The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination

Development of effective HIV-1 vaccines requires synergy between innate and adaptive immune cells. We show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC+Alum augments immunogenicity in Non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes contain cytokines/chemokines associated with heightened protection from SIV challenge in NHPs. CREB1 gene expression likely results from direct cGAMP (STING agonist) modulated p-CREB1 activity which drives the recruitment of CD4(+) T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC+Alum, immunization with ALVAC+MF59, the regimen in the HVTN702 trial which showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants which trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.