This study investigates the efficacy of rhesus cytomegalovirus (RhCMV) vector-based SIV vaccines in controlling highly pathogenic SIVmac239 infection in rhesus macaques (RM). The researchers found that RhCMV vectors, either alone or followed by adenovirus 5 (Ad5) vectors, induced high-frequency, effector-memory T cell (TEM) responses at potential sites of SIV replication. Thirteen out of 24 RM vaccinated with RhCMV vectors alone or followed by Ad5 vectors showed early complete control of SIV, with undetectable plasma virus levels. In 12 of these RM, long-term protection was observed, characterized by occasional plasma viremia blips that waned, undetectable cell-associated viral loads in blood and lymph nodes, no depletion of CD4+ memory T cells, and no induction of SIVenv-specific antibodies. The protection correlated with the magnitude of peak SIV-specific CD8+ T cell responses during the vaccine phase and was not dependent on anamnestic T cell responses. The study suggests that persistent vectors like RhCMV and their associated TEM responses could significantly contribute to an effective HIV/AIDS vaccine.This study investigates the efficacy of rhesus cytomegalovirus (RhCMV) vector-based SIV vaccines in controlling highly pathogenic SIVmac239 infection in rhesus macaques (RM). The researchers found that RhCMV vectors, either alone or followed by adenovirus 5 (Ad5) vectors, induced high-frequency, effector-memory T cell (TEM) responses at potential sites of SIV replication. Thirteen out of 24 RM vaccinated with RhCMV vectors alone or followed by Ad5 vectors showed early complete control of SIV, with undetectable plasma virus levels. In 12 of these RM, long-term protection was observed, characterized by occasional plasma viremia blips that waned, undetectable cell-associated viral loads in blood and lymph nodes, no depletion of CD4+ memory T cells, and no induction of SIVenv-specific antibodies. The protection correlated with the magnitude of peak SIV-specific CD8+ T cell responses during the vaccine phase and was not dependent on anamnestic T cell responses. The study suggests that persistent vectors like RhCMV and their associated TEM responses could significantly contribute to an effective HIV/AIDS vaccine.