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Research Letter
September 2013

Effect of Routine Vaccination on Aluminum and Essential Element Levels in Preterm Infants

Author Affiliations
  • 1Midland County Department of Public Health, Midland, Michigan
  • 2Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan
  • 3Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan
  • 4Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Michigan
  • 5College of Veterinary Medicine, Iowa State University, Ames, Iowa
JAMA Pediatr. 2013;167(9):870-872. doi:10.1001/jamapediatrics.2013.108

Parenteral feedings containing more than 4 to 5 µg/kg/d of aluminum have been shown to result in neurodevelopmental delay in preterm infants.1 However, an infant at the 2-month checkup receives multiple aluminum-containing vaccines that in combination may have as high as 1225 µg of intramuscular aluminum; this is a much higher intramuscular aluminum dose than the safely recommended intravenous aluminum dose.2 Our first objective was to measure prevaccine and postvaccine levels of aluminum in preterm infants, a population at higher risk of aluminum neurotoxic effects. Our second objective was to measure prevaccine and postvaccine levels of essential elements (EE). Inflammation from trauma can cause declines in serum levels of specific EE such as zinc and selenium3-5; there may be similar EE perturbations secondary to vaccination-induced inflammation.

Methods

After institutional review board approval and parental consent, 15 preterm infants scheduled for routine 2-month vaccinations while still hospitalized were recruited in the Sparrow Hospital neonatal intensive care unit in East Lansing, Michigan. One day prior to scheduled vaccination, 0.25-mL blood and 12-hour urine collections were obtained. Prevnar 13, PedvaxHIB, and Pediarix vaccines were administered, in total containing 1200 µg of aluminum, as determined by company literature and confirmed by testing a set of these vaccines in our laboratory. One day postvaccination, 0.25-mL blood and 12-hour urine collections were obtained. Aluminum and EE concentrations were quantified by inductively coupled plasma mass spectrometry in serum and urine. Urine data were normalized using creatinine concentration. Two-tailed P values <.05 on paired t tests (SAS software; SAS Institute Inc) were considered significant.

Results

No significant change in levels of urinary or serum aluminum were seen after vaccination (Table). Significant declines were noted postvaccination in serum iron (58.1%), manganese (25.9%), selenium (9.5%), and zinc (36.4%) levels, as was a significant increase in serum copper level (8.0%). A rise in selenium level was the only significant urine change. No significant postvaccine urinary or serum level changes were noted for phosphorus, sulfur, potassium, cobalt, nickel, molybdenum, nickel, or sodium. All participants had normal serum creatinine levels.

Table.  
Characteristics of 15 Study Participants
Characteristics of 15 Study Participants
Discussion

We were reassured to find no significant postvaccine rise in serum aluminum level after vaccination of preterm infants with vaccines containing a total of 1200 µg of aluminum. The average study infant weighed 2200 g at vaccination and thus received about 545 µg/kg of intramuscular aluminum. Thus far, infant aluminum-adjuvant dosage safety has relied on animal-to-human extrapolations6 and modeling of infant pharmacokinetics based on extrapolation from adult pharmacokinetic data to infant glomerular filtration rates.7 We know of no study prior assessing actual aluminum blood level responses to vaccination in human infants.

Our study is small (N = 15), but one of the key studies for examining the postvaccine rise in aluminum blood levels is a study of only 6 rabbits.6 That study showed that postvaccination serum aluminum levels rose 1%, peaking within 24 hours of vaccination. We thus chose 24 hours as our postvaccine measurement point.6

We observed a significant decline of serum levels of iron, manganese, zinc, and selenium and a significant increase in copper level (a marker of inflammation) on the day after vaccination. These same EE have been described as declining after inflammation from trauma or burns.3-5 Of the EE that are not known to be associated with inflammation-induced perturbations (ie, sodium and potassium), we found stability of these levels after vaccination.

None of our participants had changes in nutrition type, medications, and/or blood transfusions during the course of the study. Therefore, it is reasonable to assume that the EE changes were a result of vaccination. Because of the aforementioned stability of aluminum-influencing factors (ie, nutrition and medications), postvaccine aluminum changes, if they were to have occurred, could have been attributed to vaccination dosage.

Sequestration of certain EE into tissues with a subsequent reduction of serum levels of corresponding EE is an important component of the innate immune system.8 This immune response has likely evolved as a host defense mechanism to deprive microbial organisms of their nutrients.8 While this vaccine-induced homeostatic shift in EE levels has not previously been described in humans, it has been documented in horses. After vaccination of horses, iron and other EE become temporarily sequestered within hepatocytes and other cell types.9,10 As has also been found in other studies of EE after inflammation,3-5 we found a significant rise in postvaccine urinary selenium levels, suggesting that selenium is at least partially excreted, rather than completely sequestered like other micronutrients for which there was no postvaccination urinary rise.

Limitations of our study include its small sample size and single postvaccine measurement, as well as the absence of markers of inflammation to help quantify the inflammatory response. However, because trace elements play important roles in neurodevelopment and the immune system, the effect of vaccination on EE should be investigated in more detail.

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Article Information

Corresponding Author: Tammy Z. Movsas, MD, MPH, Midland County Department of Public Health, 220 W Ellsworth, Midland, MI 48640 (tmovsas@gmail.com).

Published Online: July 15, 2013. doi:10.1001/jamapediatrics.2013.108.

Author Contributions: All authors have seen and approved the submission of this manuscript and take full responsibility for it.

Study concept and design: Movsas, Paneth, Gewolb.

Acquisition of data: Rumbeiha, Zyskowski, Gewolb.

Analysis and interpretation of data: Movsas, Paneth, Gewolb.

Drafting of the manuscript: Movsas, Paneth, Zyskowski.

Critical revision of the manuscript for important intellectual content: Movsas, Paneth, Rumbeiha, Gewolb.

Statistical analysis: Movsas, Paneth, Gewolb.

Administrative, technical, and material support: Movsas, Paneth, Zyskowski, Gewolb.

Study supervision: Movsas, Paneth, Gewolb.

Conflict of Interest Disclosures: None reported.

Funding/Support: This project was undertaken by Dr Movsas while she was a postdoctoral fellow in the National Institutes of Health T32 Training Program in Perinatal Epidemiology at Michigan State University, grant 2T32HD046377.

References
1.
Bishop  NJ, Morley  R, Day  JP, Lucas  A.  Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions.  N Engl J Med. 1997;336(22):1557-1561.PubMedGoogle ScholarCrossref
2.
Charney  PJ; American Society for Parenteral and Enteral Nutrition Aluminum Task Force.  A.s.p.e.N. statement on aluminum in parenteral nutrition solutions.  Nutr Clin Pract. 2004;19(4):416-417.PubMedGoogle ScholarCrossref
3.
Agay  D, Anderson  RA, Sandre  C,  et al.  Alterations of antioxidant trace elements (Zn, Se, Cu) and related metallo-enzymes in plasma and tissues following burn injury in rats.  Burns. 2005;31(3):366-371.PubMedGoogle ScholarCrossref
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Wang  G, Lai  X, Yu  X, Wang  D, Xu  X.  Altered levels of trace elements in acute lung injury after severe trauma.  Biol Trace Elem Res. 2012;147(1-3):28-35.PubMedGoogle ScholarCrossref
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Selmanpakoğlu  AN, Cetin  C, Sayal  A, Işimer  A.  Trace element (Al, Se, Zn, Cu) levels in serum, urine and tissues of burn patients.  Burns. 1994;20(2):99-103.PubMedGoogle ScholarCrossref
6.
Flarend  RE, Hem  SL, White  JL,  et al.  In vivo absorption of aluminium-containing vaccine adjuvants using 26Al.  Vaccine. 1997;15(12-13):1314-1318.PubMedGoogle ScholarCrossref
7.
Mitkus  RJ, King  DB, Hess  MA, Forshee  RA, Walderhaug  MO.  Updated aluminum pharmacokinetics following infant exposures through diet and vaccination.  Vaccine. 2011;29(51):9538-9543.PubMedGoogle ScholarCrossref
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Johnson  EE, Wessling-Resnick  M.  Iron metabolism and the innate immune response to infection.  Microbes Infect. 2012;14(3):207-216.PubMedGoogle ScholarCrossref
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Andersen  SA, Petersen  HH, Ersbøll  AK, Falk-Rønne  J, Jacobsen  S.  Vaccination elicits a prominent acute phase response in horses.  Vet J. 2012;191(2):199-202.PubMedGoogle ScholarCrossref
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Mills  PC, Auer  DE, Kramer  H, Barry  D, Ng  JC.  Effects of inflammation-associated acute-phase response on hepatic and renal indices in the horse.  Aust Vet J. 1998;76(3):187-194.PubMedGoogle ScholarCrossref
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    2 Comments for this article
    EXPAND ALL
    Not Enough Time Allowed for Alum Particles to Appear in Bloodstream
    Daniel Jacobs | independent health researcher
    Taking a single blood sample from the vaccinated infants just one day after they received their 2-month vaccinations containing aluminum adjuvant, did not allow enough time to see if the alum particles would end up in their bloodstream. A team of French scientists studied the movement through mouse bodies of nano-particles resembling aluminum adjuvant particles in infant vaccines (Slow CCL2-dependent translocation of biopersistent particles from muscle to brain" (http://www.biomedcentral.com/content/pdf/1741-7015-11-99.pdf), published in "BMC Medicine" in April 2013. The French researchers injected fluorescent particles that mimic the action of alum nano-particles into the tibialis anterior (lower leg) muscle of mice. One strain of mice they injected had a leaky blood/brain barrier (BBB), modeling human infants' porous BBB. Injected particles quickly traveled from the mice's muscle to draining lymph nodes (DLNs), getting gobbled up in the process by macrophages and dendritic cells. On day 4, nano-particles — still mostly engulfed by white cells — appeared in the mice's blood, increasing to a peak blood concentration at day 21. By that time, particles had appeared in the mice's brains, beneath the pia mater; mostly freed from their original white-cell hosts, the particles had now moved inside or onto the surface of brain cells. They continued accumulating in the brains — mainly in grey matter — for up to 90 days in one strain of mice, and up to 180 days in another. Here's a possible travel route for alum particles injected into an infant along with a vaccine: Alum particles — complexed with vaccine antigens — get injected into the infant's vastus lateralis (outer thigh) muscle. Seeping through the fluid between muscle cells, the particles enter lymphatic capillaries, then flow into superficial inguinal lymph nodes. Exiting those lymph nodes, they continue their journey in lymphatic vessels upward through the abdomen. Moving through the thoracic duct up towards the collar bone, they enter the left subclavian vein to merge with the bloodstream. From there they empty into the superior vena cava, which carries them into the heart for pumping to the lungs, and then throughout the body. If it took four days for particles injected into mice's leg muscles (in the French study) to work their way into the bloodstream. Should we reasonably expect alum particles injected into the thigh muscles of infants to appear in their blood in a single day?

    CONFLICT OF INTEREST: None Reported
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    Missing Data Sets
    Summer Anderson | Entrepreneur
    It seems like the data for post-vaccination urine and serum levels are missing.
    CONFLICT OF INTEREST: None Reported
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