European Journal of Cardiovascular Medicine

Vaccination is a cornerstone of pediatric public health, significantly reducing morbidity and mortality from preventable infectious diseases worldwide. Despite the widespread implementation of immunization programs, variability in vaccine-induced immune responses among children remains a pressing concern, especially in low- and middle-income countries (LMICs) [1]. Emerging evidence indicates that nutritional status is a key determinant of vaccine efficacy in early life, influencing both humoral and cellular immune responses [2].

Infants and young children are particularly susceptible to malnutrition due to rapid growth demands, frequent infections, and limited dietary diversity [3]. Both macronutrient deficits and micronutrient deficiencies can impair the development and function of the immune system. Undernourished children often exhibit altered thymic function, reduced mucosal immunity, and diminished antibody production post-vaccination [4]. Furthermore, deficiencies in specific micronutrients such as vitamin A, vitamin D, zinc, and iron are independently associated with suboptimal vaccine responses [5].

Vitamin A is essential for the integrity of epithelial barriers and mucosal immunity and is known to enhance the immunogenicity of vaccines like measles and polio [6]. Zinc, a trace element critical for DNA synthesis and cell-mediated immunity, has shown to augment immune response to rotavirus and hepatitis B vaccines in previous trials [7]. Vitamin D modulates the innate immune response and cytokine production, with observational studies linking its deficiency to reduced seroprotection following influenza vaccination [8]. Iron is vital for lymphocyte proliferation and oxidative burst activity in neutrophils; its deficiency may attenuate the response to pneumococcal and diphtheria vaccines [9].

Given these mechanistic links, the World Health Organization recommends assessing and correcting nutritional deficiencies in high-risk populations prior to immunization where feasible [10]. However, real-world data examining the impact of integrated nutritional strategies on vaccine immunogenicity in community settings remains limited.

This study aims to assess whether nutritional interventions—specifically micronutrient supplementation and dietary improvement—can enhance immune responses to routine childhood vaccines in infants and young children. By understanding these interactions, the findings could support the integration of nutrition with immunization services to maximize vaccine effectiveness.

Study Design and Setting

A prospective, observational cohort study was conducted over a 12-month period across three government-affiliated pediatric outpatient clinics in southern India. The study evaluated the impact of targeted nutritional interventions on the immunological response to routine vaccinations among infants and young children.

Participants

A total of 300 healthy children aged 6 months to 5 years who were scheduled to receive any of the following vaccines were recruited: diphtheria-tetanus-pertussis (DTP), hepatitis B, measles-mumps-rubella (MMR), and pneumococcal conjugate vaccine (PCV). Eligibility criteria included no prior vaccination with the target vaccine, absence of acute infection at baseline, no known immunodeficiency, and informed consent from the parent or guardian.

Participants were divided into two groups based on caregiver consent for nutritional counseling and supplementation:

• Intervention Group (n=150): Received daily micronutrient supplementation (vitamin A, vitamin D, zinc, and iron) for four weeks prior to and two weeks following vaccination. Additionally, families received nutritional counseling by a trained dietitian.
• Control Group (n=150): Received standard immunization without additional nutritional support or counseling.

Nutritional Assessment

Baseline assessment included anthropometric measurements (height, weight, and mid-upper arm circumference) using WHO growth standards. Nutritional status was categorized into normal, stunted, wasted, or underweight. Serum levels of vitamin A (retinol), 25-hydroxyvitamin D, zinc, and ferritin were measured via chemiluminescent immunoassay. Hemoglobin levels were determined using a portable Hemocue device.

Dietary intake was recorded using a validated 24-hour recall form over two non-consecutive weekdays and one weekend day. Nutrient intakes were analyzed using the Indian Food Composition Tables and compared with Recommended Dietary Allowances (RDA) for age.

Vaccination and Immunological Assessment

All participants received vaccines through the Universal Immunization Programme (UIP) under standard cold chain procedures. Blood samples (2–3 mL) were collected from each child prior to vaccination and at 28–35 days post-vaccination. Serum was separated and stored at −80°C until analysis.

Antibody titers specific to vaccine antigens were measured using enzyme-linked immunosorbent assay (ELISA) kits validated for pediatric use. Seroconversion was defined as a fourfold rise in antibody titer from baseline or achievement of threshold levels specified for each vaccine. Laboratory staff were blinded to group allocation to minimize bias.

Statistical Analysis

Data were entered into Microsoft Excel and analyzed using SPSS v27.0. Continuous variables were expressed as mean ± standard deviation or median (IQR), while categorical variables were presented as frequencies and percentages. Comparisons between groups were conducted using chi-square test (for categorical variables) and independent t-test or Mann–Whitney U test (for continuous variables). Multivariate logistic regression was used to adjust for potential confounders such as age, sex, and baseline nutritional status. A p-value <0.05 was considered statistically significant.

Participant Characteristics

Out of 312 initially screened children, 300 were enrolled—150 in the intervention group and 150 in the control group. Baseline demographic and anthropometric variables were comparable between groups (p > 0.05) (Table 1). The mean age was 24.7 ± 8.6 months, with a male-to-female ratio of 1.1:1. Nearly 30% of all children were underweight, and more than 40% had at least one micronutrient deficiency.

Table 1: Baseline Characteristics of the Study Population

Nutritional Biomarkers and Supplementation

Among children in the intervention group, mean serum levels of vitamin A, zinc, and 25(OH)D improved significantly after supplementation (p < 0.001). In contrast, no significant change was observed in the control group (Table 2). At follow-up, only 15.3% of children in the intervention group had any micronutrient deficiency compared to 41.3% in the control group.

Table 2: Change in Serum Micronutrient Levels Pre- and Post-Intervention

Seroconversion and Antibody Titers

Post-vaccination seroconversion was significantly higher in the intervention group for all vaccines studied. The most pronounced difference was observed for measles and hepatitis B, where the intervention group had >90% seroconversion (Table 3). Children who remained micronutrient deficient post-supplementation showed notably lower response rates.

Table 3: Seroconversion Rates Post-Vaccination

Quantitative Antibody Responses

Quantitative assessment showed significantly higher mean post-vaccination antibody titers in the intervention group. Antibody levels for hepatitis B and MMR were elevated by 30–40% compared to controls (Table 4). Regression analysis confirmed that baseline levels of vitamin A and zinc were strong predictors of vaccine-induced antibody titers (p < 0.01 for both).

Table 4: Mean Post-Vaccination Antibody Titers (mIU/mL)

Summary of Key Findings

• Nutritional supplementation improved serum levels of vitamin A, zinc, and vitamin D significantly.
• The intervention group had 13–20% higher seroconversion rates across all vaccines.
• Antibody titers were 30–40% higher in the intervention group than in controls.
• Deficiencies in zinc and vitamin A were the strongest negative predictors of immunogenicity

This study highlights the critical role of nutritional interventions in enhancing vaccine efficacy among infants and young children. The findings reveal that children who received micronutrient supplementation and dietary counseling demonstrated significantly higher seroconversion rates and elevated antibody titers across all major vaccines studied—DTP, MMR, hepatitis B, and pneumococcal. These results strongly support the hypothesis that nutritional status is a modifiable determinant of immune response to vaccination in early childhood [11].

Micronutrient deficiencies, particularly of vitamin A, vitamin D, zinc, and iron, were prevalent among the study population at baseline—consistent with the burden reported in many low- and middle-income countries [12]. Correcting these deficiencies through supplementation led to substantial improvements in both humoral immunity and nutritional biomarkers. Notably, post-vaccination antibody titers were significantly higher in children with replete vitamin A and zinc levels, reinforcing previous evidence of the immunomodulatory effects of these nutrients [13].

Vitamin A plays a central role in maintaining mucosal integrity and modulating T-helper cell function, both of which are crucial for optimal vaccine-induced immunity. Previous mechanistic and clinical studies have linked vitamin A supplementation with improved seroprotection against measles, rotavirus, and polio vaccines [14]. Similarly, zinc is essential for thymic development, lymphocyte proliferation, and cytokine production. Zinc deficiency has been associated with impaired antibody responses to oral and parenteral vaccines, including hepatitis B and rotavirus [15]. In the present study, zinc supplementation correlated with a 17% increase in hepatitis B seroconversion, underscoring its functional relevance.

Vitamin D, often overlooked in vaccine research, is now recognized for its regulatory effects on innate immune activation and antigen presentation. In our cohort, post-supplementation improvement in serum 25(OH)D levels was associated with enhanced responses to pneumococcal and MMR vaccines. This aligns with recent reports showing that sufficient vitamin D levels can improve antigen-specific T-cell responses and enhance long-term immunity [16].

Iron, though traditionally linked to anemia, has broader implications for immune function. Iron deficiency may limit oxidative burst activity and impair cell-mediated immunity, particularly in response to bacterial polysaccharide vaccines like PCV. While the magnitude of improvement in antibody titers was modest for iron alone, its combination with other micronutrients likely produced synergistic benefits [17].

Beyond individual nutrients, the study’s findings also reflect the broader immunological impact of correcting subclinical malnutrition. Malnourished children typically exhibit thymic atrophy, dysregulated cytokine responses, and diminished B-cell maturation—all of which compromise vaccine effectiveness [18]. Our results showed that underweight and stunted children had lower baseline responses, but nutritional recovery through targeted support allowed partial immune restoration and improved vaccine outcomes.

Importantly, these findings have practical implications. Integrating nutritional screening and supplementation into routine immunization services could offer a cost-effective strategy to enhance vaccine performance in resource-constrained settings. Public health programs may benefit from revisiting vaccine delivery platforms and including pre-vaccination nutritional counseling, particularly in high-risk pediatric populations [19].

Limitations of this study include its observational design, which restricts causal inference. Although efforts were made to minimize selection bias and control confounding through multivariate analysis, randomized controlled trials are needed to confirm these results. Additionally, the study did not assess long-term antibody persistence or memory responses, which could provide deeper insights into the durability of nutrition-enhanced immunity. Despite these limitations, the consistency of the findings across multiple vaccine types strengthens the internal validity of the conclusions.

In summary, this study adds to the growing body of literature emphasizing the interplay between nutrition and immunization. The results advocate for a paradigm shift in pediatric preventive care—where nutrition and vaccination are not siloed but are integrated interventions aimed at optimizing child health outcomes [20].

The present study demonstrates that improving nutritional status—particularly through targeted supplementation of vitamin A, vitamin D, zinc, and iron—significantly enhances vaccine-induced immune responses in infants and young children. Children who received nutritional support exhibited higher seroconversion rates and greater antibody titers across all vaccines assessed, highlighting the synergistic role of adequate nutrition in promoting effective immunization.

These findings underscore the need to integrate nutrition-focused strategies into immunization programs, especially in settings where childhood malnutrition is prevalent. Pre-vaccination nutritional screening and timely correction of deficiencies could serve as low-cost, high-impact interventions to optimize vaccine efficacy and close the immunity gap in vulnerable populations.

Going forward, public health initiatives should adopt a more holistic approach that views nutrition and immunization as interdependent elements of child health. Future research should focus on long-term outcomes, cost-effectiveness, and scalability of such integrated programs, including their implementation across diverse socio-economic settings. By aligning nutritional interventions with routine immunization efforts, policymakers and healthcare providers can ensure that children not only receive vaccines—but that their bodies are prepared to respond to them effectively.

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