Review Reports - Impact of Vaccines Across the Lifespan: A New Perspective in Public Health—Conclusions of an Expert Panel—Part 1

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Overall Assessment

The manuscript explores the role of vaccination across the lifespan, integrating concepts of immunosenescence, inflammaging, and vaccine-induced immunomodulation. The topic is timely and conceptually innovative; however, the lack of an explicit methodological framework and the occasionally expansive interpretation of evidence limit the robustness of the conclusions.

Strengths

The manuscript addresses a highly relevant and timely topic, as population aging and lifelong vaccination represent key priorities in global health and public policy. It proposes an innovative conceptual framework that extends the role of vaccines beyond pathogen-specific protection, emphasizing their potential contribution to immune fitness and healthy aging. The integration of immunological, clinical, and public health perspectives further strengthens the conceptual value of the work, while the clear and logical progression of arguments enhances the manuscript’s readability and overall coherence.

Main Limitations and Recommendations

1. Predominance of observational evidence

Broad vaccine-related benefits, such as reductions in cardiovascular events, frailty, and functional decline, are largely supported by observational studies and are at times discussed using language that may imply causal relationships. To strengthen the scientific rigor of the manuscript, the authors should more explicitly distinguish between associative and causal evidence and consider grading the strength of the available evidence.

2. Conceptual overgeneralization of immunomodulation

The manuscript portrays vaccines as broad modulators of immune aging and determinants of healthy longevity, a characterization that exceeds the strength of the current evidence. To ensure conceptual precision and scientific rigor, the authors should temper the language and clearly differentiate established clinical benefits from emerging, speculative, or hypothetical mechanisms.

3. Limited translation into public health strategies

The advocacy for lifelong vaccination policies is not sufficiently developed in terms of implementation, feasibility, or cost-effectiveness, which limits the practical applicability of the proposed framework. To strengthen the translational value of the manuscript, the authors should provide concrete policy models, implementation scenarios, or examples drawn from specific health systems.

4. All three tables should be accompanied by appropriate references.

Author Response

Part 1 – Reviewer 1 Comments and Answers

Response: Thanks for your positive comments.

However, the lack of an explicit methodological framework and the occasionally expansive interpretation of evidence limit the robustness of the conclusions.

Response: The first important point is that this is not a systematic review. However, we have now included a methodological explanation on how this review article was developed at the end of the Introduction section.

Strengths

Response: Thanks for your positive comments.

Main Limitations and Recommendations

Predominance of observational evidence

Response: We agree on that. Consequently, we have revised and extended our Limitations section considering those comments.

Conceptual overgeneralization of immunomodulation

Response: We have revised different sections of the manuscript based on such comments and improvements. We improved section 2.6. Vaccine-mediated Immunomodulation.

While increasing evidence suggests that certain vaccines may influence immune homeostasis and inflammatory pathways, it is important to emphasize that the concept of vaccine-mediated immunomodulation in aging remains heterogeneous and incompletely defined [55]. At present, only selected mechanisms and clinical effects are supported by consistent empirical data, whereas many proposed pathways, particularly those related to immune rejuvenation, long-term modulation of inflammaging, or systemic anti-aging effects, remain largely exploratory [56,57]. Consequently, vaccines should primarily be regarded as established tools for preventing infection, with potential immunomodulatory effects that are context-dependent and remain under active investigation [37,58].

We improved section 2.7. From Simple Protection to Systemic Effects.

However, although these associations are biologically plausible and supported by growing observational evidence, they should not be interpreted as definitive proof of direct systemic or anti-aging effects. Many of the reported benefits are likely mediated indirectly by preventing acute infections and their downstream complications, rather than directly through modification of aging pathways. Further randomized, mechanistic studies are required to clarify the extent to which these outcomes reflect causal immunomodulatory effects [65,66].

We also added an additional sentence to Limitations.

In addition, the conceptual framework presented in this review reflects an evolving field, and some interpretations regarding vaccine-related modulation of immune aging should be viewed as hypothesis-generating rather than definitive.

Also, we adjusted the Conclusions.

Limited translation into public health strategies

Response: We thank the reviewer for this valuable suggestion. In response, we have added a new section entitled “Related Public Health Strategies” before the Limitations section. This section outlines practical implementation models, including integration into primary care and chronic disease management, opportunistic and community-based vaccination approaches, and considerations regarding feasibility and cost-effectiveness across different health system contexts. These additions aim to strengthen the translational relevance and policy applicability of the proposed lifelong vaccination framework.

All three tables should be accompanied by appropriate references.

Response: We have included references for the tables.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript by Debagg et al. “Impact of Vaccines Across the Lifespan: A New Perspective in Public Health – Conclusions of an Expert Panel – Part 1” reviews a very relevant subject regarding immunosenescence and inflammaging and the role of vaccines in promoting healthy aging and extending longevity. The article is well written, and the information is presented in a logical and orderly manner that facilitates reader comprehension. As the authors acknowledge, some of the broader benefits of vaccination and emerging concepts, such as trained immunity and vaccine-mediated immunomodulation in older adults, are not yet established as constitutive science. Nevertheless, the inclusion of these topics is valuable, as it may encourage further research into such novel and promising areas. Overall, the manuscript conveys a positive perspective on the benefits of vaccination, highlighting that its impact may extend well beyond the traditional goal of generating immunological memory against specific pathogens.

Minor Comments

1. Table 1: The information listed under “Phenomenon” is often duplicated in the column “Origin of the phenomenon.” The authors should carefully review this table and better distinguish the phenomenon itself from its underlying causes

2. The paper cites 74 articles, which I consider to be a representative sample of the published literature. There are, however, some recent reviews on related subjects that the authors may wish to take into consideration, for example:
Falahi, S., Abdoli, A., & Kenarkoohi, A. (2025). Immune aging, immunosenescence, and inflammaging: implications for vaccine response in older adults. Health Science Reports, 8(7), e71119.
Kumar, S. J., Shukla, S., Kumar, S., Mishra, P., & Mishra Sr, P. (2024). Immunosenescence and inflamm-aging: clinical interventions and the potential for reversal of aging. Cureus, 16(1).
Nguyen, T. Q. T., & Cho, K. A. (2025). Targeting immunosenescence and inflammaging: advancing longevity research. Experimental & Molecular Medicine, 57(9), 1881-1892.

Author Response

Part 1 – Reviewer 2 Comments and Answers

Response: Thanks for your very positive comments.

Minor Comments

Table 1: The information listed under “Phenomenon” is often duplicated in the column “Origin of the phenomenon.” The authors should carefully review this table and better distinguish the phenomenon itself from its underlying causes.

Response: We thank the reviewer for this helpful observation. To improve conceptual clarity and avoid redundancy, we have revised the column headings in Table 1 to better distinguish observed immunological features from their underlying biological mechanisms and associated clinical outcomes. The table caption has also been updated accordingly.

The paper cites 74 articles, which I consider to be a representative sample of the published literature. There are, however, some recent reviews on related subjects that the authors may wish to take into consideration, for example:
Falahi, S., Abdoli, A., & Kenarkoohi, A. (2025). Immune aging, immunosenescence, and inflammaging: implications for vaccine response in older adults. Health Science Reports, 8(7), e71119.
Kumar, S. J., Shukla, S., Kumar, S., Mishra, P., & Mishra Sr, P. (2024). Immunosenescence and inflamm-aging: clinical interventions and the potential for reversal of aging. Cureus, 16(1).
Nguyen, T. Q. T., & Cho, K. A. (2025). Targeting immunosenescence and inflammaging: advancing longevity research. Experimental & Molecular Medicine, 57(9), 1881-1892.

Response: Done. We have included those references.

Reviewer 3 Report

Comments and Suggestions for Authors

The review presented by Debbag R. et al., titled "Impact of Vaccines Across the Lifespan: A New Perspective in Public Health – Conclusions of an Expert Panel – Part 1" is well written and easy to understand. The work presented as review is also a panel discussion of an ad hoc expert members during two meeting of vaccinology. The idea of publishing these discussions is original and interesting to publish as review.

The review is suitable for the special issue of Vaccine development and global health.

Review is well organized in different sections, examining the intersection of aging and immunity, as well as the potential of vaccines to address challenges. In addition, authors used 75 references that is considered small number for elaborating such review. Authors highlighted and suggested in this review that public health strategies must adopt a lifelong, flexible, and equitable approach to immunization. Overall, vaccines are essential not only for preventing infection but also for promoting functional aging and health system sustainability.

The manuscript presents a potential and important scientific information regarding the topic of vaccination and public health lifespan. However, the article needs some structural corrections before its final publication.

* Introduction section: Please remove the figure in this section and try to incorporate it in the other sections. Introduction usually does not include any figure or table.

* Figure 1 and Figure 3 and their captions: should be improved to be clearer and more significates.

* Authors should also increase the number of references as the manuscript is submitted as review. 75 references is considered a small number for a review.

* I suggest for authors to remove in the title the word "Part 1". Authors can point out that a second part of the panel discussion will be published in the future. Authors then concentrate their present manuscript just only the first point of discussion, which is intersection of aging and immunity.

Author Response

Part 1 – Reviewer 3 Comments and Answers

The review is suitable for the special issue of Vaccine development and global health.

Response: Thanks for all your positive comments.

* Introduction section: Please remove the figure in this section and try to incorporate it in the other sections. Introduction usually does not include any figure or table.

Response: We checked the styles and the guidelines of the journal, and it is perfectly fine. The figure 1 is strictly related just to the Introduction.

* Figure 1 and Figure 3 and their captions: should be improved to be clearer and more significates.

Response: Done. We significantly improved the captions of both figures.

* Authors should also increase the number of references as the manuscript is submitted as review. 75 references is considered a small number for a review.

Response: Thanks. We have now 100 references.

Response: Our part 2 has been simultaneously submitted, and as we are also in the process of answering the comments to reviewers of it, we also expect to have it simultaneously published. This is a 2-part series, so we prefer to keep the title as it.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

All recommendations and comments were duly addressed and corrected by the authors.