From the Cover: Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology

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.Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder presenting in early childhood with a current prevalence ranging from 0.7% to 2.64% in the United States (1). ASD is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior (2). Genetic and environmental factors have been found to play a role in the disorder (3, 4). The neuropathology of autism is now beginning to be understood; however, there is still much to be learned. Thus far, the major neuropathological changes observed in autism are changes in neuronal size in the limbic system; decreased numbers of Purkinje cells in the cerebellum; abnormalities in the brainstem, neocortex, amygdala, and hippocampus; features of cortical dysgenesis or migration disturbances; and alterations in GABAergic and cholinergic systems [see Gadad et al. (3) and Amaral (5) for reviews]. In many autism studies, comorbid conditions such as seizure disorders or intellectual disabilities contribute to the heterogeneity of the neuropathology.An association between exposure to thimerosal-containing vaccines (TCVs) and developmental abnormalities has been debated since 1999 when the US Food and Drug Administration determined that children receiving multiple TCVs at a young age were at risk for exceeding the Environmental Protection Agency’s safe exposure limits for methylmercury (MeHg). Results from an Institute of Medicine (IOM) review on the safety of childhood vaccines found that there was not sufficient evidence to render an opinion on the relationship between exposure to TCVs or the measles, mumps, rubella (MMR) vaccine and developmental disorders in children (IOM 2001) (6). The IOM review did, however, note the possibility of such a relationship and recommended further studies be conducted. A more recent second review of TCVs and autism (IOM 2004) (7) came to the same conclusion reached earlier: that there was no epidemiological data to support a relationship between TCVs and childhood developmental disorders. Several epidemiological studies sought to determine whether TCVs resulted in neurodevelopmental disorders including autism; however, both nonsignificant and significant associations have been reported (8–12). Significant associations have been reported by Thompson et al. (11), who investigated the association between TCVs and immune globulins early in life and neuropsychological outcomes in children at 7–10 y of age. The data included the evaluation of 1,047 children and their biological mothers and 24 neuropsychological tests. The only variable that was statistically significant was tics; children who were exposed to higher doses of thimerosal were more likely to exhibit tics. In a follow-up study by Barile et al. (12) examining a subset of the data from Thompson et al. (11), they found a significant association between thimerosal dosage and tics, but only in boys. They found no statistically significant associations between thimerosal exposure from vaccines early in life and six of the seven neuropsychological constructs examined.Concern regarding the safety of childhood vaccines has had a major impact on immunization rates (13–16). It is of great importance to determine whether TCVs play a significant role in altering brain development and/or behaviors that mimic changes observed in autism. The present study provides a comprehensive analysis of the influence of TCVs on the brain and behavior in a nonhuman primate model. The study includes 79 rhesus macaques in six groups (n = 12–16 per group): (i) Control, a control group given saline injections; (ii) 1990s Pediatric, replicating the pediatric vaccination schedule used for infants in the 1990s that included several TCVs; (iii) 1990s Primate, replicating the pediatric vaccination schedule used in the 1990s but accelerated fourfold representing the faster development of infant macaques; (iv) TCVs, only TCVs and no MMR; (v) MMR, only the MMR vaccine; and (vi) 2008, the expanded pediatric schedule used in 2008 (and very similar to that used today, which also includes a prenatal influenza vaccine; 17).

Table 1.

Vaccination schedules used for the six groups of animals

Group	N	Vaccines administered
Control	16	None, all saline placebos
1990s Pediatric	12	Vaccine regimen as recommended in the 1990s
1990s Primate	12	Vaccine regimen as recommended in the 1990s accelerated fourfold
TCV’s	12	All TCVs and saline placebo for MMR
MMR	15	MMR only, all others replaced with saline placebo
2008	12	Vaccine regimen recommended in 2008

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