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

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}

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.

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.

1.

Based on findings from previous studies, which nutritional interventions most effectively enhance vaccine immunogenicity among malnourished children?

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

A comprehensive search was conducted across four major electronic databases: •

PubMed

The search was supplemented by: •

Reviewing reference lists of key articles.

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

Malnutrition AND vaccination

The search was limited to peer-reviewed articles published between 2000 and 2024 in English and French.

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.

2.3.2 Exclusion criteria •

Studies conducted only on adults or non-malnourished children.

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 meta-analysis was not feasible. Therefore, no forest or funnel plots were generated. Instead, a narrative synthesis was conducted, summarizing findings across studies by vaccine type and nutritional intervention.

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.

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 1,017 records (due to duplication and irrelevance), 2,228 abstracts were screened. Of these, 2,035 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, 193 full-text articles were assessed in detail. An additional 151 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, 42 studies met all eligibility criteria and were included in the final systematic review.

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.

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.

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

Study details (author, year, country, study type).

To enhance transparency and reproducibility, we have deposited the extended dataset in Zenodo (DOI: 10.5281/zenodo.15281976). This dataset includes the PRISMA 2020 checklist, the PRISMA flow diagram (Figure 1), Table 1 summarizing nutritional interventions and vaccine response outcomes, and the CRediT author contribution matrix. 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 Tool ¹⁹ was used to assess RCTs, considering: •

Random sequence generation

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.

2.6.1 Qualitative synthesis

A narrative synthesis was performed, categorizing studies by: •

Type of nutritional intervention.

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

Effect sizes were interpreted as: •

OR >1 → Nutritional intervention increased seroconversion.

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

Transparency in study selection and reporting.

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.

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.

After screening 3,245 records, a total of 42 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 = 15 studies)

The vaccines assessed in the studies included: •

Polio vaccine (n = 19 studies)

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

3.2.1 Vitamin A supplementation and vaccine response •

15 studies assessed the effect of vitamin A on vaccine immunogenicity. ^{4, 23– 36}

Mechanisms identified: •

Vitamin A enhances B-cell function, leading to improved antibody production. ³⁶

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}

Findings from Haut-Lomami and Tanganyika: •

Data from DRC studies ⁴ showed that zinc supplementation before OPV administration increased seroconversion rates by 20%.

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}

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.

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

3.3.1 Age and timing of supplementation •

Children under 12 months showed the greatest improvement in vaccine responses with micronutrient supplementation.

3.3.2 Severity of malnutrition •

The impact of nutrition on immunogenicity varied by malnutrition severity:

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.

•

High malnutrition prevalence negatively affected vaccine response.

1.

Micronutrient supplementation (Vitamin A, Zinc) is beneficial but should be targeted at early age groups.

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

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 that micronutrient supplementation (vitamin A, zinc), protein-energy rehabilitation, and other nutritional interventions can enhance vaccine seroconversion rates, particularly for live vaccines such as measles and oral polio vaccine (OPV).

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.

4.2.1 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

4.2.2 Impact of malnutrition on vaccine responses

Malnutrition is associated with immunosuppression, which affects both innate and adaptive immunity. ^{58, 59} Children with chronic malnutrition exhibit: •

Reduced B-cell function, leading to lower antibody production after vaccination.

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.

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. ⁶² 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%. ⁶³

However, in severely malnourished children, the benefit of vitamin A was less pronounced, possibly due to systemic immune suppression and multiple nutritional deficiencies. ⁶⁰

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. ⁶⁴

However, zinc had no effect on inactivated vaccines like hepatitis B and DTP, suggesting that its benefits are specific to mucosal immunity. ⁶⁵

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

4.4.1 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.

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.

4.4.3 Strengthening community-based nutrition programs •

Community health workers should actively screen and treat malnutrition in immunization settings.

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.

1.

Heterogeneity in Study Designs – Studies varied in intervention types and assessment methods, which may introduce bias. While randomized controlled trials (RCTs) were prioritized where available, high-quality observational studies were included to ensure contextual relevance and comprehensiveness, particularly in regions where RCT data is limited.

1.

Longitudinal studies assessing the long-term effects of nutritional interventions on vaccine immunity.

This review confirms that nutritional interventions—particularly vitamin A, zinc, and comprehensive rehabilitation—enhance vaccine immunogenicity in malnourished children. 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.

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.