, annual vaccination, immune response, vaccine effectiveness, antigenic imprinting, humoral immunity, cellular immunity

INTRODUCTION

Annual influenza vaccination is necessary due to the rapid antigenic drift of circulating strains, particularly influenza A (H3N2), which requires frequent reformulation of the vaccine. Immunity against homologous strains wanes over time, supporting the need for yearly immunization. In many countries, annual influenza vaccination is part of public health recommendations. However, evidence suggests that vaccine effectiveness may decrease after repeated administrations. Influenza remains a major health problem because of its direct clinical impact and its broader social and economic consequences, especially among the elderly, people with chronic diseases, and immunocompromised individuals [1,2].

Recent studies indicate that repeated vaccination may reduce antibody responses in some cases, particularly in older adults, partly due to immunological imprinting, also referred to as original antigenic sin. For example, Sullivan et al. [1] reported reduced vaccine effectiveness against A(H3N2) in individuals vaccinated in consecutive seasons, whereas Guiomar et al. [13] found that repeated vaccination maintained protective antibody levels even against mismatched strains. In contrast, cellular immunity appears more stable and may even improve with repeated vaccination, indicating a complex pattern of immune protection [3,4].

While some earlier reviews have addressed this topic, many have overlooked recent findings on age-related variability in immune responses. For example, Kitamura et al. [6] observed no significant change in antibody titers after repeated vaccination in elderly individuals, whereas Matsumoto et al. [11] reported maintained or improved vaccine effectiveness in young children receiving annual doses. Similarly, Fox et al. [2] demonstrated that enhanced vaccine formulations in older adults can extend antibody reactivity, although prior vaccination effects persist. In particular, there is a lack of comprehensive data on the long-term immunological effects of repeated vaccination across different age groups, on how prior vaccination history modifies both humoral and cellular immunity, and on whether specific vaccine formulations can mitigate potential reductions in effectiveness. The role of targeted vaccination strategies, including high-dose and adjuvanted formulations, has been insufficiently examined.

The present review focuses on studies published between January 2020 and March 2025, retrieved exclusively from PubMed, Google Scholar, and ResearchGate, and limited to articles written in English. These restrictions, along with the absence of a formal risk of bias meta-analysis, should be considered when interpreting the findings. The search was guided by predefined key terms including “influenza vaccine”, “repeated vaccination”, “annual vaccination”, “immune response”, “immunoprotection”, and “antibody titer”.

This review aims to address existing knowledge gaps and to provide evidence-based insights to inform clinical decision-making and public health immunization policies. Understanding the long-term effects of repeated vaccination is essential for optimizing strategies and improving protection for populations at highest risk of severe influenza outcomes. In this context, a systematic review of recent studies can clarify the magnitude and direction of the impact of repeated vaccination on different components of the immune response and on overall vaccine effectiveness.

MATERIALS AND METHODS

A systematic literature review was conducted in accordance with the PRISMA 2020 guidelines. Three databases - PubMed, Google Scholar, and ResearchGate - were searched for relevant peer-reviewed studies published between January 2020 and March 2025. The review protocol was not registered in PROSPERO or other registries, which is acknowledged as a methodological limitation.

Eligibility criteria

Studies were included if they:

• reported on the effects of repeated or annual influenza vaccination;
• measured immunological outcomes (e.g., antibody titers, seroconversion rates, cellular immunity);
• were conducted in human populations of any age;
• were published in peer-reviewed journals;
• were written in English.

Exclusion criteria:

• animal studies;
• reviews, commentaries, editorials, or conference abstracts without full data;
• studies that did not differentiate between first-time and repeated vaccination.

Search strategy

Searches were performed in PubMed, Google Scholar, and ResearchGate for articles published between January 2020 and March 25, 2025. The search combined keywords and MeSH terms using Boolean operators. For example, the PubMed search string was: ("influenza vaccine"[MeSH Terms] OR "influenza vaccine"[All Fields]) AND ("repeated vaccination" OR "annual vaccination") AND ("immune response" OR "immunoprotection" OR "antibody titer").

Equivalent search strings were adapted to the syntax of each database (full search strings for all databases are provided in Supplementary Material S1). No filters other than publication date and language (English) were applied at the search stage.

In addition to database searches, manual searches were conducted using the reference lists of all included articles to identify further eligible studies not captured by the initial search.

Study selection

All records were exported into EndNote X9 (Clarivate Analytics), where duplicates were removed automatically and verified manually. Two independent reviewers screened titles and abstracts for relevance. Full texts of potentially eligible articles were retrieved and assessed against the inclusion and exclusion criteria. Discrepancies between reviewers were resolved by discussion or, when necessary, by consulting a third reviewer. The inter-reviewer agreement at the full-text screening stage was 92% (Cohen’s kappa = 0.84).

Data extraction

Data were extracted independently by two reviewers using a standardized extraction form. Extracted variables included:

• first author and year of publication
• study design (randomized controlled trial, cohort, case-control, cross-sectional)
• study population and sample size
• vaccination history (repeated vs. naïve)
• type of vaccine used (standard dose, high dose, adjuvanted, live attenuated)
• immune outcomes (seroprotection, seroconversion, antibody titers, T-cell responses)
• summary of results
• immunoprotection effect (categorized as positive, negative, or no effect)

Quality assessment

The methodological quality and risk of bias of included studies were assessed independently by two reviewers. Randomized controlled trials were evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool. Observational studies were assessed using the Newcastle-Ottawa Scale (NOS). Disagreements were resolved through consensus. Detailed quality assessment results for each study are provided in Supplementary Material S2

PRISMA flow diagram

The initial search yielded 198 records. After removal of 2 duplicates, 196 records were screened. Of these, 156 were excluded as irrelevant, leaving 40 for title and abstract screening. Four records were excluded at this stage. The remaining 36 full-text articles were retrieved, of which 4 could not be accessed. Thirty-two articles were assessed for eligibility, and 6 were excluded (1 animal study, 1 computational modeling study, 4 reviews/commentaries). In total, 26 studies met all inclusion criteria and were included in the final synthesis (Figure 1).

Figure 1. Flow chart of the systematic literature search

RESULTS

The table below presents the years during which the studies were conducted, the type of publication, the number of participants, the influenza seasons covered by the research, as well as the characteristics of the vaccine itself, and the effects of repeated vaccination.

To facilitate direct comparison of study outcomes, a standardized table summarizing key quantitative results has been prepared. Table 4 presents essential data on study populations, vaccine characteristics, and measured effects of repeated influenza vaccination.

A total of 26 publications were included in the final analysis, encompassing various study designs such as systematic reviews, meta-analyses, prospective studies, and retrospective studies (both cohort and case-control). The influenza seasons analyzed ranged from individual years to extended periods, including up to five consecutive seasons. The publication dates spanned from 2020 to 2025.

The characteristics of the studied populations were diverse ranging from older adults to adults subjected to routine vaccinations, to specific groups such as beneficiaries of military healthcare systems. The sample sizes ranged from small cohorts to groups encompassing several thousand individuals.

The studies analyzed evaluated the effectiveness and immunological consequences of repeated influenza vaccination. In most cases, inactivated vaccines (trivalent or quadrivalent) were used, while subunit or recombinant vaccines were less common. The immune response was assessed based on clinical efficacy against specific virus strains (e.g., A(H1N1), A(H3N2)), often relying on serological indicators such as antibody titers in the hemagglutination inhibition (HI) test.

The impact of repeated vaccination was assessed in each of the studies. The following relationships were observed:

• 10 studies showed a beneficial effect of repeat vaccinations, associated with increased protection [3,5,7–15];
• 9 publications reported a negative effect, indicating a potential weakening of the immune response after subsequent doses [1,16–22];
• In 7 cases, no significant impact of repeated vaccination on effectiveness or immune response was noted [2,6,12,23–26].

DISCUSSION

From birth, humans develop a complex immunological history shaped by repeated influenza infections and vaccinations. Early influenza exposures create long-lasting immune memory, known as immunological imprinting or original antigenic sin, which can influence recognition of new viral strains [29]. In older adults, immunosenescence - thymic involution, reduced T and B lymphocytes, impaired macrophage activity, lower antibody levels, and receptor changes - diminishes both humoral and cellular vaccine responses[30]. Repeated influenza vaccinations enhance antibody titers and expand CD4+ and CD8+ memory T cells, improving long-term protection; however, they may also induce immune tolerance or "exhaustion," limiting further B cell activation and antibody maturation. Vaccine formulation, such as adjuvanted or high-dose inactivated vaccines, can slightly modulate the immune profile, but both effectively induce protective responses in older adults [31,32].

This systematic review examined the immunological effects of repeated influenza vaccination across diverse populations and study designs. The included studies reveal a complex and sometimes contradictory picture of how repeated annual vaccination influences immunoprotection.

Several studies [1,2,6,12,16–19,21,23–27] report diminished or plateauing antibody responses with repeated vaccination, especially in older adults. These effects may be attributed to immunosenescence or immune tolerance mechanisms. Conversely, other studies [5,7–15,28] demonstrate sustained or improved antibody titers, particularly in younger or immunocompetent individuals.

Repeated vaccination appears to consistently support cellular immune components, such as memory B-cells responses [5]. This suggests that even when humoral responses wane or plateau, cellular mechanisms may continue to improve, offering protection against severe disease and viral shedding.

Age, baseline immune status, and underlying health conditions (e.g., HIV, immunocompromise) significantly modulate vaccine response. Elderly individuals may show weaker responses [16,21], while children and younger adults often benefit from repeated immunization [7,12].

Few studies discuss the role of antigenic mismatch and immune imprinting in vaccine effectiveness. Ye et al. [17] and Sullivan et al. [1] highlight how previous exposures can skew immune responses, limiting effectiveness against new strains (original antigenic sin). However, Guiomar et al. [13] and Sinilaite et al. [9] show that repeated vaccination can still provide cross-protection, even with mismatched strains. Richards et al. [21] and Cowling et al. [20] suggest that factors such as age and prior immunity may influence how antigenic changes impact the immune response, emphasizing the need for adaptive vaccine strategies.

Despite immunological nuances, several studies [10,14] support the continued practice of annual vaccination, particularly in high-risk groups. While some evidence points to diminishing returns or interference effects, the broader public health benefit—especially in terms of severe disease prevention and population-level immunity remains evident.

The results obtained indicate a high level of heterogeneity in the data, which may stem from differences in study designs, populations, influenza seasons, and the vaccines used. The issue of the impact of repeated seasonal influenza vaccinations remains unresolved and requires further research, taking into account individual and population factors.

An additional limitation of this review is the absence of a formal risk of bias assessment for the included studies, which should be addressed in future research to strengthen the validity of the conclusions.

CONCLUSIONS

In conclusion, this review synthesizes recent evidence on the immunological consequences of repeated influenza vaccination across different age groups, integrating both humoral and cellular response data. While some studies report attenuated antibody responses, particularly in older adults and in the context of antigenic imprinting, the majority of findings support the continued benefit of annual vaccination, especially when tailored vaccine formulations are used. Age-specific patterns of immune modulation, the relative stability of cellular immunity, and the potential for targeted strategies such as high-dose or adjuvanted vaccines can help mitigate reduced humoral responses. Reported effects were generally small to moderate in magnitude, with limited evidence on their statistical significance and insufficient data to fully assess clinical relevance. The main limitations include heterogeneity of study designs, variable quality of included research, lack of standardized outcome measures, and absence of pooled quantitative synthesis. Future studies should incorporate robust bias assessment, longer follow-up, and standardized immunological endpoints to improve comparability and to refine vaccination strategies aimed at enhancing breadth and durability of protection.

DISCLOSURES

Authors’ contributions

ŁS and HD conceptualized the study and designed the methodology. ŁS, HD, BB, JD, OH, KK, AH, JM and MR performed the literature review and data extraction. ŁS and HD drafted the manuscript. All authors critically revised the manuscript for intellectual content and approved the final version.

Use of AI

AI tools were used to assist with language editing during manuscript preparation. The authors reviewed and approved all content.

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