Microarray analysis of correlates of vaccine immunogenecity following ALVAC vaccination in NHP in Study 36

The RV144 HIV vaccine trial remains the only study to demonstrate significant protection from future HIV-1 acquisition. One of the key components of the RV144 vaccine was the use of the canarypox vector ALVAC as the priming component. Since AIDSVAX, the booster component, alone failed to provide protection we hypothesized that the ALVAC prime contributed significantly to the generation of protection. To test this, we designed a NHP immunogenicity trial to mechanistically link ALVAC vaccination with the magnitude of V1V2 titers, the most significant immune correlate of reduced HIV-1 acquisition in RV144. Our objective was to use a systems biology approach to identify the transcription factors, target genes and immune pathways which were being induced by ALVAC vaccination and associated with higher V1V2 titers. We identified the transcription factor CREB1 and its target genes as rapidly induced by ALVAC in multiple immune subsets and that CREB1 drives the expression and activation of a network of other TFs which are critical for modulating immune responses. Pathways induced by this ALVAC-CREB1 axis include lymphocyte/leukocyte migration, lymphocyte differentiation, antigen processing and presentation, T cell co-stimulation and cytokine signaling. Study 36 was an immunogenicity study designed to test the impact of ALVAC priming on the magnitude and durability of V1V2 antibody responses. There were 2 experimental arms, each comprised of 5 Chinese-origin Rhesus macaque. Both arms used 2 primes with ALVAC and 2 boost with ALVAC + gp120 B/E protein. In Arm I, the ALVAC vector contained no HIV DNA insert which is referred to as empty ALVAC. In Arm II, the ALVAC vector contained the vCP1521 insert which was used in RV144 and encodes for HIV gag, pol and env. Vaccine administration schedule was: Prime 1 in Week 0, Prime 2 in Week 4, Boost 1 in Week 12 and Boost 2 at Week 23. PBMCs were isolated at 2-3 days post Prime 1, 2-weeks post Prime 1 and 2-weeks post Boost 2. DCs, CD4+ T cells and B cells were sorted using flow cytometry and RNA extracted from each sorted subset. V1V2 antibody titers were quantified at four timepoints: Week 14, Week 25, Week 53 and Week 55.