Effects of Respiratory Vaccines in Older Adults with Cardiovascular Diseases: A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript focuses on an clinically and epidemiological important topic - impact of respiratory vaccine on cardiovascular events.  There is growing amount of literature on the topic so there is a high value in the publication of a scoping review.  The approach in reviewing the existing literature is consistent with currently well accepted approach and follows a process for ensuring a highly valuable review of the literature.  I have categorized my comments as Major & Minor.   

MAJOR:

1) Discussion:   After going through the Methods and Results sections, I was excited to read the discussion. I was disappointed that the authors didn't better provide a more thorough amalgamation of the various publications.  There were different study designs, cohorts, how endpoints were defined, and even more unique difference between these studies.   However, in the discussion - there were limited to none of the papers cited in which the team had reviewed.  This was disappointing.  I would suggest that the authors revise the discussion section to better scope what is known, what topics are in conflicts between studies with insights as to why.   I would also suggest a more specific assessment of the gap in the literature.

2) Tables:  The tables are difficult to read and to follow.  I would suggest that the tables be placed in landscape - as the tables' columns are too narrow and hard to read.  In addition, there needs to be a consistent approach in the studies included in the tables.  For example, some of the papers are listed in the order of their reference, however it is not clear why citation 39 (Miro et al) is listed in the row after Akbar et al. (citation #40).  This also happens for citation #35 placed in a row prior to citations #33 & #34.  Further, for the cardiovascular disease column, there is no consistency in the order for how the different diseases are listed.  Sometimes it seems by the prevalence, other times it is not.  Consistency is needed.

3) The study is to examine the literature on the effects of respiratory vaccines in older adults with cardiovascular disease.  It seems there are many studies included in which the prevalence of cardiovascular disease is a minor percentage of the study population.   Are the results present only of the cohort with cardiovascular disease? Are the endpoints cited also inclusive of individuals without cardiovascular?   Clarity is needed.

MINOR:

1) How many studies were included in this scoping review?  The abstract stated 26.  In the manuscript it states 25 studies were included.  In counting the studies - it seems there are 26, but this needs to be clarified.

2) Figure 1.    Is it possible to provide additional detail on during screening why 580 studies were excluded?  Why were the 50 reports not retrieved?   Clarity is helpful for readers to understand if results are reflective of bias.

3) Line 199-200.  Clarify what the study authors mean by dual sequential vaccination.

4) Line 222.  Using this as an example.  The endpoint of ICU survivors - - was admit to ICU due to cardiovascular disease or was this ICU admit due to any reason?   This bouncing of endpoints that seem non-cardiovascular specific is not highlighted or a reason provided that the endpoints included are relevant.  Please clarify.

5) Line 274-275.  Mention that mRNA vaccines were not associated with increased risk of a number of AEs.  However, need to clarify what the comparator population was.  Is this finding of a lack in increased risk compared to recipients of other COVID-19 vaccines?

 

 

Author Response

Reviewer #1

MAJOR:

1) Discussion:   After going through the Methods and Results sections, I was excited to read the discussion. I was disappointed that the authors didn't better provide a more thorough amalgamation of the various publications.  There were different study designs, cohorts, how endpoints were defined, and even more unique difference between these studies.   However, in the discussion - there were limited to none of the papers cited in which the team had reviewed.  This was disappointing.  I would suggest that the authors revise the discussion section to better scope what is known, what topics are in conflicts between studies with insights as to why.   I would also suggest a more specific assessment of the gap in the literature.

- Dear reviewer, we have extensively expanded and revised the discussion of the included studies. We also detailed the differences in methodology, study designs, populations, and other relevant variables present in the reviewed studies. Our aim was to integrate the evidence more comprehensively, highlighting conflicts between studies and providing possible explanations for these discrepancies, as well as identifying specific gaps in the literature.

 2) Tables:  The tables are difficult to read and to follow.  I would suggest that the tables be placed in landscape - as the tables' columns are too narrow and hard to read.  In addition, there needs to be a consistent approach in the studies included in the tables.  For example, some of the papers are listed in the order of their reference, however it is not clear why citation 39 (Miro et al) is listed in the row after Akbar et al. (citation #40).  This also happens for citation #35 placed in a row prior to citations #33 & #34.  Further, for the cardiovascular disease column, there is no consistency in the order for how the different diseases are listed.  Sometimes it seems by the prevalence, other times it is not.  Consistency is needed.

- The tables have been reformatted in landscape orientation to improve readability. Although the citations originally followed the order of appearance in the manuscript rather than in the tables, we have corrected this to ensure consistent ordering within each table. In addition, cardiovascular conditions are now presented in a predefined order, providing consistency and facilitating comparisons across all tables.

3) The study is to examine the literature on the effects of respiratory vaccines in older adults with cardiovascular disease.  It seems there are many studies included in which the prevalence of cardiovascular disease is a minor percentage of the study population.   Are the results present only of the cohort with cardiovascular disease? Are the endpoints cited also inclusive of individuals without cardiovascular?   Clarity is needed.

- In this scoping review, our primary focus was older adults with cardiovascular disease (CVD). Whenever possible, we specifically identified and analyzed data corresponding to participants with cardiovascular disease within each study. However, as this is a scoping review, we also reported the total study population, including both vaccinated and unvaccinated individuals, to provide a comprehensive overview of the available evidence. Data specific to patients with cardiovascular disease are presented separately in the tables corresponding to each vaccine type. Nevertheless, in several included studies, the exact number of participants with CVD or outcomes stratified by this condition were not explicitly reported, limiting our ability to isolate results exclusively for this population. We acknowledge that a more precise quantification of effects restricted to older adults with CVD would require studies with stratified analyses or a meta-analysis by vaccine type, which exceeds the scope of this scoping review. This point has been explicitly included in the limitations section (5th limitation).

MINOR:

1) How many studies were included in this scoping review?  The abstract stated 26.  In the manuscript it states 25 studies were included.  In counting the studies - it seems there are 26, but this needs to be clarified.

- Thank you for this valuable observation. After review, we confirm that the total number of included studies is 25. The study by Miró et al. [39] reports information on both influenza and COVID-19 vaccines.

2) Figure 1.    Is it possible to provide additional detail on during screening why 580 studies were excluded?  Why were the 50 reports not retrieved?   Clarity is helpful for readers to understand if results are reflective of bias.

- The reasons for exclusion have been detailed in section 3.1 (Study Selection). The 580 studies were removed during the title and abstract screening for reporting outcomes different from those of interest. The remaining 50 studies were excluded after full-text evaluation.

3) Line 199-200.  Clarify what the study authors mean by dual sequential vaccination.

- Thank you for your observation. A definition has been added in the discussion: “The study by Tong et al. [21] demonstrated that dual sequential pneumococcal vaccination, defined as an immunization strategy that administers two different vaccines at separate time points to maximize protection, is associated with a lower risk of cardiovascular events.”

4) Line 222.  Using this as an example.  The endpoint of ICU survivors - - was admit to ICU due to cardiovascular disease or was this ICU admit due to any reason?   This bouncing of endpoints that seem non-cardiovascular specific is not highlighted or a reason provided that the endpoints included are relevant.  Please clarify.

- Dear reviewer, the patients analyzed were ICU survivors admitted for various reasons, not necessarily cardiovascular-related, according to the inclusion criteria of the original study (Christiansen et al. [26], Danish Intensive Care Database). This point has been clarified in the qualitative description of the findings in the Results section.

5) Line 274-275.  Mention that mRNA vaccines were not associated with increased risk of a number of AEs.  However, need to clarify what the comparator population was.  Is this finding of a lack in increased risk compared to recipients of other COVID-19 vaccines?

- It has been specified that the studies compared two cohorts: patients with heart failure who were vaccinated versus unvaccinated, clarifying that the safety findings refer to this comparison.

Reviewer 2 Report

Comments and Suggestions for Authors

This scoping review synthesizes evidence from 26 studies on the effects of respiratory vaccines in over 1.7 million adults aged ≥60 with cardiovascular disease (CVD). It finds that vaccination against RSV, pneumococcus, influenza, and COVID-19 offers significant cardiovascular benefits beyond infection prevention. RSV vaccines were linked to fewer cardiorespiratory hospitalizations and strokes. Sequential pneumococcal vaccination was associated with a lower risk of cardiovascular events. Influenza vaccination consistently reduced mortality, hospitalizations, and major adverse cardiovascular events. COVID-19 vaccines showed dose-dependent reductions in mortality and hospitalizations with a favorable safety profile. The review concludes that respiratory vaccinations are a safe and effective strategy for improving clinical outcomes in older adults with CVD.

I have several concerns that need clarification and improvements:

1. The manuscript states the final literature search was conducted on "January 11, 2026," and the protocol was registered on the same future date. This is chronologically impossible. Please explain this discrepancy and provide the actual, correct dates for the literature search and protocol registration.

2. Please verify that all dates throughout the manuscript, including study periods and follow-up times, are accurate and have been thoroughly checked.

3. There is an inconsistency in the number of studies reported. The abstract mentions 26 studies, the text initially states 25 studies were included, but the sum of studies described per vaccine (2 RSV + 1 Pneumococcal + 18 Influenza + 5 COVID-19) totals 26. Please clarify the exact final number of studies included in this review.

4. Table 5 (Page 12) is titled "Characteristics and effects of Influenza Vaccines in older adults," but the content clearly refers to COVID-19 studies. Please correct this title accordingly.

5. The data columns in Table 1 (Page 6) are misaligned, making the results difficult to interpret. Please reformat this table for clarity.

6. The results section (Page 12) mentions that the study by Miró et al. [39] found an association between COVID-19 vaccination and "an increase in hospitalizations," yet also reports lower in-hospital mortality. The discussion (Page 17) mentions this "heterogeneity of results" but does not critically analyze it. Please provide a more in-depth discussion of this and any other contradictory findings. What factors (e.g., study design, patient characteristics, definitions of outcomes) might explain these discrepancies?

Author Response

Reviewer #2

1. The manuscript states the final literature search was conducted on "January 11, 2026," and the protocol was registered on the same future date. This is chronologically impossible. Please explain this discrepancy and provide the actual, correct dates for the literature search and protocol registration.

- Dear Reviewer, thank you for your valuable observation. The protocol registration date is correct and was completed on January 11, 2026. However, the final literature search was conducted through February 11, 2026. This discrepancy was due to a drafting error, which has now been corrected in the revised version of the manuscript.

2. Please verify that all dates throughout the manuscript, including study periods and follow-up times, are accurate and have been thoroughly checked.

- Thank you for this observation. All dates throughout the manuscript, including study periods and follow-up times, have been carefully reviewed and corrected where necessary. Additionally, to improve consistency and clarity across tables, follow-up data have been standardized by reporting only the duration in years for each study.

3. There is an inconsistency in the number of studies reported. The abstract mentions 26 studies, the text initially states 25 studies were included, but the sum of studies described per vaccine (2 RSV + 1 Pneumococcal + 18 Influenza + 5 COVID-19) totals 26. Please clarify the exact final number of studies included in this review.

- Thank you for your observation. This inconsistency resulted from a drafting error. The final number of included studies is 25. Although 26 studies were initially counted, the study by Miró et al. [39] reports results for two vaccine types (influenza and COVID-19), which led to double counting. This issue has been corrected and clarified in the manuscript.

4. Table 5 (Page 12) is titled "Characteristics and effects of Influenza Vaccines in older adults," but the content clearly refers to COVID-19 studies. Please correct this title accordingly.

- Thank you for your observation. The title of Table 5 has been revised to accurately reflect its content.

5. The data columns in Table 1 (Page 6) are misaligned, making the results difficult to interpret. Please reformat this table for clarity.

- Thank you for your observation. Table 1 and 2 has been reformatted to improve column alignment and enhance the clarity and interpretability of the data.

6. The results section (Page 12) mentions that the study by Miró et al. [39] found an association between COVID-19 vaccination and "an increase in hospitalizations," yet also reports lower in-hospital mortality. The discussion (Page 17) mentions this "heterogeneity of results" but does not critically analyze it. Please provide a more in-depth discussion of this and any other contradictory findings. What factors (e.g., study design, patient characteristics, definitions of outcomes) might explain these discrepancies?

- Thank you for your comment. A detailed review of the study by Miró et al. [39] was conducted, and an additional paragraph has been incorporated into the Discussion section (page 18) to provide a more in-depth analysis of these apparently contradictory findings. This analysis considers potential explanatory factors, including differences in study design, patient characteristics, indication bias, and variability in outcome definitions, particularly regarding hospitalizations.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I’m comfortable with the author’s revisions and have nothing further to add.