Dear Dr. Fournais,

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Kind regards,

Ahmad Khalid Aalemi, M.D., M.Sc., Ph.D.

Academic Editor

PLOS ONE

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Additional Editor Comments :

Dear Louise,

Please revise your manuscript based on the reviewer comments.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: As written, the introduction does not provide an adequate argument for the need for the study. The background should be very strong to persuade the reader. Need more references for citing in the discussion. The language of the article will become even better and more understandable with the revision.

Reviewer #2: Review the information between lines 311 to 315, there is some extra spaces and the information could be adjusted to stay in the same paragraph.

The manuscript is easy to read and the information is clear. I would suggest make the figures bigger, except the figure 1, and colorful to make the differences or not more visible.

Reviewer #3: Overall Assessment

This manuscript presents a systematic review and meta-analysis assessing the hypothesis that standard-titre measles vaccines (STMV) have beneficial non-specific effects on mortality and morbidity. The study follows PRISMA guidelines and includes Trial Sequential Analysis (TSA) to ensure robustness. The authors conclude that their meta-analysis of randomized controlled trials (RCTs) does not support the hypothesis of non-specific effects of STMV, while historical high-titre measles vaccines (HTMV) were associated with increased female mortality.

The manuscript is well-structured, follows rigorous methodological standards, and provides a valuable contribution to the ongoing discussion about the non-specific effects of vaccines. However, there are areas where improvements could be made, particularly in the depth of discussion, clarity in statistical reporting, and consideration of potential limitations.

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Major Strengths

1. Rigorous Methodology and Meta-Analysis Approach

• The study adheres to PRISMA guidelines and follows Cochrane Handbook recommendations for systematic reviews.

• The use of TSA is a significant strength, ensuring that conclusions are drawn from an adequate amount of data.

• Inclusion criteria were stringent, only considering RCTs, which minimizes bias from observational studies.

2. Comprehensive Literature Review

• The authors conducted a systematic search in major databases (EMBASE and PubMed) and repeated it weekly for nearly a year.

• The screening process involved independent reviewers with a clear conflict-resolution strategy.

3. Robust Statistical Analysis

• Meta-analysis includes both fixed and random effects models, which appropriately account for heterogeneity.

• TSA provides a higher level of confidence in the conclusions by assessing whether sufficient data exist to confirm or reject the hypothesis.

• Sex-stratified analyses enhance the understanding of differential effects.

⸻

Major Weaknesses and Areas for Improvement

1. Interpretation of Findings

• The authors state that their meta-analysis “did not support the hypothesis of non-specific effects of STMV.” However, the confidence intervals in several analyses are wide, and the rejection of a 25% or 33% risk reduction does not rule out smaller potential benefits.

• The authors could discuss the implications of their findings in the context of potential smaller effects that might be clinically relevant but undetectable within the current dataset.

2. Statistical Considerations

• The TSA was performed using a predefined 25% RRR, but this threshold is somewhat arbitrary. The authors should justify why this specific reduction was chosen.

• While TSA helps assess whether sufficient data have been collected, some meta-analyses still showed confidence intervals that include potential small effects. This should be discussed more explicitly.

3. Discussion on Potential Biases

• While RCTs are considered the highest level of evidence, there are limitations:

• Many trials had substantial loss to follow-up, which can introduce attrition bias.

• The lack of blinding in many trials could have influenced results, particularly for morbidity outcomes where subjective reporting may be involved.

• Heterogeneity among studies, particularly regarding intervention timing and population characteristics, could have affected outcomes. This heterogeneity should be explored more thoroughly in the discussion.

4. Consideration of Alternative Explanations

• Some prior observational studies have reported non-specific effects of measles vaccines, whereas this meta-analysis does not find such effects in RCTs. The authors should explore why observational studies might have produced different results (e.g., confounding, healthy vaccinee bias).

• The review does not consider potential age-related immune system differences that might influence vaccine effects. Could earlier vaccination (before 9 months) have an impact that was not captured in the TSA?

⸻

Minor Issues and Suggestions

1. Clarity in Presentation

• Some of the statistical results in the text could be more clearly presented. For example, rather than just stating “TSA showed that enough data was collected to conclusively reject the hypothesis,” the authors should specify the exact thresholds and explain them in a more intuitive manner.

• Figures and tables should be better integrated into the discussion. The manuscript refers to supplementary figures often, but some key findings should be highlighted directly in the main text.

2. Ethical Considerations

• The manuscript states that ethical approval was not needed. However, it would be useful to briefly explain why, especially since some of the included studies involved human participants.

3. Formatting and Writing Style

• The manuscript is generally well-written, but some sentences are long and difficult to follow. Simplifying complex statements and breaking them into smaller sentences would improve readability.

⸻

Conclusion and Recommendation

This manuscript presents a well-executed systematic review and meta-analysis that rigorously evaluates the hypothesis of non-specific effects of measles vaccines. While the findings do not support a strong beneficial effect of STMV, the discussion could be improved by acknowledging the potential for smaller effects, addressing study limitations in more depth, and better justifying statistical choices.

Reviewer #4: This is a clearly written systematic review and meta-analysis of randomised controlled trials with both standard titre and high titre live attenuated measles containing vaccines as intervention and other vaccines or placebo as comparator. The primary outcomes were mortality and morbidity Other secondary outcomes were examined as well. The analysis was interesting in that the authors added the Trial Sequential Analysis (TSA) approach having some advantageous features which was explained in the supplement.

The systematic review was routine and well done in that the investigators used PRISMA and PROSPERO. The studies included were only RCT’s . The approach to the Systematic search and screening and Quality assessment, resolution of reviewer differences as well as data extraction were explained adequately. Risk of bias assessment and other such features were reasonably outlined in the supplemental material. Obviously, publication bias was not discussed as the number of articles was perhaps inadequate for such. This should be made known to the reader.

Analysis was presented with Forest plots and the usual efficacy and heterogeneity type statistics were included.

The analysis appeared to confirm that the present review and meta-analysis did not support the hypothesized beneficial non-specific effects of STMV and found the historical HTMV to be possibly associated with increased female mortality.

There are some minor statistical concerns. The limitations are adequately noted by the investigators . However, they should mention to the reader, as noted above, why the lack of publication bias discussion, unless this reviewer missed it. Also, they should note the small number of articles in Figures S9 and S11 prompting one to interpret any p-values with caution. Also, any discussion would be helpful of heterogeneity or other causes of unusually wide confidence bands on any of the Forest plots both in the manuscript and supplement.

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: Yes:  DR. YAHYA H. Y. ALFARRA, BDS (Hons), MSc, PhD

Reviewer #2: No

Reviewer #3: Yes:  Mohamed Samy Abousenna

Reviewer #4: No

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Measles vaccines and non-specific effects on mortality or morbidity. A systematic review and meta-analysis.

PONE-D-24-29586R1

Dear Dr. Louis Amstrup Fournis,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ahmad Khalid Aalemi, M.D., M.Sc., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: (No Response)

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: (No Response)

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: (No Response)

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Reviewer #2: (No Response)

Reviewer #3: Thank you for your thoughtful and thorough revision of the manuscript titled "Measles vaccines and nonspecific effects on mortality or morbidity. A systematic review and meta-analysis." I appreciate the effort you made to address each of the points raised during the initial review.

Reviewer #4: (No Response)

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #2: No

Reviewer #3: Yes:  Mohamed Samy Abousenna

Reviewer #4: No

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