Abstract Body

The simian immunodeficiency virus (SIV)-targeted vaccine vectors based on rhesus cytomegalovirus (RhCMV) strain 68-1 harboring deletion of viral open-reading frames UL128 and UL130 elicit potent cellular immune responses that fully protect rhesus macaques (RM) against SIV infection through T cell-mediated viral clearance. When these viral ORFs were restored, the resulting 68-1.2 vaccine vectors failed to protect RM against SIV challenge. To define the molecular features of the protective 68-1 vaccine response, we interrogated and compared the transcriptomic host response from five groups of RMs: two groups vaccinated with 68-1 (subcutaneous or oral delivery), one group with 68-1.2 (subcutaneous delivery), one group with 68-1.2 UL128 (subcutaneous delivery), and one group with a combination of 68-1 and 68-1.2 (subcutaneous delivery).

Following vaccination, animals were subjected to repeated limiting dose intrarectal SIVmac239 challenge until infected by either detection of plasma virus or de novo development of T cell responses to SIVvif. Regardless of delivery mode, slightly over half of the animals that received the 68-1 vaccine manifested stringent aviremic control of the virus. There was no such control in any animal that received only a version of the 68-1.2 vaccine. Transcriptomic analysis (mRNA-seq) was performed on blood samples from all groups obtained during the vaccination phase. Bioinformatics analyses compared the transcriptional profiles between the protected and non-protected animal groups.

These analyses identified gene expression changes as early as three days after the first vaccination that distinguish protected from non-protected animals. Specifically, differences in the RNA profiles between protected and non-protected animals included magnitude and directionality of differentially expressed genes involved in several innate immune networks including innate immune activation, inflammation, and immune programming.

These defined gene signatures for both protected and non-protected animals are being used to guide efforts to 1) understand the mechanisms responsible for the unique ‘control and clear’ efficacy manifested by the 68-1 RhCMV vectors, 2) define intracellular response pathways of protection, 3) develop a modified vaccine that further enhances these features to achieve efficacy beyond the current ~55%, and 4) translate these vectors from nonhuman primates to people for protection against HIV infection.