ABSTRACT
Although thimerosal, an ethylmercury-based preservative, has been removed from most pediatric vaccines in the United States, some multidose vaccines, such as influenza vaccines, still contain thimerosal. Considering that a growing number of studies indicate involvement of the gut microbiome in infant immune development and vaccine responses, it is important to elucidate the impact of pediatric vaccines, including thimerosal-containing vaccines, on gut microbial structure and function. Here, a non-human primate model was utilized to assess how two vaccine schedules affect the gut microbiome in infants (5-9 days old) and juveniles (77-88 weeks old) through 16S ribosomal RNA sequencing and metabolomics analyses of the fecal samples. Two treatment groups (n = 12/group) followed either the vaccine schedule that was in place during the 1990s (intensive exposure to thimerosal) or an expanded schedule administered in 2008 (prenatal and postnatal exposure to thimerosal mainly via influenza vaccines), and were compared with a control group (n = 16) that received saline injections. The primary impact on gut microbial structure and function was age. Although a few statistically significant impacts of the two common pediatric vaccine schedules were observed when confounding factors were considered, the magnitude of the differences was small, and appeared to be positive with vaccination.
Subject(s)
Gastrointestinal Microbiome , Animals , Feces/microbiology , Gastrointestinal Microbiome/drug effects , Immunization Schedule , Influenza Vaccines/immunology , Macaca mulatta/growth & development , Metabolomics , RNA, Ribosomal, 16S/chemistry , RNA, Ribosomal, 16S/genetics , Thimerosal/pharmacology , VaccinationABSTRACT
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Some anecdotal reports suggest that ASD is related to exposure to ethyl mercury, in the form of the vaccine preservative, thimerosal, and/or receiving the measles, mumps, rubella (MMR) vaccine. Using infant rhesus macaques receiving thimerosal-containing vaccines (TCVs) following the recommended pediatric vaccine schedules from the 1990s and 2008, we examined behavior, and neuropathology in three brain regions found to exhibit neuropathology in postmortem ASD brains. No neuronal cellular or protein changes in the cerebellum, hippocampus, or amygdala were observed in animals following the 1990s or 2008 vaccine schedules. Analysis of social behavior in juvenile animals indicated that there were no significant differences in negative behaviors between animals in the control and experimental groups. These data indicate that administration of TCVs and/or the MMR vaccine to rhesus macaques does not result in neuropathological abnormalities, or aberrant behaviors, like those observed in ASD.
Subject(s)
Autistic Disorder/diagnosis , Brain Diseases/diagnosis , Thimerosal/administration & dosage , Vaccines/administration & dosage , Amygdala/drug effects , Amygdala/metabolism , Animals , Animals, Newborn , Autistic Disorder/chemically induced , Blotting, Western , Brain Diseases/chemically induced , Calbindins/metabolism , Calcium-Binding Proteins/metabolism , Cerebellum/drug effects , Cerebellum/metabolism , Glial Fibrillary Acidic Protein/metabolism , Glutamate Decarboxylase/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Immunohistochemistry , Macaca mulatta , Male , Microfilament Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Neuropathology/methods , Preservatives, Pharmaceutical/administration & dosage , Preservatives, Pharmaceutical/adverse effects , Thimerosal/adverse effects , Time Factors , Vaccination/methods , Vaccines/adverse effectsABSTRACT
BACKGROUND: In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal-containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today. OBJECTIVES: The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model. METHODS: We administered vaccines to six groups of infant male rhesus macaques (n = 12-16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles-mumps-rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age-matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate. RESULTS: We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors. CONCLUSIONS: This comprehensive 5-year case-control study, which closely examined the effects of pediatric vaccines on early primate development, provided no consistent evidence of neurodevelopmental deficits or aberrant behavior in vaccinated animals.
