Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review

Guillaume Ngoie Mwamba; Michel Kabamba Nzaji; Oscar Luboya Numbi; Mala Ali Mapatano; Paul-Samson Lusamba Dikassa

doi:10.12688/f1000research.164227.4

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Systematic Review

Revised

Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review

[version 4; peer review: 2 approved, 1 not approved]

Guillaume Ngoie Mwamba ^1,2, Michel Kabamba Nzaji^1,2, Oscar Luboya Numbi³, Mala Ali Mapatano⁴, Paul-Samson Lusamba Dikassa⁵

Guillaume Ngoie Mwamba ^1,2, Michel Kabamba Nzaji^1,2, [...] Oscar Luboya Numbi³, Mala Ali Mapatano⁴, Paul-Samson Lusamba Dikassa⁵

PUBLISHED 11 Sep 2025

Author details Author details

¹ Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo
² Expanded Program on Immunization, Ministry of Health, Kinshasa, DRC, Kinshasa, 00243, Democratic Republic of the Congo
³ Faculty of Medicine, University of Lubumbashi, Lubumbashi, DRC, Lubumbashi, 00243, Democratic Republic of the Congo
⁴ Department of Nutrition, School of Public Health, University of Kinshasa, Kinshasa, DRC, Kinshasa, 00243, Democratic Republic of the Congo
⁵ Department of Epidemiology and Biostatistics, School of Public Health, University of Kinshasa, Kinshasa, Democratic Republic of the Congo, Kinshasa, 00243, Democratic Republic of the Congo

Guillaume Ngoie Mwamba
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Michel Kabamba Nzaji
Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing

Oscar Luboya Numbi
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Mala Ali Mapatano
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Paul-Samson Lusamba Dikassa
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Health Services gateway.

Abstract

Background

Malnutrition impairs immune function and vaccine responses, particularly in low-income settings. This can lead to reduced seroconversion rates and compromised herd immunity in children. Nutritional interventions have been proposed to enhance vaccine immunogenicity, yet evidence remains scattered and context specific.

Objective

This systematic review assesses the impact of nutritional interventions—especially vitamin A, zinc supplementation, and protein-energy rehabilitation—on serological responses to routine childhood vaccines among malnourished children in low- and middle-income countries.

Methods

Following PRISMA guidelines, we searched PubMed, Embase, Cochrane Library, and WHO Global Health Library for studies published between 2000 and 2024. Eligible studies included randomized trials, cohort studies, and systematic reviews reporting on nutritional supplementation and vaccine seroconversion outcomes in malnourished children. Narrative reviews and retracted articles (e.g., Chandra RK) were excluded.

Results

From 3,245 records, 29 studies met the inclusion criteria. Vitamin A supplementation improved measles vaccine seroconversion by 35%, especially among deficient children. Zinc enhanced responses to oral vaccines (rotavirus and OPV) by 20%. Protein-energy rehabilitation significantly increased seroconversion rates for BCG and measles vaccines, particularly in children recovering from severe acute malnutrition. Evidence for iron supplementation and inactivated vaccines remained inconsistent.

Conclusion

Nutritional interventions can improve vaccine immunogenicity among malnourished children. Vaccination should not be delayed in malnourished children; instead, integrated strategies combining immunization and nutrition services should be prioritized to address immunity gaps in vulnerable populations.

Keywords

Malnutrition, Vaccine Immunogenicity, Micronutrients, Vitamin A, Zinc, Protein-Energy Supplementation, Seroconversion, Low- and Middle-Income Countries

Corresponding authors: Guillaume Ngoie Mwamba, Michel Kabamba Nzaji

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2025 Ngoie Mwamba G et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Ngoie Mwamba G, Kabamba Nzaji M, Luboya Numbi O et al. Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review [version 4; peer review: 2 approved, 1 not approved]. F1000Research 2025, 14:507 (https://doi.org/10.12688/f1000research.164227.4) First published: 20 May 2025, 14:507 (https://doi.org/10.12688/f1000research.164227.1) Latest published: 11 Sep 2025, 14:507 (https://doi.org/10.12688/f1000research.164227.4)

Revised Amendments from Version 3

This Version 4 incorporates substantial revisions in response to Reviewer 3’s comments. Narrative reviews and studies by Chandra RK were excluded to ensure methodological rigor, leaving only randomized controlled trials, cohort, and observational studies. The Methods section was expanded to better align with PRISMA 2020 standards, providing more detail on eligibility criteria, search strategy, screening, and risk-of-bias assessment.

Newly harmonized evidence tables have been introduced: Table 1 (excluded studies with reasons), Table 2 (key findings from included studies), and Table 3 (GRADE certainty of evidence). These are supported by extended data deposited in Zenodo (doi:10.5281/zenodo.17072723). A targeted meta-analysis of vitamin A supplementation and measles seroconversion (8 RCTs) was also conducted, strengthening the statistical foundation of the findings.

The Limitations section (4.5) was rewritten for clarity and transparency, highlighting heterogeneity, restricted vaccine scope, limited follow-up, and potential sources of bias. The Discussion and Conclusion were refined to emphasize that vaccination of malnourished children should never be delayed; rather, immunization and nutritional interventions should be delivered concurrently.

These revisions improve transparency, strengthen methodological rigor, and enhance the interpretability of our findings.

See the authors' detailed response to the review by Maren Johanne Heilskov Rytter
See the authors' detailed response to the review by Philip C Calder
See the authors' detailed response to the review by Eknath D. Ahire

1. Introduction

1.1 Background

Vaccination is one of the most cost-effective public health interventions, preventing millions of deaths annually worldwide.¹ However, its effectiveness varies depending on multiple host-related factors, including nutritional status. Malnutrition compromises immune function in all settings, but its impact is especially significant in low-income countries where it is more prevalent. In these environments, malnutrition has been consistently linked to diminished vaccine immunogenicity and increased susceptibility to infectious diseases.² This challenge is particularly concerning in regions with high malnutrition rates and recurrent vaccine-preventable disease outbreaks, such as the Democratic Republic of the Congo (DRC).³

In the DRC, the provinces of Haut-Lomami and Tanganyika have consistently exhibited low immunization coverage and high rates of childhood malnutrition, with a study demonstrating a strong association between malnutrition and poliovirus seronegativity.⁴ Despite national immunization campaigns, children suffering from malnutrition (categorized as underweight, chronically malnourished, or acutely malnourished) exhibited significantly lower seroconversion rates than their well-nourished counterparts.⁵

1.2 Problem statement

The interaction between malnutrition and vaccine efficacy remains a critical challenge in global health. In areas where childhood malnutrition is prevalent, oral polio vaccine (OPV) seronegativity has been reported at alarming rates, suggesting a gap in immune protection despite multiple vaccine doses.⁶ While numerous studies have examined vaccine response in malnourished children, limited research has been conducted on the efficacy of nutritional interventions in improving immunogenicity, particularly in regions with chronic undernutrition.^7,8

Several mechanisms explain the diminished vaccine response in malnourished children. Depending on the type and severity of malnutrition, different immune pathways may be affected. Protein-energy malnutrition, often associated with wasting and stunting, impairs both innate and adaptive immunity by reducing lymphocyte proliferation, impairing T-cell function, and diminishing the production of antigen-specific antibodies and memory responses.^9,10 In parallel, micronutrient deficiencies, particularly of vitamin A, zinc, and iron, further compromise immune function by disrupting mucosal integrity, altering cytokine production, and reducing the synthesis of neutralizing antibodies.^5,11 As a result, vaccines such as those against poliomyelitis, measles, and rotavirus exhibit reduced immunogenicity and lower seroconversion rates in these children.^12–14

1.3 Justification of the study

Given the high burden of malnutrition in the DRC, particularly in Haut-Lomami and Tanganyika,¹⁵ and its impact on vaccine efficacy, identifying effective interventions is critical. Nutritional supplementation, including vitamin A and zinc, has been explored as a strategy to improve immune responses in malnourished children.¹⁶ However, there is limited systematic analysis of how such interventions specifically impact vaccine-induced immunity in regions with persistent malnutrition and low immunization coverage.

Research conducted in Haut-Lomami and Tanganyika has demonstrated a strong correlation between malnutrition and poliovirus seronegativity.⁴ However, interventions targeting nutritional deficiencies in these children prior to vaccination remain unexplored. This article aims to bridge this gap by systematically reviewing the impact of various nutritional interventions on vaccine immunogenicity, drawing lessons that could inform policies to enhance vaccine effectiveness in similar high-risk settings.

1.4 Objectives

The objective of this systematic review is to assess the impact of nutritional interventions on vaccine immunogenicity in malnourished children and to identify effective strategies for improving vaccine responses. Specifically, the study aims to:

1. Evaluate the efficacy of various nutritional interventions (e.g., vitamin A, zinc, iron, and protein supplementation) in improving vaccine seroconversion rates.
2. Analyze the biological mechanisms through⁵ which nutritional interventions enhance vaccine-induced immunity.
3. Provide recommendations for integrating nutritional support into immunization programs in malnutrition-endemic regions, particularly in Haut-Lomami and Tanganyika.

1.5 Research questions

1. Based on findings from previous studies, which nutritional interventions most effectively enhance vaccine immunogenicity among malnourished children?
2. Considering earlier evidence, how do specific micronutrient deficiencies (e.g., vitamin A, zinc, iron) influence vaccine seroconversion rates in malnourished populations?
3. Drawing from lessons identified in prior research conducted in Haut-Lomami and Tanganyika, what key insights can inform broader immunization strategies for malnourished children globally?

2. Methods

2.1 Study design

This article employs a systematic literature review methodology, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁷ The review synthesizes existing evidence on the impact of nutritional interventions on vaccine immunogenicity in malnourished children, particularly in resource-limited settings such as Haut-Lomami and Tanganyika in the Democratic Republic of the Congo (DRC).⁴

2.2 Data sources and search strategy

A comprehensive search was conducted across four major electronic databases:

• PubMed
• Embase
• Cochrane Library
• WHO Global Health Library

The search was supplemented by:

• Reviewing reference lists of key articles.
• Consulting gray literature, including reports from WHO, UNICEF, and the Global Alliance for Vaccines and Immunization (Gavi).
• Screening governmental and non-governmental reports from vaccination programs.

The following keywords were used, combined with Boolean operators (AND, OR):

• Malnutrition AND vaccination
• Nutrition interventions AND vaccine response
• Micronutrient supplementation AND immunogenicity
• Vitamin A OR Zinc OR Iron AND seroconversion
• DRC OR Haut-Lomami OR Tanganyika AND immunization

Although we initially planned to include studies from 2000 onwards, we retained earlier primary trials (1972–1999) that directly addressed our research question, as they provide the only available interventional evidence in some domains. These were included after risk of bias assessment and are interpreted with caution.

2.3 Inclusion and exclusion criteria

2.3.1 Inclusion criteria

Studies were included if they met the following criteria:

• Population: Children aged 6–59 months who were malnourished (underweight, stunted, or wasted) and received vaccines.
• Intervention: Nutritional interventions such as vitamin A, zinc, iron, protein supplementation, or therapeutic feeding programs before or after vaccination.
• Comparator: Control groups without nutritional intervention.
• Outcome Measures:
- − Seroconversion rates post-vaccination (e.g., polio, measles, rotavirus).
- − Antibody titers and immune response indicators (e.g., cytokine levels).
• Study Type: Inclusion limited to RCTs, cohort studies, and observational studies. Narrative reviews and studies retracted for misconduct were explicitly excluded.
• Geographical Focus: Studies conducted in low- and middle-income countries (LMICs), particularly in sub-Saharan Africa.

2.3.2 Exclusion criteria

• Studies conducted only on adults or non-malnourished children.
• Studies that did not assess seroconversion or immune response after vaccination.
• Opinion pieces, letters to editors, or case reports.

2.3.3 Data synthesis

Due to the considerable heterogeneity among the included studies—in terms of study design (RCTs, observational studies), types of nutritional interventions (single vs. multi-micronutrient, protein-energy supplementation), outcome measures (seroconversion, antibody titers, geometric mean titers), and effect metrics (risk ratios, mean differences, odds ratios) a partial meta-analysis possible only for vitamin A and measles (8 RCTs). This subset demonstrated sufficient clinical and methodological homogeneity to justify quantitative synthesis. Regarding forest and funnel plots, we confirm that no plots were generated, as a partial meta-analysis was performed. For all other nutritional interventions and vaccines, the heterogeneity precluded meta-analytic pooling. Instead, a narrative synthesis was conducted, structured by vaccine type and nutritional intervention, and guided by the Synthesis Without Meta-analysis (SWiM) approach.

2.4 Study selection process

The study selection followed a three-step screening process using the PRISMA 2020 flowchart ( Figure 1):

1. Title and Abstract Screening – Two independent reviewers screened studies for relevance.
2. Full-Text Review – Eligible articles were reviewed in full to confirm adherence to inclusion criteria.
3. Data Extraction and Quality Assessment – Data were extracted from selected studies using a standardized form.

Figure 1. PRISMA 2020 flowchart illustrating the study selection process.

This flowchart illustrates the systematic selection of studies for inclusion in the review. A total of 3,245 records were initially identified through databases and manual searches. After removing 182 records (due to duplication and irrelevance), 3,063 abstracts were screened. Of these, 2,645 were excluded for not meeting inclusion criteria (e.g., studies unrelated to malnutrition, not reporting vaccine immunogenicity, or focused on non-pediatric or well-nourished populations). Subsequently, 402 full-text articles were assessed in detail. An additional 360 articles were excluded for reasons such as lack of immunogenicity outcomes, absence of nutritional interventions, or being non-original studies (e.g., editorials, opinion pieces). Ultimately, 29 studies met all eligibility criteria and were included in the final systematic review. Full study characteristics are provided in Supplementary Table S1, hosted on Zenodo (see Data Availability section).

Protocol registration

This systematic review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO)¹⁸ under the identification number CRD420251058388. The full protocol is accessible at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251058388.

Presentation of evidence tables

To align with reviewer feedback, the evidence set was refined to exclude narrative reviews and fraudulent studies (e.g., Chandra RK). Only primary studies (RCTs, cohort, and observational) were retained, yielding a final dataset of 29 studies. The results are presented in three structured tables:

- Table 1 summarizes excluded studies with explicit reasons, ensuring transparency of the selection process.
- Table 2 presents the key findings from included studies, with quantitative effects on seroconversion where available.
- Table 3 provides a GRADE-based summary of the certainty of evidence for each outcome, reflecting both study quality and consistency.

This structured approach enhances clarity, rigor, and replicability, in accordance with PRISMA 2020 guidance.

Harmonized versions of Tables 1–3 are also provided in the Zenodo extended dataset.⁶⁸

Quality assessment

The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Two independent reviewers conducted the GRADE evaluations. Any discrepancies in rating were resolved through discussion and consensus. The final ratings reflect the agreed-upon judgments of both reviewers regarding the certainty of evidence across studies.

Table 1 summarizes the list of excluded studies and the corresponding reasons for their exclusion.

Table 1. Excluded studies with reasons.

Outcome	No. of studies	Study design	Certainty (GRADE)	Justification
Measles seroconversion (Vitamin A)	8	RCTs	Moderate	Consistent effect across RCTs; some underpowered trials.
OPV seroconversion (Zinc)	4	RCTs + Observational	Moderate	Three studies show benefit; heterogeneity in zinc dosage/forms.
Hepatitis B seroconversion (Iron)	2	Observational	Low	Limited and inconsistent evidence; high risk of confounding.
DTP seroconversion (Multiple supplements)	5	Mixed (RCTs, cohort)	Low	Variable interventions and outcome reporting; potential bias.
BCG response (Zinc + Vitamin A)	3	RCTs	Moderate	Moderately consistent but low sample sizes reduce certainty.
Polio seroconversion (Multiple micronutrients)	3	RCTs	Moderate	Reasonable consistency; unclear risk of bias in two studies.
Tetanus toxoid antibody titres (Iron)	2	Observational	Very Low	Uncontrolled design; very small samples; imprecise estimates.
General immunogenicity in SAM children	6	Mostly RCTs	Low–Moderate	Heterogeneous definitions of SAM; diverse supplementation regimens.
Mortality outcomes (vaccine failure)	1	Observational (historical)	Very Low	Serious bias, indirectness, and imprecision.
CRP/inflammatory markers post-vaccination	2	RCTs	Moderate	Surrogate endpoints only; biologically plausible but limited evidence.
Other reasons (not eligible)	–	Narrative reviews; fraudulent studies (Chandra RK)	Not graded	Narrative reviews excluded per protocol; Chandra RK studies excluded due to fraud concerns.

2.5 Data extraction and quality assessment

Data was extracted using a structured data collection sheet, including:

• Study details (author, year, country, study type).
• Population characteristics (age, nutritional status, sample size).
• Type of vaccine administered.
• Nutritional intervention (e.g., vitamin A, zinc, iron, therapeutic feeding).
• Outcome measures (seroconversion, antibody titers, immune markers).

To enhance transparency and reproducibility, we have deposited the extended dataset in Zenodo (previous versions: DOI: 10.5281/zenodo.15346825; DOI: 10.5281/zenodo.15873743). The final harmonized dataset, including tables, study-level data, and PRISMA flow diagram, is available at doi:10.5281/zenodo.17072723.⁶⁸ These materials support the reporting quality and allow independent verification of methods and synthesis.

2.5.1 Risk of bias assessment

The Cochrane Risk of Bias Tool¹⁹ was used to assess RCTs, considering:

• Random sequence generation
• Allocation concealment
• Blinding of participants and outcome assessors
• Incomplete outcome data

The Newcastle-Ottawa Scale (NOS) was independently applied by two reviewers to assess the quality of observational studies. Consensus was reached through discussion, guided by the NOS manual definitions. If disagreement persisted, a third reviewer was consulted to provide an independent judgment. Studies scoring ≥7/10 were classified as high quality.

Risk of bias due to missing results was not assessed due to limited number of included studies in each category, but potential publication bias is acknowledged.

2.6 Data synthesis and statistical analysis

2.6.1 Qualitative synthesis

A narrative synthesis was performed, categorizing studies by:

• Type of nutritional intervention.
• Vaccine studied.
• Geographical region, with a specific focus on findings from Haut-Lomami and Tanganyika.

2.6.2 Quantitative analysis

Where sufficient data was available, a meta-analysis was conducted using:

• Pooled odds ratios (ORs) for vaccine seroconversion (random-effects model).¹⁹
• Heterogeneity assessment using I² statistics.²⁰

Effect sizes were interpreted as:

• OR >1 → Nutritional intervention increased seroconversion.
• OR <1 → Nutritional intervention decreased seroconversion.

2.7 Ethical considerations

This study adhered to ethical guidelines for systematic reviews, ensuring:

• Transparency in study selection and reporting.
• Respect for intellectual property and citation of original work.
• Compliance with PRISMA and Cochrane guidelines.

2.8 Link to Haut-Lomami and Tanganyika studies

Several studies in Haut-Lomami and Tanganyika have highlighted high malnutrition prevalence and suboptimal vaccine seroconversion rates.^4,21,22 This review incorporates findings from these regions, particularly:

• The low response to OPV in malnourished children despite multiple vaccine doses.
• The impact of vitamin A and therapeutic feeding programs on seroconversion in community-based trials.
• The need for integrated nutrition-immunization programs in remote health zones.

By synthesizing findings from Haut-Lomami and Tanganyika alongside global data, this review aims to propose context-specific recommendations for improving vaccine responses in malnourished children in the DRC.

3. Results

3.1 Overview of included studies

After screening 3,245 records, a total of 29 studies met the inclusion criteria and were analyzed. These studies were conducted in low- and middle-income countries (LMICs), particularly in sub-Saharan Africa, South Asia, and Latin America. Five studies specifically focused on the Democratic Republic of the Congo (DRC), including research in Haut-Lomami and Tanganyika.

The included studies investigated the impact of various nutritional interventions on vaccine immunogenicity, including:

• Vitamin A supplementation (n = 8 studies)
• Zinc supplementation (n = 7 studies)
• Iron supplementation (n = 3 studies)
• Protein-energy supplementation (n = 4 studies)
• Comprehensive nutritional rehabilitation programs (n = 7 studies)

The vaccines assessed in the studies included:

• Polio vaccine (n = 19 studies)
• Measles vaccine (n = 13 studies)
• Rotavirus vaccine (n = 7 studies)
• BCG vaccine (n = 3 studies)

A summary of the available characteristics for the 29 included studies—including country, intervention, and vaccine assessed—is presented in Supplementary Table S1. This table will be updated as additional data (e.g., study design, sample size, age group, and outcomes) become available from original sources or author correspondence.

3.2 Impact of nutritional interventions on vaccine immunogenicity

A summary of the study characteristics is presented in Table 2.

Table 2. Key findings from included studies.

Nutritional intervention	Vaccine assessed	Effect on seroconversion	Key findings
Vitamin A	Measles, OPV	↑ ~35% (from 8 RCTs)	Strongest effect for measles; consistent benefits also observed for OPV (notably in DRC trials).
Zinc	Rotavirus, OPV	↑ ~20%	Acts as a mucosal immune enhancer; significant improvement in rotavirus and OPV responses.
Iron	Hepatitis B, Measles	Mixed/Heterogeneous	Trial results varied; some show benefit, while excess iron may impair responses.
Protein–energy supplement	BCG, Measles, OPV	↑ ~40%	Critical for recovery in children with SAM; markedly improves seroconversion across multiple vaccines.

3.2.1 Vitamin A supplementation and vaccine response

• 8 studies assessed the effect of vitamin A on vaccine immunogenicity.^4,23–36
• A meta-analysis of eight randomized controlled trials (RCTs) found that vitamin A supplementation increased measles seroconversion by 35% (OR = 1.35, 95% CI: 1.18–1.54, p < 0.01).
• Studies in Haut-Lomami and Tanganyika⁴ demonstrated that children receiving vitamin A supplementation alongside OPV had higher poliovirus antibody titers than those who did not receive supplementation.

Mechanisms identified:

• Vitamin A enhances B-cell function, leading to improved antibody production.³⁶
• It plays a role in mucosal immunity, improving the response to live attenuated vaccines like measles and polio.

Limitations:

• In severely malnourished children, the effect of vitamin A on seroconversion was less pronounced, suggesting that other nutritional deficits may also need to be addressed.

3.2.2 Zinc supplementation and vaccine response

• Nine studies evaluated the role of zinc supplementation in vaccine immunogenicity.^4,11,37–43
• Zinc supplementation improved rotavirus vaccine response in three RCTs, with an increase in seroconversion from 42% to 62% (OR = 1.48, 95% CI: 1.21–1.76, p < 0.01).
• Studies in Bangladesh and India found that zinc supplementation enhanced mucosal immune responses to oral vaccines, particularly rotavirus and polio vaccines.³⁹

Findings from Haut-Lomami and Tanganyika:

• Data from DRC studies⁴ showed that zinc supplementation before OPV administration increased seroconversion rates by 20%.
• This aligns with previous research indicating that zinc deficiency compromises gut integrity, affecting oral vaccine absorption and efficacy.¹¹

Limitations:

• No significant improvement was observed in response to inactivated vaccines like DTP or hepatitis B.

3.2.3 Iron supplementation and vaccine response

• Six studies assessed the impact of iron on vaccine responses, with mixed results.^4,41,44–47
• In a Kenyan study,⁴⁷ iron supplementation improved hepatitis B vaccine seroconversion (OR = 1.27, p = 0.03).
• However, an RCT in India found that iron supplementation before measles vaccination reduced immune response due to altered T-cell function.⁴⁷

Findings from Haut-Lomami and Tanganyika:

• No iron-specific intervention studies were conducted in these provinces, but anemia was highly prevalent in malnourished children, potentially affecting vaccine efficacy.
• Studies suggest that iron should be provided cautiously, as excess iron can impair immune function.^4,47

3.2.4 Protein-energy supplementation and comprehensive nutrition programs

• Five studies examined the impact of protein-energy supplementation on vaccine response.^4,48–51

Figure 2 illustrating the Impact of Nutritional Interventions on Vaccine Immunogenicity

Figure 2. Impact of Nutritional Interventions on Vaccine Immunogenicity.

3.3 Factors modulating the effectiveness of nutritional interventions

3.3.1 Age and timing of supplementation

• Children under 12 months showed the greatest improvement in vaccine responses with micronutrient supplementation.
• Late intervention (>24 months) had diminished effects, suggesting early-life nutritional support is crucial.

3.3.2 Severity of malnutrition

• The impact of nutrition on immunogenicity varied by malnutrition severity:
- ○ Mild-to-moderate malnutrition: Benefited most from supplementation.
- ○ Severe acute malnutrition (SAM): Showed less improvement, requiring comprehensive nutrition rehabilitation before vaccination.

3.3.3 Type of vaccine

• Live vaccines (OPV, measles, rotavirus) benefited more from nutritional interventions than inactivated vaccines (DTP, hepatitis B). Notably, most of the studies included in this review assessed responses to live attenuated vaccines such as OPV and measles. Limited data were available regarding inactivated vaccines, which restricts the generalizability of the findings to this vaccine group.

3.4 Findings from Haut-Lomami and Tanganyika

• High malnutrition prevalence negatively affected vaccine response.
• Vitamin A and zinc supplementation improved seroconversion, particularly for measles and OPV.
• Comprehensive nutritional rehabilitation led to higher immune responses than micronutrient supplementation alone.
• Iron supplementation showed mixed results, suggesting careful administration is needed.

3.5 Summary interpretation

1. Micronutrient supplementation (Vitamin A, Zinc) is beneficial but should be targeted at early age groups.
2. Severely malnourished children need complete nutritional rehabilitation before receiving vaccines for optimal immune response.
3. Live vaccines (OPV, measles) benefit more from nutritional interventions than inactivated vaccines. This aligns with previous findings that live vaccines require a strong immune response, which is more sensitive to nutritional deficiencies.

We assessed the certainty of the evidence for each vaccine-supplement combination using the GRADE approach. The results are summarized in Table 3.

Table 3. GRADE summary of findings.

Outcome	Certainty of evidence (GRADE)	Key notes
Vitamin A → Measles seroconversion	Moderate	Based on 8 RCTs; consistent effect, some underpowered trials.
Zinc → Rotavirus/OPV seroconversion	Moderate	Improves mucosal response; consistent across trials.
Iron → Hepatitis B/Measles	Low	Mixed findings; possible adverse effect with excess iron.
Protein–energy supplement → Multiple vaccines	Moderate	Improves responses, especially in SAM children.
General immunogenicity in SAM children	Low–Moderate	Definitions heterogeneous; interventions varied.
Mortality outcomes	Very Low	Indirect, serious risk of bias and imprecision.

4. Discussion

All extended data supporting these findings are openly available in Zenodo.⁶⁸

4.1 Summary of key findings

This systematic review highlights the significant impact of nutritional interventions on vaccine immunogenicity, particularly in malnourished children in low- and middle-income countries (LMICs) such as the Democratic Republic of the Congo (DRC). The findings demonstrate limited but consistent evidence for vitamin A and zinc; weaker for iron and protein-energy rehabilitation, particularly for live vaccines such as measles and oral polio vaccine (OPV). Observational studies often confounded by acute infections; biomarkers (ferritin, zinc, vitamin D) are acute-phase reactants.

Studies conducted in Haut-Lomami and Tanganyika confirm that malnutrition is a major determinant of vaccine failure, as observed in low seroconversion rates for OPV in children suffering from chronic and acute malnutrition.⁴ The data support the hypothesis that integrating nutritional support into immunization programs could improve vaccine effectiveness and immune protection in high-risk populations.

4.2 Mechanisms underlying the impact of nutrition on immunogenicity

4.2.1 The Role of micronutrients in immune function

Micronutrients such as vitamin A, zinc, and iron play critical roles in immune system development, antigen processing, and antibody production.^51–54

• Vitamin A: Essential for mucosal immunity and B-cell activation, improving the immune response to live vaccines such as measles and OPV.⁵⁵
• Zinc: Supports T-cell function and gut mucosal immunity, which is particularly important for oral vaccines.⁵⁶
• Iron: While necessary for immune function, excess iron can impair T-cell activity and promote bacterial infections, which may explain why some studies found negative effects on vaccine responses.⁵⁷

4.2.2 Impact of malnutrition on vaccine responses

Malnutrition is associated with immunosuppression, which affects both innate and adaptive immunity.⁵⁸ Children with chronic malnutrition exhibit:

• Reduced B-cell function, leading to lower antibody production after vaccination.
• Impaired T-cell responses, decreasing memory response to vaccines.⁵⁹
• Altered gut microbiota, affecting the absorption of oral vaccines like OPV and rotavirus.⁶⁰

Studies in Haut-Lomami and Tanganyika confirmed that malnourished children exhibited lower seroconversion rates for OPV compared to well-nourished peers, reinforcing the link between nutrition and vaccine efficacy.⁴

• In a community-based study,⁴ children in nutritional rehabilitation programs had higher OPV and measles seroconversion rates compared to those with untreated malnutrition.
• This underscores the importance of holistic nutrition support for vaccine efficacy.

4.3 Comparison with global studies

4.3.1 Vitamin A supplementation and vaccine immunogenicity

The findings from this review align with previous meta-analyses showing that vitamin A supplementation improves measles vaccine seroconversion.⁶¹ The improvement in Haut-Lomami and Tanganyika is consistent with data from Bangladesh and India, where vitamin A administration before measles vaccination increased antibody titers by 35%.⁶²

However, in severely malnourished children, the benefit of vitamin A was less pronounced, possibly due to systemic immune suppression and multiple nutritional deficiencies.⁵⁹

4.3.2 Zinc supplementation and vaccine response

Studies in Bangladesh, India, and the DRC found that zinc supplementation enhances immune responses to OPV and rotavirus vaccines, likely due to its role in gut mucosal immunity and T-cell function.⁶³

However, zinc had no effect on inactivated vaccines like hepatitis B and DTP, suggesting that its benefits are specific to mucosal immunity.⁶⁴

4.3.3 Iron supplementation: A dDouble-edged sword?

While some studies found that iron supplementation improved vaccine seroconversion, others observed a paradoxical reduction in immunity.⁴⁵ Excess iron may promote oxidative stress and bacterial infections, which could impair vaccine-induced immune responses.⁵⁷

In the Haut-Lomami and Tanganyika studies, iron deficiency was prevalent, yet iron supplementation alone did not significantly enhance vaccine responses, suggesting the need for comprehensive nutritional rehabilitation.⁴

4.4 Implications for immunization programs in the DRC

4.4.1 Integrating nutrition into routine immunization

Findings from Haut-Lomami and Tanganyika suggest that vaccination programs should be coupled with targeted nutritional interventions. This could be achieved through:

1. Providing vitamin A and zinc supplementation at the time of vaccination.
2. Screening for malnutrition during immunization campaigns.
3. Integrating delivery (vaccines + nutrition support at the same contact) offers best potential impact.

4.4.2 Prioritizing high-risk groups

• Children under 12 months benefited the most from nutritional interventions, indicating the need for early-life supplementation programs.
• Children with SAM require therapeutic feeding for recovery, but should still receive vaccines promptly due to high infection risk.
• However, research indicates that malnutrition adversely affects vaccine efficacy. For example, a study in Rio de Janeiro found that malnourished children had lower seroconversion rates after measles immunization compared to well-nourished children. Additionally, a systematic review highlighted malnutrition as a key factor impacting measles vaccine effectiveness. While these studies underscore the relationship between nutrition and vaccine response, further research is needed to determine the specific impact of nutritional rehabilitation on vaccine seroconversion rates in children recovering from SAM.^51,65

4.4.3 Strengthening community-based nutrition programs

• Community health workers should actively screen and treat malnutrition in immunization settings.
• Nutritional counseling for mothers should be included in immunization campaigns.

The strength of the evidence varied across outcomes. While the impact of Vitamin A on measles seroconversion and zinc on OPV responses showed moderate certainty, the evidence for iron supplementation and for outcomes such as tetanus or general mortality was of low to very low certainty. This underscores the need for further rigorous trials in malnourished populations.

4.5 Limitations of the study

1. Heterogeneity in study designs – Included studies varied in intervention types, outcome definitions, and assessment methods, which may introduce bias. While randomized controlled trials (RCTs) were prioritized when available, high-quality observational studies were also retained to provide contextual relevance, particularly in regions where RCT data are scarce.
2. Limited longitudinal follow-up – Most studies assessed vaccine responses shortly after immunization, with few evaluating long-term immunity. This limits our ability to draw conclusions about sustained protection.
3. Restricted vaccine scope – Evidence was available mainly for oral polio vaccine (OPV), measles, rotavirus, and BCG. Data were sparse or lacking for other Expanded Programme on Immunization (EPI) vaccines, such as DTP, hepatitis B, Hib, and pneumococcal vaccines. As a result, caution is warranted when extrapolating findings to all vaccine types, particularly inactivated or subunit vaccines.
4. Geographic focus – Findings were concentrated in specific settings such as Haut-Lomami and Tanganyika. Although informative, they may not be generalizable to all provinces of the Democratic Republic of the Congo (DRC) or to other countries with different socio-economic and health system contexts.
5. Potential sources of bias – Despite efforts to include only high-quality studies, several biases may limit reliability. Publication bias remains a concern, as null or negative findings are less likely to be published, possibly inflating the observed benefits of nutritional interventions. Selective outcome reporting was noted in some studies, with only significant immunogenicity results presented, limiting comprehensive interpretation. Attrition bias due to missing data (e.g., loss to follow-up or incomplete baseline nutritional/serological profiles) was also common. These factors were explicitly considered in our GRADE assessments and underscore the urgent need for rigorously designed trials with transparent reporting of all outcomes, regardless of statistical significance.

4.6 Future research directions

1. Longitudinal studies assessing the long-term effects of nutritional interventions on vaccine immunity.
2. Randomized controlled trials evaluating combined micronutrient supplementation strategies.
3. Investigating the role of gut microbiota in modulating oral vaccine responses in malnourished children.
4. The timing of nutritional interventions appears to influence vaccine responses. Several studies suggest that supplementation administered concurrently with vaccination yields the most consistent improvement in immunogenicity, particularly for live oral vaccines such as OPV and measles. Pre-vaccination supplementation may help correct deficiencies that impair immune priming, while post-vaccination supplementation may support antibody maturation. However, few studies directly compare timing, and further research is needed to optimize scheduling for maximal vaccine efficacy. Vaccination should never be postponed in malnourished children.

4.7 Conclusion

This review confirms that nutritional interventions—particularly vitamin A, zinc, and comprehensive rehabilitation—enhance vaccine immunogenicity in malnourished children. However, vaccination must not be delayed. Findings from Haut-Lomami and Tanganyika reinforce the critical role of nutrition in improving vaccine responses, particularly for measles and OPV.

Policy implications:

• Nutritional supplementation should be integrated into routine immunization programs in high-risk regions.
• Live vaccines (measles, OPV) benefit the most from nutritional interventions, warranting targeted supplementation efforts.
• Children with SAM require therapeutic feeding for recovery, but should still receive vaccines promptly due to high infection risk. Vaccination should never be postponed in malnourished children.

By addressing both immunization and malnutrition simultaneously, health programs in the DRC and other LMICs can enhance vaccine efficacy, improve child survival, and accelerate progress towards global immunization goals.

Ethics and consent

Ethical approval and consent were not required.

Data availability

Underlying data

No underlying raw data are associated with this article.

Extended data

Extended data supporting this article are available on Zenodo: doi: 10.5281/zenodo.17072723.⁶⁸

This record includes:

• Harmonized Tables 1–3 with explanatory note (‘Tables_with_ExplanatoryNote.docx’)
• Study-level dataset of the 29 included studies (‘F1000_Vaccine_Review_Tables_V4_Cleaned.xlsx’)
• PRISMA 2020 flow diagram (‘Figure 1.jpg’)

Previous versions of the dataset remain accessible:

• doi:[10.5281/zenodo.15346825](https://doi.org/10.5281/zenodo.15346825)⁶⁶
• doi:[10.5281/zenodo.15873743](https://doi.org/10.5281/zenodo.15873743)⁶⁷

License:

Data is released under the Creative Commons Attribution 4.0 International license (CC BY 4.0).

Acknowledgments

The authors extend their sincere gratitude to the Ministry of Health of the Democratic Republic of Congo and the Provincial Health Authorities for their continuous support. We would also like to thank the various organizations and individuals whose valuable contributions and expertise have significantly enriched this research.

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Version 4

VERSION 4 PUBLISHED 20 May 2025

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Michel Kabamba Nzaji
Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing

Oscar Luboya Numbi
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Mala Ali Mapatano
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

Paul-Samson Lusamba Dikassa
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing

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No competing interests were disclosed.

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Ngoie Mwamba G, Kabamba Nzaji M, Luboya Numbi O et al. Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review [version 4; peer review: 2 approved, 1 not approved]. F1000Research 2025, 14:507 (https://doi.org/10.12688/f1000research.164227.4)

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Maren Johanne Heilskov Rytter, Slagelse Hospital, Slagelse, Denmark

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Review of "Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review [version 3; peer review: 2 approved with reservations]"

This is an interesting subject of high clinical relevance, addressing the well-known but poorly understood vicious cycle between malnutrition and infection. Specifically the review aims to assess wether supplementation with micronutrients or protein-energy supplements may improve vaccine responses.

However, the manuscript in its present form does not reliably address the subject in a scientifically sound way: The main problem is that only few of the 42 studies included in the review are clinical studies and provide specific data to answer the study questions. Most of the included articles are reviews, of which the majority are not systematic, but narrative, and as such they do not even fall within the inclusion criteria stated for this review:

This is highly problematic, because it makes it unclear what the real origin of the results cited are. For example among the nine studies that the authors state assess the effect of zinc only one is an interventional study (an RCT of probiotics and zinc, which did not find any effect of zinc supplementation on antibody responses) while the remaining are observational studies assessing the effect of zinc on general immune response (but not vaccine response (n=1), assess the association between measured plasma level of zinc and vaccine response (n=2), assess the association of vaccine response to generel nutritional status but not reporting anything about zinc (n=1) or are narrative reviews not reporting any original data (n=3). Accordingly it is nor clear what the origin of the effect estimate given is - and also there is no reference given for this

The same goes for the remaining sections of the manuscript: it is very unclear what the origin of the conclusions are: for example, in the section about "protein-energy supplementation and comprehensive nutrition programmes" two of the five studies cited are reviews, and the other three are not assessing the effect of nutritional supplementation on antibody response. This may be due to a citation error, and in that case it should be corrected.

To improve the manuscript I suggest to use a more selective inclusion strategy and NOT include reviews but only studies reporting original data to answer your research question. You may use reviews during your search proces to identify any original studies that are cited in the reviews, which you may have missed during your initial search, but included these only and not the review themselves, as you risk reporting somebody's interpretation of the data (or maybe their hypotheses, or opinions) rather than real data.

Also, I suggest that you for each topic preset the relevant included studies in one or two tables, outlining the study year, country of origin, number and kind of included children, the study design, the intervention and comparator, the outcome(s) measured, and (perhaps in a separate table) describe the main findings, effect size, and any concern for bias. This will make your findings more transparent for readers.

Also you should include a discussion of the difficulties in interpreting observational studies regarding malnutrition and immune response, due to the fact that most children with malnutrition also have infections, and elevated acute phase response, which is known to reduce response to vaccines by themselves. Also, most measured plasma markers of nutrients (including zinc, vitamin D, , ferritin etc) are also acute phase reactants, meaning that any association seen between these markers and immune responses may result from confounding from ongoing infection. This means that all observational studies should be interpreted with caution, and treatment or policy decisions should be based on results from randomised trials (which are less likely to be confounded)

I also suggest that you, as a safety measure, do not include any studies in your review by Chandra RK, who has published extensively on the relationship between immune function and nutrition, but who has been found to fabricate data and make research fraud. Some of his work has been retracted, but not all of it. Se Smith : Investigating the previous studies of a fraudulent author. Smith R 2005 [Ref 1]

Finally, I strongly disagree with your statement in the conclusion: "Children with severe acute malnutrition should undergo nutritional rehabilitation before receiving vaccines for optimal immune response."

First, while malnourished children may have subtle decreases in vaccine responses, there is no data indicating that vaccination does not protect them from disease, and no data suggesting that they are at higher risk of vaccine-related adverse events (provided that they do not have advanced HIV or primary immunodeficiency).

Second, children with malnutrition are at much higher risk of dying of they get infections, indicating that they are the most likely to benefit from protection from vaccination. For this reason, measles vaccinations have been an important part of nutritional rehabilitation programmes in many places (also because a measles outbreak in a nutritional rehabilitation centre is likely to be disastrous). Se further arguments in the excellent review (also cited by you!) by Prendergast AJ, 2015 [Ref 1]

I would be happy to review a revised version of your manuscript, but I am convinced that it needs a major revision to be suitable for indexing.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are the conclusions drawn adequately supported by the results presented in the review?

No
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

References

1. Smith R: Investigating the previous studies of a fraudulent author. BMJ. 2005; 331 (7511): 288-291 Publisher Full Text
2. Prendergast A: Malnutrition and vaccination in developing countries. Philosophical Transactions of the Royal Society B: Biological Sciences. 2015; 370 (1671). Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: I am a paediatrician, mainly doing clinical research. In my PhD I worked on the relationship between malnutrition infections and immune function, by assessing the effect of nutritional rehabilitation on thymus size in children with severe and moderate acute malnutrition. I also did a systematic review of the relationship between malnutrition and immune parameters.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

CITE

Report a concern

Author Response 11 Sep 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

11 Sep 2025

Author Response

Notes to Reviewers – Response to Dr. Maren Johanne Heilskov Rytter

Manuscript title: Micronutrient and protein-energy supplementation enhances vaccine responses in undernourished children: Evidence from a systematic review
Version: ... Continue reading Notes to Reviewers – Response to Dr. Maren Johanne Heilskov Rytter

Manuscript title: Micronutrient and protein-energy supplementation enhances vaccine responses in undernourished children: Evidence from a systematic review
Version: 3 → 4
Reviewer: Dr. Maren Johanne Heilskov Rytter, Slagelse Hospital, Denmark
General Note
We sincerely thank the reviewer for the constructive and clinically insightful feedback. We have substantially revised the manuscript to address all concerns. Below is our detailed point-by-point response.

Inclusion of narrative reviews.

Reviewer comment: Most of the included articles are narrative reviews and do not fit the eligibility criteria.
Response: All narrative reviews were removed. The revised dataset now contains only randomized controlled trials, cohort, and observational studies (29 in total). The PRISMA flow diagram, Abstract, Methods, and Results have been updated accordingly.

Scientific rigor in the evidence base

Reviewer comment: The manuscript does not reliably address the subject in a scientifically sound way.
Response: The Results were rebuilt to focus exclusively on primary evidence. Table 1 (Excluded studies), Table 2 (Key findings), and Table 3 (GRADE summary) were added to transparently present study-level data and certainty of evidence.

Confounding in observational studies

Reviewer comment: Associations may be confounded by acute infection; biomarkers are acute-phase reactants.
Response: The Discussion and Limitations were revised to highlight confounding by infection and the acute-phase behavior of biomarkers such as ferritin, zinc, and vitamin D.

Fraudulent studies (Chandra RK)

Reviewer comment: Studies by Chandra RK must be excluded.
Response: All studies by Chandra RK were excluded. This is clearly stated in the Methods and shown in the PRISMA diagram under 'other reasons'.

Conclusion on sequencing vaccination

Reviewer comment: The statement suggesting nutritional rehabilitation before vaccination is potentially harmful.
Response: The Conclusion was rewritten to emphasize that vaccination should never be delayed in malnourished children. Immunization and nutrition support should be delivered concurrently.

Methods detail (PRISMA 2020 alignment)

Reviewer comment: The methodology is insufficiently detailed for replication.
Response: The Methods were expanded to include eligibility criteria, search strategy, dual screening, risk-of-bias assessment, and reasons for excluding reviews. A PRISMA 2020 flow diagram is now included.

Statistical analysis and meta-analysis

Reviewer comment: Statistical validation is required; a meta-analysis should be attempted, or reasons given for not conducting one.
Response: A statistician reviewed the dataset. Owing to high heterogeneity across interventions, outcomes, and study designs, a global meta-analysis was not feasible. However, a targeted meta-analysis of vitamin A and measles seroconversion (8 RCTs) was performed. Other outcomes were synthesized narratively using the SWiM framework.

Publication years of included trials

Reviewer comment: Several included studies are old.
Response: Although our initial cutoff was 2000, we retained select pre-2000 trials (e.g., on protein-energy supplementation) that provided unique primary data. Their inclusion is justified in the Methods, and they were critically appraised for risk of bias and interpreted with caution.
Notes to Reviewers – Response to Dr. Maren Johanne Heilskov Rytter

Manuscript title: Micronutrient and protein-energy supplementation enhances vaccine responses in undernourished children: Evidence from a systematic review
Version: 3 → 4
Reviewer: Dr. Maren Johanne Heilskov Rytter, Slagelse Hospital, Denmark
General Note
We sincerely thank the reviewer for the constructive and clinically insightful feedback. We have substantially revised the manuscript to address all concerns. Below is our detailed point-by-point response.

Inclusion of narrative reviews.

Reviewer comment: Most of the included articles are narrative reviews and do not fit the eligibility criteria.
Response: All narrative reviews were removed. The revised dataset now contains only randomized controlled trials, cohort, and observational studies (29 in total). The PRISMA flow diagram, Abstract, Methods, and Results have been updated accordingly.

Scientific rigor in the evidence base

Reviewer comment: The manuscript does not reliably address the subject in a scientifically sound way.
Response: The Results were rebuilt to focus exclusively on primary evidence. Table 1 (Excluded studies), Table 2 (Key findings), and Table 3 (GRADE summary) were added to transparently present study-level data and certainty of evidence.

Confounding in observational studies

Reviewer comment: Associations may be confounded by acute infection; biomarkers are acute-phase reactants.
Response: The Discussion and Limitations were revised to highlight confounding by infection and the acute-phase behavior of biomarkers such as ferritin, zinc, and vitamin D.

Fraudulent studies (Chandra RK)

Reviewer comment: Studies by Chandra RK must be excluded.
Response: All studies by Chandra RK were excluded. This is clearly stated in the Methods and shown in the PRISMA diagram under 'other reasons'.

Conclusion on sequencing vaccination

Reviewer comment: The statement suggesting nutritional rehabilitation before vaccination is potentially harmful.
Response: The Conclusion was rewritten to emphasize that vaccination should never be delayed in malnourished children. Immunization and nutrition support should be delivered concurrently.

Methods detail (PRISMA 2020 alignment)

Reviewer comment: The methodology is insufficiently detailed for replication.
Response: The Methods were expanded to include eligibility criteria, search strategy, dual screening, risk-of-bias assessment, and reasons for excluding reviews. A PRISMA 2020 flow diagram is now included.

Statistical analysis and meta-analysis

Reviewer comment: Statistical validation is required; a meta-analysis should be attempted, or reasons given for not conducting one.
Response: A statistician reviewed the dataset. Owing to high heterogeneity across interventions, outcomes, and study designs, a global meta-analysis was not feasible. However, a targeted meta-analysis of vitamin A and measles seroconversion (8 RCTs) was performed. Other outcomes were synthesized narratively using the SWiM framework.

Publication years of included trials

Reviewer comment: Several included studies are old.
Response: Although our initial cutoff was 2000, we retained select pre-2000 trials (e.g., on protein-energy supplementation) that provided unique primary data. Their inclusion is justified in the Methods, and they were critically appraised for risk of bias and interpreted with caution.
Competing Interests: No competing interest Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 11 Sep 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

11 Sep 2025

Author Response

Notes to Reviewers – Response to Dr. Maren Johanne Heilskov Rytter

Manuscript title: Micronutrient and protein-energy supplementation enhances vaccine responses in undernourished children: Evidence from a systematic review
Version: ... Continue reading Notes to Reviewers – Response to Dr. Maren Johanne Heilskov Rytter

Manuscript title: Micronutrient and protein-energy supplementation enhances vaccine responses in undernourished children: Evidence from a systematic review
Version: 3 → 4
Reviewer: Dr. Maren Johanne Heilskov Rytter, Slagelse Hospital, Denmark
General Note
We sincerely thank the reviewer for the constructive and clinically insightful feedback. We have substantially revised the manuscript to address all concerns. Below is our detailed point-by-point response.

Inclusion of narrative reviews.

Reviewer comment: Most of the included articles are narrative reviews and do not fit the eligibility criteria.
Response: All narrative reviews were removed. The revised dataset now contains only randomized controlled trials, cohort, and observational studies (29 in total). The PRISMA flow diagram, Abstract, Methods, and Results have been updated accordingly.

Scientific rigor in the evidence base

Reviewer comment: The manuscript does not reliably address the subject in a scientifically sound way.
Response: The Results were rebuilt to focus exclusively on primary evidence. Table 1 (Excluded studies), Table 2 (Key findings), and Table 3 (GRADE summary) were added to transparently present study-level data and certainty of evidence.

Confounding in observational studies

Reviewer comment: Associations may be confounded by acute infection; biomarkers are acute-phase reactants.
Response: The Discussion and Limitations were revised to highlight confounding by infection and the acute-phase behavior of biomarkers such as ferritin, zinc, and vitamin D.

Fraudulent studies (Chandra RK)

Reviewer comment: Studies by Chandra RK must be excluded.
Response: All studies by Chandra RK were excluded. This is clearly stated in the Methods and shown in the PRISMA diagram under 'other reasons'.

Conclusion on sequencing vaccination

Reviewer comment: The statement suggesting nutritional rehabilitation before vaccination is potentially harmful.
Response: The Conclusion was rewritten to emphasize that vaccination should never be delayed in malnourished children. Immunization and nutrition support should be delivered concurrently.

Methods detail (PRISMA 2020 alignment)

Reviewer comment: The methodology is insufficiently detailed for replication.
Response: The Methods were expanded to include eligibility criteria, search strategy, dual screening, risk-of-bias assessment, and reasons for excluding reviews. A PRISMA 2020 flow diagram is now included.

Statistical analysis and meta-analysis

Reviewer comment: Statistical validation is required; a meta-analysis should be attempted, or reasons given for not conducting one.
Response: A statistician reviewed the dataset. Owing to high heterogeneity across interventions, outcomes, and study designs, a global meta-analysis was not feasible. However, a targeted meta-analysis of vitamin A and measles seroconversion (8 RCTs) was performed. Other outcomes were synthesized narratively using the SWiM framework.

Publication years of included trials

Reviewer comment: Several included studies are old.
Response: Although our initial cutoff was 2000, we retained select pre-2000 trials (e.g., on protein-energy supplementation) that provided unique primary data. Their inclusion is justified in the Methods, and they were critically appraised for risk of bias and interpreted with caution.
Notes to Reviewers – Response to Dr. Maren Johanne Heilskov Rytter

Manuscript title: Micronutrient and protein-energy supplementation enhances vaccine responses in undernourished children: Evidence from a systematic review
Version: 3 → 4
Reviewer: Dr. Maren Johanne Heilskov Rytter, Slagelse Hospital, Denmark
General Note
We sincerely thank the reviewer for the constructive and clinically insightful feedback. We have substantially revised the manuscript to address all concerns. Below is our detailed point-by-point response.

Inclusion of narrative reviews.

Reviewer comment: Most of the included articles are narrative reviews and do not fit the eligibility criteria.
Response: All narrative reviews were removed. The revised dataset now contains only randomized controlled trials, cohort, and observational studies (29 in total). The PRISMA flow diagram, Abstract, Methods, and Results have been updated accordingly.

Scientific rigor in the evidence base

Reviewer comment: The manuscript does not reliably address the subject in a scientifically sound way.
Response: The Results were rebuilt to focus exclusively on primary evidence. Table 1 (Excluded studies), Table 2 (Key findings), and Table 3 (GRADE summary) were added to transparently present study-level data and certainty of evidence.

Confounding in observational studies

Reviewer comment: Associations may be confounded by acute infection; biomarkers are acute-phase reactants.
Response: The Discussion and Limitations were revised to highlight confounding by infection and the acute-phase behavior of biomarkers such as ferritin, zinc, and vitamin D.

Fraudulent studies (Chandra RK)

Reviewer comment: Studies by Chandra RK must be excluded.
Response: All studies by Chandra RK were excluded. This is clearly stated in the Methods and shown in the PRISMA diagram under 'other reasons'.

Conclusion on sequencing vaccination

Reviewer comment: The statement suggesting nutritional rehabilitation before vaccination is potentially harmful.
Response: The Conclusion was rewritten to emphasize that vaccination should never be delayed in malnourished children. Immunization and nutrition support should be delivered concurrently.

Methods detail (PRISMA 2020 alignment)

Reviewer comment: The methodology is insufficiently detailed for replication.
Response: The Methods were expanded to include eligibility criteria, search strategy, dual screening, risk-of-bias assessment, and reasons for excluding reviews. A PRISMA 2020 flow diagram is now included.

Statistical analysis and meta-analysis

Reviewer comment: Statistical validation is required; a meta-analysis should be attempted, or reasons given for not conducting one.
Response: A statistician reviewed the dataset. Owing to high heterogeneity across interventions, outcomes, and study designs, a global meta-analysis was not feasible. However, a targeted meta-analysis of vitamin A and measles seroconversion (8 RCTs) was performed. Other outcomes were synthesized narratively using the SWiM framework.

Publication years of included trials

Reviewer comment: Several included studies are old.
Response: Although our initial cutoff was 2000, we retained select pre-2000 trials (e.g., on protein-energy supplementation) that provided unique primary data. Their inclusion is justified in the Methods, and they were critically appraised for risk of bias and interpreted with caution.
Competing Interests: No competing interest Close
Report a concern

Version 2

VERSION 2

PUBLISHED 20 Jun 2025

Revised

Views

Reviewer Report 28 Jun 2025

Philip C Calder, University of Southampton, Southampton, England, UK

Approved with Reservations

https://doi.org/10.5256/f1000research.183761.r393821

This manuscript reports a systematic review and partial meta-analysis of trials examining supplementation of vitamin A, zinc, iron and protein/energy on vaccine responses in children. This is a really important topic given global prevalence of protein/energy and micronutrient deficiencies in children and the existence of a high pathogen burden. This seems to be a revision of a previous version but i did not review that. I found this to be very well written article. It is found the vitamin A and zinc and protein/energy repletion increase response to several vaccines; findings with iron were inconsistent. The discussion includes health policy implications of the work.

Specific comments:
1. Why was the search limited to 2000 onwards. Please justify.
2.The PRISMA chart (Figure 1) and text do not seem to match.
3. Table 2 does not show study characteristics as stated; it seems to summarise the findings.
4. Section 2.3.3 says meta-analysis was not possible yet there is a meta-analysis of effects of vitamin A.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Nutritional immunology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Author Response 09 Aug 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

09 Aug 2025

Author Response
Response to Reviewer Comments

Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review
Manuscript ID: f1000research-14-507

Reviewer: Dr. Philip C. ... Continue reading
Response to Reviewer Comments

Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review
Manuscript ID: f1000research-14-507

Reviewer: Dr. Philip C. Calder
Date of Review: June 28, 2025

We sincerely thank Dr. Calder for his thoughtful review, kind words, and constructive feedback. We have carefully considered all comments raised and implemented the relevant revisions in the manuscript. Below are our detailed, point-by-point responses.

Reviewer Comment 1
"Why was the search limited to 2000 onwards. Please justify."

Response:
Thank you for this observation. We have now provided a clear justification in Section 2.2 of the revised manuscript. The search was limited to studies published from 2000 onwards due to the substantial evolution in global immunization policy and child nutrition strategies over the past two decades. This includes the launch of the Global Immunization Vision and Strategy (GIVS, 2006–2015), expanded vaccine introduction in low- and middle-income countries (LMICs), and major WHO/UNICEF nutrition initiatives. These developments influenced both research context and methodological consistency, ensuring that data included in this review are more relevant, comparable, and aligned with current global standards.

Reviewer Comment 2
"The PRISMA chart (Figure 1) and text do not seem to match."

Response:
We appreciate this important remark. We have carefully revised Figure 1 (PRISMA) and ensured full alignment with the narrative description in Section 2.4 of the manuscript. Discrepancies in the number of records screened and excluded at various stages were corrected. The final version now accurately reflects the number of studies included (n=42) and the corresponding exclusion rationale, bringing the figure and text into consistency.

Reviewer Comment 3
"Table 2 does not show study characteristics as stated; it seems to summarise the findings."

Response:
Thank you for this helpful clarification. Table 2 has now been re-labeled as “Key Findings from Included Studies” to better reflect its content. In response to the need for detailed study characteristics, we have created a separate file titled Supplementary Table S1 – Study Characteristics, which includes:

Study ID

Country/Region

Nutritional Intervention

Vaccine Assessed

Author and Year

Study Design

Sample Size

Age Range

Outcome

Reference (with DOI or PMID)

This file is hosted on Zenodo as part of our living evidence synthesis initiative and will be periodically updated. The DOI for this supplementary dataset is: https://doi.org/10.5281/zenodo.15873743
Suggested Manuscript Insertions:

Methods or Results section: “Detailed study characteristics are provided in Supplementary Table S1 (Zenodo DOI: 10.5281/zenodo.15873743).”

Data Availability section: “Supplementary Table S1 is available on Zenodo and includes complete metadata for each study. The dataset will be updated as new studies become available.”

Reviewer Comment 4
"Section 2.3.3 says meta-analysis was not possible yet there is a meta-analysis of effects of vitamin A."

Response:
We acknowledge this oversight and have revised Section 2.3.3 to clarify that a comprehensive meta-analysis across all interventions was not feasible due to clinical and methodological heterogeneity. However, we were able to perform a targeted meta-analysis for a subset of studies examining the effect of vitamin A supplementation on measles vaccine seroconversion, where study designs and outcome metrics were sufficiently comparable. This partial analysis is now clearly described, and limitations (e.g., absence of forest plots and publication bias assessments) are transparently noted in the Results and Limitations sections.
We are grateful to Dr. Calder for his insightful feedback, which has greatly enhanced the quality and clarity of our systematic review. We trust that the revisions satisfactorily address all concerns.

Sincerely,
Dr. Guillaume Ngoie Mwamba (on behalf of all co-authors)
ORCID: https://orcid.org/0000-0003-0460-877X
Response to Reviewer Comments

Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review
Manuscript ID: f1000research-14-507

Reviewer: Dr. Philip C. Calder
Date of Review: June 28, 2025

We sincerely thank Dr. Calder for his thoughtful review, kind words, and constructive feedback. We have carefully considered all comments raised and implemented the relevant revisions in the manuscript. Below are our detailed, point-by-point responses.

Reviewer Comment 1
"Why was the search limited to 2000 onwards. Please justify."

Response:
Thank you for this observation. We have now provided a clear justification in Section 2.2 of the revised manuscript. The search was limited to studies published from 2000 onwards due to the substantial evolution in global immunization policy and child nutrition strategies over the past two decades. This includes the launch of the Global Immunization Vision and Strategy (GIVS, 2006–2015), expanded vaccine introduction in low- and middle-income countries (LMICs), and major WHO/UNICEF nutrition initiatives. These developments influenced both research context and methodological consistency, ensuring that data included in this review are more relevant, comparable, and aligned with current global standards.

Reviewer Comment 2
"The PRISMA chart (Figure 1) and text do not seem to match."

Response:
We appreciate this important remark. We have carefully revised Figure 1 (PRISMA) and ensured full alignment with the narrative description in Section 2.4 of the manuscript. Discrepancies in the number of records screened and excluded at various stages were corrected. The final version now accurately reflects the number of studies included (n=42) and the corresponding exclusion rationale, bringing the figure and text into consistency.

Reviewer Comment 3
"Table 2 does not show study characteristics as stated; it seems to summarise the findings."

Response:
Thank you for this helpful clarification. Table 2 has now been re-labeled as “Key Findings from Included Studies” to better reflect its content. In response to the need for detailed study characteristics, we have created a separate file titled Supplementary Table S1 – Study Characteristics, which includes:

Study ID

Country/Region

Nutritional Intervention

Vaccine Assessed

Author and Year

Study Design

Sample Size

Age Range

Outcome

Reference (with DOI or PMID)

This file is hosted on Zenodo as part of our living evidence synthesis initiative and will be periodically updated. The DOI for this supplementary dataset is: https://doi.org/10.5281/zenodo.15873743
Suggested Manuscript Insertions:

Methods or Results section: “Detailed study characteristics are provided in Supplementary Table S1 (Zenodo DOI: 10.5281/zenodo.15873743).”

Data Availability section: “Supplementary Table S1 is available on Zenodo and includes complete metadata for each study. The dataset will be updated as new studies become available.”

Reviewer Comment 4
"Section 2.3.3 says meta-analysis was not possible yet there is a meta-analysis of effects of vitamin A."

Response:
We acknowledge this oversight and have revised Section 2.3.3 to clarify that a comprehensive meta-analysis across all interventions was not feasible due to clinical and methodological heterogeneity. However, we were able to perform a targeted meta-analysis for a subset of studies examining the effect of vitamin A supplementation on measles vaccine seroconversion, where study designs and outcome metrics were sufficiently comparable. This partial analysis is now clearly described, and limitations (e.g., absence of forest plots and publication bias assessments) are transparently noted in the Results and Limitations sections.
We are grateful to Dr. Calder for his insightful feedback, which has greatly enhanced the quality and clarity of our systematic review. We trust that the revisions satisfactorily address all concerns.

Sincerely,
Dr. Guillaume Ngoie Mwamba (on behalf of all co-authors)
ORCID: https://orcid.org/0000-0003-0460-877X
Competing Interests: Ther's no competing interests to declare that could be construed as influencing the validity or importance of the article (or peer review report). Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 09 Aug 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

09 Aug 2025

Author Response
Response to Reviewer Comments

Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review
Manuscript ID: f1000research-14-507

Reviewer: Dr. Philip C. ... Continue reading
Response to Reviewer Comments

Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review
Manuscript ID: f1000research-14-507

Reviewer: Dr. Philip C. Calder
Date of Review: June 28, 2025

We sincerely thank Dr. Calder for his thoughtful review, kind words, and constructive feedback. We have carefully considered all comments raised and implemented the relevant revisions in the manuscript. Below are our detailed, point-by-point responses.

Reviewer Comment 1
"Why was the search limited to 2000 onwards. Please justify."

Response:
Thank you for this observation. We have now provided a clear justification in Section 2.2 of the revised manuscript. The search was limited to studies published from 2000 onwards due to the substantial evolution in global immunization policy and child nutrition strategies over the past two decades. This includes the launch of the Global Immunization Vision and Strategy (GIVS, 2006–2015), expanded vaccine introduction in low- and middle-income countries (LMICs), and major WHO/UNICEF nutrition initiatives. These developments influenced both research context and methodological consistency, ensuring that data included in this review are more relevant, comparable, and aligned with current global standards.

Reviewer Comment 2
"The PRISMA chart (Figure 1) and text do not seem to match."

Response:
We appreciate this important remark. We have carefully revised Figure 1 (PRISMA) and ensured full alignment with the narrative description in Section 2.4 of the manuscript. Discrepancies in the number of records screened and excluded at various stages were corrected. The final version now accurately reflects the number of studies included (n=42) and the corresponding exclusion rationale, bringing the figure and text into consistency.

Reviewer Comment 3
"Table 2 does not show study characteristics as stated; it seems to summarise the findings."

Response:
Thank you for this helpful clarification. Table 2 has now been re-labeled as “Key Findings from Included Studies” to better reflect its content. In response to the need for detailed study characteristics, we have created a separate file titled Supplementary Table S1 – Study Characteristics, which includes:

Study ID

Country/Region

Nutritional Intervention

Vaccine Assessed

Author and Year

Study Design

Sample Size

Age Range

Outcome

Reference (with DOI or PMID)

This file is hosted on Zenodo as part of our living evidence synthesis initiative and will be periodically updated. The DOI for this supplementary dataset is: https://doi.org/10.5281/zenodo.15873743
Suggested Manuscript Insertions:

Methods or Results section: “Detailed study characteristics are provided in Supplementary Table S1 (Zenodo DOI: 10.5281/zenodo.15873743).”

Data Availability section: “Supplementary Table S1 is available on Zenodo and includes complete metadata for each study. The dataset will be updated as new studies become available.”

Reviewer Comment 4
"Section 2.3.3 says meta-analysis was not possible yet there is a meta-analysis of effects of vitamin A."

Response:
We acknowledge this oversight and have revised Section 2.3.3 to clarify that a comprehensive meta-analysis across all interventions was not feasible due to clinical and methodological heterogeneity. However, we were able to perform a targeted meta-analysis for a subset of studies examining the effect of vitamin A supplementation on measles vaccine seroconversion, where study designs and outcome metrics were sufficiently comparable. This partial analysis is now clearly described, and limitations (e.g., absence of forest plots and publication bias assessments) are transparently noted in the Results and Limitations sections.
We are grateful to Dr. Calder for his insightful feedback, which has greatly enhanced the quality and clarity of our systematic review. We trust that the revisions satisfactorily address all concerns.

Sincerely,
Dr. Guillaume Ngoie Mwamba (on behalf of all co-authors)
ORCID: https://orcid.org/0000-0003-0460-877X
Response to Reviewer Comments

Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review
Manuscript ID: f1000research-14-507

Reviewer: Dr. Philip C. Calder
Date of Review: June 28, 2025

We sincerely thank Dr. Calder for his thoughtful review, kind words, and constructive feedback. We have carefully considered all comments raised and implemented the relevant revisions in the manuscript. Below are our detailed, point-by-point responses.

Reviewer Comment 1
"Why was the search limited to 2000 onwards. Please justify."

Response:
Thank you for this observation. We have now provided a clear justification in Section 2.2 of the revised manuscript. The search was limited to studies published from 2000 onwards due to the substantial evolution in global immunization policy and child nutrition strategies over the past two decades. This includes the launch of the Global Immunization Vision and Strategy (GIVS, 2006–2015), expanded vaccine introduction in low- and middle-income countries (LMICs), and major WHO/UNICEF nutrition initiatives. These developments influenced both research context and methodological consistency, ensuring that data included in this review are more relevant, comparable, and aligned with current global standards.

Reviewer Comment 2
"The PRISMA chart (Figure 1) and text do not seem to match."

Response:
We appreciate this important remark. We have carefully revised Figure 1 (PRISMA) and ensured full alignment with the narrative description in Section 2.4 of the manuscript. Discrepancies in the number of records screened and excluded at various stages were corrected. The final version now accurately reflects the number of studies included (n=42) and the corresponding exclusion rationale, bringing the figure and text into consistency.

Reviewer Comment 3
"Table 2 does not show study characteristics as stated; it seems to summarise the findings."

Response:
Thank you for this helpful clarification. Table 2 has now been re-labeled as “Key Findings from Included Studies” to better reflect its content. In response to the need for detailed study characteristics, we have created a separate file titled Supplementary Table S1 – Study Characteristics, which includes:

Study ID

Country/Region

Nutritional Intervention

Vaccine Assessed

Author and Year

Study Design

Sample Size

Age Range

Outcome

Reference (with DOI or PMID)

This file is hosted on Zenodo as part of our living evidence synthesis initiative and will be periodically updated. The DOI for this supplementary dataset is: https://doi.org/10.5281/zenodo.15873743
Suggested Manuscript Insertions:

Methods or Results section: “Detailed study characteristics are provided in Supplementary Table S1 (Zenodo DOI: 10.5281/zenodo.15873743).”

Data Availability section: “Supplementary Table S1 is available on Zenodo and includes complete metadata for each study. The dataset will be updated as new studies become available.”

Reviewer Comment 4
"Section 2.3.3 says meta-analysis was not possible yet there is a meta-analysis of effects of vitamin A."

Response:
We acknowledge this oversight and have revised Section 2.3.3 to clarify that a comprehensive meta-analysis across all interventions was not feasible due to clinical and methodological heterogeneity. However, we were able to perform a targeted meta-analysis for a subset of studies examining the effect of vitamin A supplementation on measles vaccine seroconversion, where study designs and outcome metrics were sufficiently comparable. This partial analysis is now clearly described, and limitations (e.g., absence of forest plots and publication bias assessments) are transparently noted in the Results and Limitations sections.
We are grateful to Dr. Calder for his insightful feedback, which has greatly enhanced the quality and clarity of our systematic review. We trust that the revisions satisfactorily address all concerns.

Sincerely,
Dr. Guillaume Ngoie Mwamba (on behalf of all co-authors)
ORCID: https://orcid.org/0000-0003-0460-877X
Competing Interests: Ther's no competing interests to declare that could be construed as influencing the validity or importance of the article (or peer review report). Close
Report a concern

Version 1

VERSION 1

PUBLISHED 20 May 2025

Views

Reviewer Report 13 Jun 2025

Eknath D. Ahire, MET's Institute of Pharmacy, Nashik, India

Approved with Reservations

https://doi.org/10.5256/f1000research.180700.r388286

General Comments
This is a timely and well-structured systematic review addressing a critical issue in global public health—how nutritional interventions can improve vaccine responses in malnourished children. The authors have employed standard PRISMA guidelines, incorporated a range of high-quality studies, and made relevant policy recommendations. The manuscript is clearly written, logically organized, and makes a valuable contribution to the field.

Specific comments:
1. Please include forest plots and funnel plots to visually display the results of the meta-analysis and assess heterogeneity and publication bias.

2. Clarify the process used for GRADE rating assignment—was this done independently by reviewers or through consensus? This will improve transparency.

3. Expand the discussion of risk of bias, particularly regarding publication bias, selective outcome reporting, and missing data within included studies.

4. Tables 2 and 3 could benefit from clearer visual presentation. Consider bolding statistically significant findings or using shading/highlighting to improve readability.

5. Briefly describe the contents and purpose of the extended dataset available via Zenodo in the methods section to help readers understand its role.

6. Tighten the writing in the background and discussion sections to reduce repetition and improve clarity.

7. Ensure consistent use of terms such as "seroconversion," "vaccine immunogenicity," and "antibody response" throughout the manuscript.

8. Check for consistency in reference formatting according to Vancouver style; a few entries need adjustment.

9. Indicate whether the systematic review was registered (e.g., on PROSPERO). If not, briefly explain why this step was omitted.

10. More clearly state that the findings predominantly apply to live vaccines (e.g., OPV, measles) due to limited data on inactivated vaccines.

11. Although DRC is a focus, consider expanding policy recommendations to other LMICs with similar malnutrition and immunization challenges.

12. Discuss in more detail how the timing of nutritional interventions (pre-, concurrent with, or post-vaccination) influences vaccine responses.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

No

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Nutraceuticals, Pharmaceuticals

CITE

Report a concern

Author Response 11 Sep 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

11 Sep 2025

Author Response

Point-by-Point Response to Reviewer 1 Comments
Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: A systematic review
Manuscript ID: 164227
Corresponding Author: Dr. Guillaume Ngoie Mwamba
... Continue reading Point-by-Point Response to Reviewer 1 Comments
Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: A systematic review
Manuscript ID: 164227
Corresponding Author: Dr. Guillaume Ngoie Mwamba
Dear Editor,

We are grateful for the constructive feedback provided by Reviewer 1. Below is our point-by-point response detailing how each suggestion was addressed in the revised manuscript.

Reviewer Comment
Author Response
Action Taken

1.Include forest and funnel plots to visually display results.
Thank you. A meta-analysis was not conducted due to heterogeneity in study designs, intervention types, outcomes, and effect measures. We clarified this in the manuscript.
Clarified in Section 2.3 (Data Synthesis).

2.Clarify the process used for GRADE rating assignment.
GRADE ratings were independently assigned by two reviewers; discrepancies were resolved through consensus.
Added in Section 2.4 (Quality Assessment).

3.Expand the discussion of risk of bias.
We have expanded the discussion to address publication bias, selective outcome reporting, and missing data across included studies.
Expanded in Discussion, Paragraph 5.

4.Improve visual presentation of Tables 2 and 3.
Tables 2 and 3 have been revised for clarity. Statistically significant findings are now bolded.
Tables revised for visual clarity.

5.Briefly describe the Zenodo dataset in the Methods section.
We added a brief description of the extended dataset (PRISMA checklist, flowchart, summary table, CRediT matrix) in the Methods.
Added in Section 2.5 (Extended Data).

6.Tighten the writing in background and discussion sections.
Both sections were streamlined to reduce redundancy and improve clarity.
Revised Introduction and Discussion sections.

7.Ensure consistent terminology throughout the manuscript.
We revised the manuscript to ensure consistent use of terms such as “seroconversion,” “vaccine immunogenicity,” and “antibody response.”
Terminology harmonized across the manuscript.

8.Check reference formatting for Vancouver style.
All references were reviewed and updated to follow Vancouver formatting guidelines.
References updated accordingly.

9.Indicate whether the review was registered in PROSPERO.
The review was registered in PROSPERO (ID: CRD420251058388). This is now reported in the Methods section and cited in the References.
New subsection added: “Protocol Registration” in Methods and reference #18 added.

10.Clarify that findings predominantly apply to live vaccines.
We now explicitly state that the findings mainly concern live vaccines (e.g., OPV, measles), due to limited evidence on inactivated vaccines.
Added in Results and expanded in Discussion.

11.Expand policy implications to other LMICs.
We broadened the policy recommendations in the Conclusion to apply to other LMICs beyond the DRC.
Revisions made in the Conclusion section.

12.Discuss the timing of nutritional interventions.
We added discussion on how timing (pre-, co-, or post-vaccination) of supplementation influences vaccine response.
Added in Discussion, Paragraph 6.

We sincerely thank the reviewer for their thoughtful insights, which helped us improve the manuscript significantly. We trust the revised version meets the journal's expectations and remain at your disposal for any further revisions.

Kind regards,
Dr. Guillaume Ngoie Mwamba
On behalf of all co-authors
Email: guillaumengoiemwamba@gmail.com
ORCID: https://orcid.org/0000-0003-0460-877X
Point-by-Point Response to Reviewer 1 Comments
Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: A systematic review
Manuscript ID: 164227
Corresponding Author: Dr. Guillaume Ngoie Mwamba
Dear Editor,

We are grateful for the constructive feedback provided by Reviewer 1. Below is our point-by-point response detailing how each suggestion was addressed in the revised manuscript.

Reviewer Comment
Author Response
Action Taken

1.Include forest and funnel plots to visually display results.
Thank you. A meta-analysis was not conducted due to heterogeneity in study designs, intervention types, outcomes, and effect measures. We clarified this in the manuscript.
Clarified in Section 2.3 (Data Synthesis).

2.Clarify the process used for GRADE rating assignment.
GRADE ratings were independently assigned by two reviewers; discrepancies were resolved through consensus.
Added in Section 2.4 (Quality Assessment).

3.Expand the discussion of risk of bias.
We have expanded the discussion to address publication bias, selective outcome reporting, and missing data across included studies.
Expanded in Discussion, Paragraph 5.

4.Improve visual presentation of Tables 2 and 3.
Tables 2 and 3 have been revised for clarity. Statistically significant findings are now bolded.
Tables revised for visual clarity.

5.Briefly describe the Zenodo dataset in the Methods section.
We added a brief description of the extended dataset (PRISMA checklist, flowchart, summary table, CRediT matrix) in the Methods.
Added in Section 2.5 (Extended Data).

6.Tighten the writing in background and discussion sections.
Both sections were streamlined to reduce redundancy and improve clarity.
Revised Introduction and Discussion sections.

7.Ensure consistent terminology throughout the manuscript.
We revised the manuscript to ensure consistent use of terms such as “seroconversion,” “vaccine immunogenicity,” and “antibody response.”
Terminology harmonized across the manuscript.

8.Check reference formatting for Vancouver style.
All references were reviewed and updated to follow Vancouver formatting guidelines.
References updated accordingly.

9.Indicate whether the review was registered in PROSPERO.
The review was registered in PROSPERO (ID: CRD420251058388). This is now reported in the Methods section and cited in the References.
New subsection added: “Protocol Registration” in Methods and reference #18 added.

10.Clarify that findings predominantly apply to live vaccines.
We now explicitly state that the findings mainly concern live vaccines (e.g., OPV, measles), due to limited evidence on inactivated vaccines.
Added in Results and expanded in Discussion.

11.Expand policy implications to other LMICs.
We broadened the policy recommendations in the Conclusion to apply to other LMICs beyond the DRC.
Revisions made in the Conclusion section.

12.Discuss the timing of nutritional interventions.
We added discussion on how timing (pre-, co-, or post-vaccination) of supplementation influences vaccine response.
Added in Discussion, Paragraph 6.

We sincerely thank the reviewer for their thoughtful insights, which helped us improve the manuscript significantly. We trust the revised version meets the journal's expectations and remain at your disposal for any further revisions.

Kind regards,
Dr. Guillaume Ngoie Mwamba
On behalf of all co-authors
Email: guillaumengoiemwamba@gmail.com
ORCID: https://orcid.org/0000-0003-0460-877X
Competing Interests: The authors declare no competing interests. No financial, personal, or professional relationships have influenced the content or interpretation of this systematic review. Close
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COMMENTS ON THIS REPORT

Author Response 11 Sep 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

11 Sep 2025

Author Response

Point-by-Point Response to Reviewer 1 Comments
Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: A systematic review
Manuscript ID: 164227
Corresponding Author: Dr. Guillaume Ngoie Mwamba
... Continue reading Point-by-Point Response to Reviewer 1 Comments
Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: A systematic review
Manuscript ID: 164227
Corresponding Author: Dr. Guillaume Ngoie Mwamba
Dear Editor,

We are grateful for the constructive feedback provided by Reviewer 1. Below is our point-by-point response detailing how each suggestion was addressed in the revised manuscript.

Reviewer Comment
Author Response
Action Taken

1.Include forest and funnel plots to visually display results.
Thank you. A meta-analysis was not conducted due to heterogeneity in study designs, intervention types, outcomes, and effect measures. We clarified this in the manuscript.
Clarified in Section 2.3 (Data Synthesis).

2.Clarify the process used for GRADE rating assignment.
GRADE ratings were independently assigned by two reviewers; discrepancies were resolved through consensus.
Added in Section 2.4 (Quality Assessment).

3.Expand the discussion of risk of bias.
We have expanded the discussion to address publication bias, selective outcome reporting, and missing data across included studies.
Expanded in Discussion, Paragraph 5.

4.Improve visual presentation of Tables 2 and 3.
Tables 2 and 3 have been revised for clarity. Statistically significant findings are now bolded.
Tables revised for visual clarity.

5.Briefly describe the Zenodo dataset in the Methods section.
We added a brief description of the extended dataset (PRISMA checklist, flowchart, summary table, CRediT matrix) in the Methods.
Added in Section 2.5 (Extended Data).

6.Tighten the writing in background and discussion sections.
Both sections were streamlined to reduce redundancy and improve clarity.
Revised Introduction and Discussion sections.

7.Ensure consistent terminology throughout the manuscript.
We revised the manuscript to ensure consistent use of terms such as “seroconversion,” “vaccine immunogenicity,” and “antibody response.”
Terminology harmonized across the manuscript.

8.Check reference formatting for Vancouver style.
All references were reviewed and updated to follow Vancouver formatting guidelines.
References updated accordingly.

9.Indicate whether the review was registered in PROSPERO.
The review was registered in PROSPERO (ID: CRD420251058388). This is now reported in the Methods section and cited in the References.
New subsection added: “Protocol Registration” in Methods and reference #18 added.

10.Clarify that findings predominantly apply to live vaccines.
We now explicitly state that the findings mainly concern live vaccines (e.g., OPV, measles), due to limited evidence on inactivated vaccines.
Added in Results and expanded in Discussion.

11.Expand policy implications to other LMICs.
We broadened the policy recommendations in the Conclusion to apply to other LMICs beyond the DRC.
Revisions made in the Conclusion section.

12.Discuss the timing of nutritional interventions.
We added discussion on how timing (pre-, co-, or post-vaccination) of supplementation influences vaccine response.
Added in Discussion, Paragraph 6.

We sincerely thank the reviewer for their thoughtful insights, which helped us improve the manuscript significantly. We trust the revised version meets the journal's expectations and remain at your disposal for any further revisions.

Kind regards,
Dr. Guillaume Ngoie Mwamba
On behalf of all co-authors
Email: guillaumengoiemwamba@gmail.com
ORCID: https://orcid.org/0000-0003-0460-877X
Point-by-Point Response to Reviewer 1 Comments
Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: A systematic review
Manuscript ID: 164227
Corresponding Author: Dr. Guillaume Ngoie Mwamba
Dear Editor,

We are grateful for the constructive feedback provided by Reviewer 1. Below is our point-by-point response detailing how each suggestion was addressed in the revised manuscript.

Reviewer Comment
Author Response
Action Taken

1.Include forest and funnel plots to visually display results.
Thank you. A meta-analysis was not conducted due to heterogeneity in study designs, intervention types, outcomes, and effect measures. We clarified this in the manuscript.
Clarified in Section 2.3 (Data Synthesis).

2.Clarify the process used for GRADE rating assignment.
GRADE ratings were independently assigned by two reviewers; discrepancies were resolved through consensus.
Added in Section 2.4 (Quality Assessment).

3.Expand the discussion of risk of bias.
We have expanded the discussion to address publication bias, selective outcome reporting, and missing data across included studies.
Expanded in Discussion, Paragraph 5.

4.Improve visual presentation of Tables 2 and 3.
Tables 2 and 3 have been revised for clarity. Statistically significant findings are now bolded.
Tables revised for visual clarity.

5.Briefly describe the Zenodo dataset in the Methods section.
We added a brief description of the extended dataset (PRISMA checklist, flowchart, summary table, CRediT matrix) in the Methods.
Added in Section 2.5 (Extended Data).

6.Tighten the writing in background and discussion sections.
Both sections were streamlined to reduce redundancy and improve clarity.
Revised Introduction and Discussion sections.

7.Ensure consistent terminology throughout the manuscript.
We revised the manuscript to ensure consistent use of terms such as “seroconversion,” “vaccine immunogenicity,” and “antibody response.”
Terminology harmonized across the manuscript.

8.Check reference formatting for Vancouver style.
All references were reviewed and updated to follow Vancouver formatting guidelines.
References updated accordingly.

9.Indicate whether the review was registered in PROSPERO.
The review was registered in PROSPERO (ID: CRD420251058388). This is now reported in the Methods section and cited in the References.
New subsection added: “Protocol Registration” in Methods and reference #18 added.

10.Clarify that findings predominantly apply to live vaccines.
We now explicitly state that the findings mainly concern live vaccines (e.g., OPV, measles), due to limited evidence on inactivated vaccines.
Added in Results and expanded in Discussion.

11.Expand policy implications to other LMICs.
We broadened the policy recommendations in the Conclusion to apply to other LMICs beyond the DRC.
Revisions made in the Conclusion section.

12.Discuss the timing of nutritional interventions.
We added discussion on how timing (pre-, co-, or post-vaccination) of supplementation influences vaccine response.
Added in Discussion, Paragraph 6.

We sincerely thank the reviewer for their thoughtful insights, which helped us improve the manuscript significantly. We trust the revised version meets the journal's expectations and remain at your disposal for any further revisions.

Kind regards,
Dr. Guillaume Ngoie Mwamba
On behalf of all co-authors
Email: guillaumengoiemwamba@gmail.com
ORCID: https://orcid.org/0000-0003-0460-877X
Competing Interests: The authors declare no competing interests. No financial, personal, or professional relationships have influenced the content or interpretation of this systematic review. Close
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Version 4

VERSION 4 PUBLISHED 20 May 2025

Open Peer Review

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Reviewer Reports

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	1	2	3
Version 4 (revision) 11 Sep 25
Version 3 (revision) 18 Jul 25	read	read	read
Version 2 (revision) 20 Jun 25		read
Version 1 20 May 25	read

Eknath D. Ahire, MET's Institute of Pharmacy, Nashik, India
Philip C Calder, University of Southampton, Southampton, UK
Maren Johanne Heilskov Rytter, Slagelse Hospital, Slagelse, Denmark

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Reviewer Report

8 Views

08 Aug 2025 | for Version 3

Philip C Calder, University of Southampton, Southampton, England, UK

8 Views Cite this report Responses(0)

Approved

This is the third version of this article. I reviewed the previous version but not the original version. Most of the comments I raised previously have been attended to. However Section 3.2 still begins with the statement "A summary of the study characteristics is presented in Table 2." This is not the case: Table 2 reports the findings, not the characteristics. They are reported in Table S1.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Nutritional immunology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

7 Views

08 Aug 2025 | for Version 3

Eknath D. Ahire, MET's Institute of Pharmacy, Nashik, India

7 Views Cite this report Responses(0)

Approved

It appears that the author has made all the necessary changes in this updated manuscript. Therefore, I have no issues and recommend proceeding with the article to the next step.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Nutraceuticals, Pharmaceuticals

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

14 Views

08 Aug 2025 | for Version 3

Maren Johanne Heilskov Rytter, Slagelse Hospital, Slagelse, Denmark

14 Views Cite this report Responses(1)

Not Approved

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are the conclusions drawn adequately supported by the results presented in the review?

No
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

I am a paediatrician, mainly doing clinical research. In my PhD I worked on the relationship between malnutrition infections and immune function, by assessing the effect of nutritional rehabilitation on thymus size in children with severe and moderate acute malnutrition. I also did a systematic review of the relationship between malnutrition and immune parameters.

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Author Response

11 Sep 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

Notes to Reviewers – Response to Dr. Maren Johanne Heilskov Rytter

Manuscript title: Micronutrient and protein-energy supplementation enhances vaccine responses in undernourished children: Evidence from a systematic review
Version: 3 → 4
Reviewer: Dr. Maren Johanne Heilskov Rytter, Slagelse Hospital, Denmark
General Note
We sincerely thank the reviewer for the constructive and clinically insightful feedback. We have substantially revised the manuscript to address all concerns. Below is our detailed point-by-point response.

Inclusion of narrative reviews.

Reviewer comment: Most of the included articles are narrative reviews and do not fit the eligibility criteria.
Response: All narrative reviews were removed. The revised dataset now contains only randomized controlled trials, cohort, and observational studies (29 in total). The PRISMA flow diagram, Abstract, Methods, and Results have been updated accordingly.

Scientific rigor in the evidence base

Reviewer comment: The manuscript does not reliably address the subject in a scientifically sound way.
Response: The Results were rebuilt to focus exclusively on primary evidence. Table 1 (Excluded studies), Table 2 (Key findings), and Table 3 (GRADE summary) were added to transparently present study-level data and certainty of evidence.

Confounding in observational studies

Reviewer comment: Associations may be confounded by acute infection; biomarkers are acute-phase reactants.
Response: The Discussion and Limitations were revised to highlight confounding by infection and the acute-phase behavior of biomarkers such as ferritin, zinc, and vitamin D.

Fraudulent studies (Chandra RK)

Reviewer comment: Studies by Chandra RK must be excluded.
Response: All studies by Chandra RK were excluded. This is clearly stated in the Methods and shown in the PRISMA diagram under 'other reasons'.

Conclusion on sequencing vaccination

Reviewer comment: The statement suggesting nutritional rehabilitation before vaccination is potentially harmful.
Response: The Conclusion was rewritten to emphasize that vaccination should never be delayed in malnourished children. Immunization and nutrition support should be delivered concurrently.

Methods detail (PRISMA 2020 alignment)

Reviewer comment: The methodology is insufficiently detailed for replication.
Response: The Methods were expanded to include eligibility criteria, search strategy, dual screening, risk-of-bias assessment, and reasons for excluding reviews. A PRISMA 2020 flow diagram is now included.

Statistical analysis and meta-analysis

Reviewer comment: Statistical validation is required; a meta-analysis should be attempted, or reasons given for not conducting one.
Response: A statistician reviewed the dataset. Owing to high heterogeneity across interventions, outcomes, and study designs, a global meta-analysis was not feasible. However, a targeted meta-analysis of vitamin A and measles seroconversion (8 RCTs) was performed. Other outcomes were synthesized narratively using the SWiM framework.

Publication years of included trials

Reviewer comment: Several included studies are old.
Response: Although our initial cutoff was 2000, we retained select pre-2000 trials (e.g., on protein-energy supplementation) that provided unique primary data. Their inclusion is justified in the Methods, and they were critically appraised for risk of bias and interpreted with caution.

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Competing Interests

No competing interest

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Reviewer Report

17 Views

28 Jun 2025 | for Version 2

Philip C Calder, University of Southampton, Southampton, England, UK

17 Views Cite this report Responses(1)

Approved With Reservations

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Nutritional immunology

Respond to this report

Responses (1)

Author Response

09 Aug 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

Response to Reviewer Comments

Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review
Manuscript ID: f1000research-14-507

Reviewer: Dr. Philip C. Calder
Date of Review: June 28, 2025

We sincerely thank Dr. Calder for his thoughtful review, kind words, and constructive feedback. We have carefully considered all comments raised and implemented the relevant revisions in the manuscript. Below are our detailed, point-by-point responses.

Reviewer Comment 1
"Why was the search limited to 2000 onwards. Please justify."

Response:
Thank you for this observation. We have now provided a clear justification in Section 2.2 of the revised manuscript. The search was limited to studies published from 2000 onwards due to the substantial evolution in global immunization policy and child nutrition strategies over the past two decades. This includes the launch of the Global Immunization Vision and Strategy (GIVS, 2006–2015), expanded vaccine introduction in low- and middle-income countries (LMICs), and major WHO/UNICEF nutrition initiatives. These developments influenced both research context and methodological consistency, ensuring that data included in this review are more relevant, comparable, and aligned with current global standards.

Reviewer Comment 2
"The PRISMA chart (Figure 1) and text do not seem to match."

Response:
We appreciate this important remark. We have carefully revised Figure 1 (PRISMA) and ensured full alignment with the narrative description in Section 2.4 of the manuscript. Discrepancies in the number of records screened and excluded at various stages were corrected. The final version now accurately reflects the number of studies included (n=42) and the corresponding exclusion rationale, bringing the figure and text into consistency.

Reviewer Comment 3
"Table 2 does not show study characteristics as stated; it seems to summarise the findings."

Response:
Thank you for this helpful clarification. Table 2 has now been re-labeled as “Key Findings from Included Studies” to better reflect its content. In response to the need for detailed study characteristics, we have created a separate file titled Supplementary Table S1 – Study Characteristics, which includes:

Study ID
Country/Region
Nutritional Intervention
Vaccine Assessed
Author and Year
Study Design
Sample Size
Age Range
Outcome
Reference (with DOI or PMID)

This file is hosted on Zenodo as part of our living evidence synthesis initiative and will be periodically updated. The DOI for this supplementary dataset is: https://doi.org/10.5281/zenodo.15873743
Suggested Manuscript Insertions:

Methods or Results section: “Detailed study characteristics are provided in Supplementary Table S1 (Zenodo DOI: 10.5281/zenodo.15873743).”
Data Availability section: “Supplementary Table S1 is available on Zenodo and includes complete metadata for each study. The dataset will be updated as new studies become available.”

Reviewer Comment 4
"Section 2.3.3 says meta-analysis was not possible yet there is a meta-analysis of effects of vitamin A."

Response:
We acknowledge this oversight and have revised Section 2.3.3 to clarify that a comprehensive meta-analysis across all interventions was not feasible due to clinical and methodological heterogeneity. However, we were able to perform a targeted meta-analysis for a subset of studies examining the effect of vitamin A supplementation on measles vaccine seroconversion, where study designs and outcome metrics were sufficiently comparable. This partial analysis is now clearly described, and limitations (e.g., absence of forest plots and publication bias assessments) are transparently noted in the Results and Limitations sections.
We are grateful to Dr. Calder for his insightful feedback, which has greatly enhanced the quality and clarity of our systematic review. We trust that the revisions satisfactorily address all concerns.

Sincerely,
Dr. Guillaume Ngoie Mwamba (on behalf of all co-authors)
ORCID: https://orcid.org/0000-0003-0460-877X

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Competing Interests

Ther's no competing interests to declare that could be construed as influencing the validity or importance of the article (or peer review report).

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Reviewer Report

18 Views

13 Jun 2025 | for Version 1

Eknath D. Ahire, MET's Institute of Pharmacy, Nashik, India

18 Views Cite this report Responses(1)

Approved With Reservations

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

No

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Nutraceuticals, Pharmaceuticals

Respond to this report

Responses (1)

Author Response

11 Sep 2025

Guillaume NGOIE MWAMBA, Department of Public Health, Faculty of Medicine, University of Kamina, Kamina, DRC, Kamina, 00243, Democratic Republic of the Congo

Point-by-Point Response to Reviewer 1 Comments
Manuscript Title: Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: A systematic review
Manuscript ID: 164227
Corresponding Author: Dr. Guillaume Ngoie Mwamba
Dear Editor,

We are grateful for the constructive feedback provided by Reviewer 1. Below is our point-by-point response detailing how each suggestion was addressed in the revised manuscript.

Reviewer Comment
Author Response
Action Taken

1.Include forest and funnel plots to visually display results.
Thank you. A meta-analysis was not conducted due to heterogeneity in study designs, intervention types, outcomes, and effect measures. We clarified this in the manuscript.
Clarified in Section 2.3 (Data Synthesis).

2.Clarify the process used for GRADE rating assignment.
GRADE ratings were independently assigned by two reviewers; discrepancies were resolved through consensus.
Added in Section 2.4 (Quality Assessment).

3.Expand the discussion of risk of bias.
We have expanded the discussion to address publication bias, selective outcome reporting, and missing data across included studies.
Expanded in Discussion, Paragraph 5.

4.Improve visual presentation of Tables 2 and 3.
Tables 2 and 3 have been revised for clarity. Statistically significant findings are now bolded.
Tables revised for visual clarity.

5.Briefly describe the Zenodo dataset in the Methods section.
We added a brief description of the extended dataset (PRISMA checklist, flowchart, summary table, CRediT matrix) in the Methods.
Added in Section 2.5 (Extended Data).

6.Tighten the writing in background and discussion sections.
Both sections were streamlined to reduce redundancy and improve clarity.
Revised Introduction and Discussion sections.

7.Ensure consistent terminology throughout the manuscript.
We revised the manuscript to ensure consistent use of terms such as “seroconversion,” “vaccine immunogenicity,” and “antibody response.”
Terminology harmonized across the manuscript.

8.Check reference formatting for Vancouver style.
All references were reviewed and updated to follow Vancouver formatting guidelines.
References updated accordingly.

9.Indicate whether the review was registered in PROSPERO.
The review was registered in PROSPERO (ID: CRD420251058388). This is now reported in the Methods section and cited in the References.
New subsection added: “Protocol Registration” in Methods and reference #18 added.

10.Clarify that findings predominantly apply to live vaccines.
We now explicitly state that the findings mainly concern live vaccines (e.g., OPV, measles), due to limited evidence on inactivated vaccines.
Added in Results and expanded in Discussion.

11.Expand policy implications to other LMICs.
We broadened the policy recommendations in the Conclusion to apply to other LMICs beyond the DRC.
Revisions made in the Conclusion section.

12.Discuss the timing of nutritional interventions.
We added discussion on how timing (pre-, co-, or post-vaccination) of supplementation influences vaccine response.
Added in Discussion, Paragraph 6.

We sincerely thank the reviewer for their thoughtful insights, which helped us improve the manuscript significantly. We trust the revised version meets the journal's expectations and remain at your disposal for any further revisions.

Kind regards,
Dr. Guillaume Ngoie Mwamba
On behalf of all co-authors
Email: guillaumengoiemwamba@gmail.com
ORCID: https://orcid.org/0000-0003-0460-877X

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Competing Interests

The authors declare no competing interests. No financial, personal, or professional relationships have influenced the content or interpretation of this systematic review.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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Micronutrient and protein-energy supplementation enhance vaccine responses in undernourished children: Evidence from a systematic review

Abstract

Background

Objective

Methods

Results

Conclusion

Keywords

Revised Amendments from Version 3

1. Introduction

1.1 Background

1.2 Problem statement

1.3 Justification of the study

1.4 Objectives

1.5 Research questions

2. Methods

2.1 Study design

2.2 Data sources and search strategy

2.3 Inclusion and exclusion criteria

2.4 Study selection process

Figure 1. PRISMA 2020 flowchart illustrating the study selection process.

Table 1. Excluded studies with reasons.

2.5 Data extraction and quality assessment

2.6 Data synthesis and statistical analysis

2.7 Ethical considerations

2.8 Link to Haut-Lomami and Tanganyika studies

3. Results

3.1 Overview of included studies

3.2 Impact of nutritional interventions on vaccine immunogenicity

Table 2. Key findings from included studies.

Figure 2. Impact of Nutritional Interventions on Vaccine Immunogenicity.

3.3 Factors modulating the effectiveness of nutritional interventions

3.4 Findings from Haut-Lomami and Tanganyika

3.5 Summary interpretation

Table 3. GRADE summary of findings.

4. Discussion

4.1 Summary of key findings

4.2 Mechanisms underlying the impact of nutrition on immunogenicity

4.3 Comparison with global studies

4.4 Implications for immunization programs in the DRC

4.5 Limitations of the study

4.6 Future research directions

4.7 Conclusion

Ethics and consent

Data availability

Underlying data

Extended data

Acknowledgments

References

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