The SIVmac251 macaque model has been used to evaluate the efficacy of vaccine for HIV. Exposure of macaques to a single high dose of SIVmac251 results in transmission of multiple viral variants, which contrasts the few HIV variants typically transmitted in humans. In here, we investigated whether the dose of SIVmac251 challenge affected vaccination efficacy and found that exposure of the immunized macaques to single high dose of SIVmac251 resulted in no vaccine efficacy, whereas exposure to a tenfold lower dose resulted in protection from SIVmac251 acquisition and protection from disease in animals that become infected. The dose of challenge did not affect the expression of inflammatory genes in the gut in acute infection, but at set point, a significant down regulation of interferon responsive genes and up regulation of genes involved in B and T-cell responses, was observed only in vaccinated animals exposed to a lower dose of SIVmac251. Accordingly, in these animals, we also found a significant correlation with vaccine induced T-cell responses and protection from disease. These data demonstrate that the evaluation of the efficacy of vaccine candidates for HIV relies on accurate modeling in macaques to better mimic HIV transmission to humans.