Modulation of RAS Pathways as a Biomarker of Protection against HIV and as a Means to Improve Vaccine Efficacy

P03.04 LB

Background: Adjuvants modulate the immune response and can improve the immunogenicity of vaccines. Immunogenicity studies in humans suggest that MF59 is a more efficient adjuvant than alum as it triggers enhanced B and T cell immune responses.

Methods: We performed a study (P162MRV144) in macaques using repeated challenges with SIVmac251 powered to benchmark the results of RV144 vaccine that showed limited efficacy in a phase III clinical trial in Thailand. We compared the efficacy of ALVAC-SIV/gp120 vaccine administered with alum or MF59 adjuvants to placebo in the SIV mac251 model. Transcriptional profiling of blood from 54 immunized macaques before vaccination (pre-vax), after immunization with ALVAC-SIV alone (post-1^st) and after immunization with ALVAC-SIV combined with the protein/adjuvant MF59 or Alum immunization (post-3^rd) was performed. Differential expression analysis and pathway enrichment analysis was used to identify genes and pathways associated with protection. A naïve Bayes classifier was build to predict vaccine protection.

Results: We found that alum protected macaques from SIVmac251 acquisition (log-rank test: p = 0.0205), confirming the main results of the RV144 study. However MF59 did not protect macaques from SIVmac251 acquisition (log-rank test: p = 0.562), despite MF59's ability to elicit higher systemic T-cell and antibodies responses. Association between the changes in transcriptional profiles and risk of SIVmac251 acquisition resulted in the identification of 12-gene expression signature able to predict prior to vaccination protection by ALVAC + alum (ROC: Accuracy = 65.2%, p ≤ 0.05). Seven of the twelve genes of the signature were related to Ras signaling.

Conclusions: System biology revealed that RAS, a signal transducer that facilitates cross talk among B-cells, T-cells and antigen presenting cells, as a biomarker of vaccine efficacy in the ALVAC + alum treated animals. These data suggest that activation of RAS may constitute a novel approach to improve vaccine efficacy against HIV.