LAUSR

Transcriptomic signatures before and after immunization predict protection against malaria induced by sporozoite and RTS,S/AS01E immunization. Predicting protection A highly effective malaria vaccine would save many lives but correlates of protection remain ill-defined. Moncunill et al. studied peripheral blood cells isolated from individuals that had received sporozoites under chemoprophylaxis or the RTS,S vaccine. Transcriptomic analysis of gene expression after in vitro stimulation of cells revealed preimmunization and postimmunization signatures, which were validated with separate cohorts. The preimmunization signatures hint at mechanisms of differential vaccine responses between individuals; once validated in additional studies, the postimmunization signatures could be used as a surrogate for protection in clinical trials, possibly accelerating vaccine development. Identifying immune correlates of protection and mechanisms of immunity accelerates and streamlines the development of vaccines. RTS,S/AS01E, the most clinically advanced malaria vaccine, has moderate efficacy in African children. In contrast, immunization with sporozoites under antimalarial chemoprophylaxis (CPS immunization) can provide 100% sterile protection in naïve adults. We used systems biology approaches to identifying correlates of vaccine-induced immunity based on transcriptomes of peripheral blood mononuclear cells from individuals immunized with RTS,S/AS01E or chemoattenuated sporozoites stimulated with parasite antigens in vitro. Specifically, we used samples of individuals from two age cohorts and three African countries participating in an RTS,S/AS01E pediatric phase 3 trial and malaria-naïve individuals participating in a CPS trial. We identified both preimmunization and postimmunization transcriptomic signatures correlating with protection. Signatures were validated in independent children and infants from the RTS,S/AS01E phase 3 trial and individuals from an independent CPS trial with high accuracies (>70%). Transcription modules revealed interferon, NF-κB, Toll-like receptor (TLR), and monocyte-related signatures associated with protection. Preimmunization signatures suggest that priming the immune system before vaccination could potentially improve vaccine immunogenicity and efficacy. Last, signatures of protection could be useful to determine efficacy in clinical trials, accelerating vaccine candidate testing. Nevertheless, signatures should be tested more extensively across multiple cohorts and trials to demonstrate their universal predictive capacity.