Delayed Acquisition of Neonatal Reflexes in newborn Primates receiving A Thimerosal-containing HepatitiS B Vaccine: influence of gestational age and Birth weight

Delayed Acquisition of Neonatal Reflexes in newborn Primates receiving A Thimerosal-containing HepatitiS B Vaccine: influence of gestational age and Birth weight
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Laura Hewitsona, c, , , Lisa A. Housera, Carol Stottc, Gene Sackettb, Jaime L. Tomkoa, David Atwoodd, Lisa Blued, E. Railey Whited and Andrew J. Wakefieldc

doi:10.1016/j.neuro.2009.09.008

Abstract
This study examined whether acquisition of neonatal reflexes and sensorimotor skills in newborn rhesus macaques (Macaca mulatta) is influenced by receipt of the single neonatal dose of Hepatitis B (HB) vaccine containing the preservative thimerosal (Th). HB vaccine containing a standardized weight-adjusted Th dose was administered to male macaques within 24 hours of birth (n = 13). Unexposed animals received saline placebo (n = 4) or no injection (n = 3). Infants were raised identically and tested daily for acquisition of 9 survival, motor, and sensorimotor reflexes by a blinded observer. In exposed animals there was a significant delay in the acquisition of three survival reflexes: root, snout and suck, compared with unexposed animals. No neonatal responses were significantly delayed in unexposed animals compared with exposed. Gestational age (GA) and birth weight were not significantly correlated. Cox regression models were used to evaluate the main effects and interactions of exposure with birth weight and GA as independent predictors and time-invariant covariates. Significant main effects remained for exposure on root and suck when controlling for GA and birth weight such that exposed animals were relatively delayed in time-to-criterion. There was a significant effect of GA on visual follow far when controlling for exposure such that increasing GA was associated with shorter time-to-criterion. Interaction models indicated that while there were no main effects of GA or birth weight on root, suck or snout reflexes there were various interactions between exposure, GA, and birth weight such that inclusion of the relevant interaction terms significantly improved model fit. This, in turn, indicated important influences of birth weight and/or GA on the effect of exposure which, in general, operated in a way that lower birth weight and/or lower GA exacerbated the detrimental effect of vaccine exposure. This primate model provides a possible means of assessing adverse neurodevelopmental outcomes from neonatal Th-containing HB vaccine exposure, particularly in infants of lower GA or low birth weight. The mechanism of these effects and the requirements for Th is not known and requires further study.