Trace elements, inflammation, and rotavirus vaccine response among a cohort of infants in El Alto, Bolivia Open Access

Miller, Christopher (Spring 2018)

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Rotavirus infection is the most common cause of fatal diarrhea in infants despite the existence of effective rotavirus vaccines. Over 90% of rotavirus deaths occur in low- and middle-income countries (LMIC’s). One such LMIC, Bolivia, experiences the highest under-5 mortality rate in Spanish speaking South America, with numerous deaths attributable to rotavirus infection. Yet, in LMIC’s like Bolivia, rotavirus vaccines are less effective than in high-income countries. The Nutrition, Immunology, Diarrhea in Infants (NIDI) study in El Alto, Bolivia was created to explore the factors related to reduced immune response to the rotavirus vaccine in Bolivia. NIDI investigators enrolled 461 infants in the study. Blood was drawn up to three times – once pre-vaccination, at approximately 2 months, and twice post-vaccination, at approximately 6 months and 12-18 months – and analyzed for several biomarkers, including: serum concentrations of calcium, copper, iron, magnesium, and zinc; concentrations of systemic inflammatory markers α-1-acid glycoprotein (AGP) and C-reactive protein (CRP); and rotavirus-specific IgA antibodies. There is a need to understand how micronutrient levels play a role in the rotavirus vaccine’s reduced performance in low income settings. To meet this need, a secondary analysis was completed on the NIDI data. Spearman’s correlation analyses revealed moderate positive correlations between serum copper and both AGP (ρ = 0.51-0.71, p <0.01) and CRP (ρ = 0.46-0.55, p<0.01). The distributions of values for trace element concentrations were described, with many values falling outside of reference ranges in the literature, especially values for serum magnesium and zinc (up to 55% and 67% of the time, respectively). There were no significant relationships between any serum element and rotavirus-specific IgA seroconversion using logistic regression analyses, but Spearman’s analyses revealed inverse relationships between both serum copper (ρ = -0.14, p=0.01) and CRP (ρ = -0.16, p<0.01) and the fold-change in rotavirus-specific IgA following vaccination. These results indicate a need to account for inflammation when assessing copper status, as well as a need to refine the reference ranges for serum element concentrations in infants. Furthermore, the findings suggest that higher inflammatory burden may blunt the strength of the immune response to rotavirus vaccination.

Table of Contents

Table of Contents

Rotavirus Infection & Vaccination: A literature review of the role of trace elements and inflammation in vaccine response. 3

I. Rotavirus. 3

I.a. The Virus. 3

I.b. Transmission and Pathogenesis. 4

I.c. Clinical Symptoms, Diagnosis, and Treatment 4

II. Immunity and Vaccination. 5

II.a. Immunity. 5

II.b. Rotavirus Vaccination. 7

II.c. Reduced Vaccine Effectiveness in Low and Middle-Income Countries. 8

III. Nutrition and Trace Elements. 8

IV.a. Copper 10

IV.b. The Copper/Zinc Ratio. 12

IV.c. Magnesium, Calcium, and Iron. 13

IV.d. Inflammation and Elemental Micronutrient Concentrations. 15

IV.a. Bolivia. 17

IV.b. Rotavirus Vaccination in Bolivia. 17

IV.c. El Alto. 17

IV.d. Nutrition, Immunology, Diarrhea in Infants Study. 18

V. Conclusion. 18

VI. Significance. 19

Analysis. 21

VII. Methods. 21

VII.a. The NIDI Study Population and Design. 21

VII.b. Statistical Methods. 22

VII.c. Linear Regression to Correct Copper for AGP and CRP. 23

VIII. Results. 25

IX. Discussion. 31

X. Conclusion. 37

XI. Public Health Implications. 38

XII. Tables. 40

XIII. Appendices. 47

References. 50

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