By studying samples from two independent clinical trials of malaria vaccines, Gemma Moncunill and colleagues have linked signatures in the immune system to better vaccine protection from the disease in children and adults. Their analysis of the RTS,S vaccine and sporozoite immunization provides generalizable benchmarks that future studies could use to evaluate the effectiveness of malaria vaccine candidates. Malaria continues to pose a huge health burden around the world, with an estimated 218 million cases in 2018. The RTS,S vaccine is the only candidate to have advanced far into clinical trials, but it has shown only modest protection. Researchers have also tested alternative strategies; one approach that combines weakened malaria parasites with preventative drug treatment (CPS immunization) displayed 100% efficacy in experimental trials in adults. Nevertheless, the rollout of a malaria vaccine has been seriously impeded by limited knowledge of the mechanisms of immunity, as well as by a lack of immune surrogates that can predict vaccine efficacy. Using transcriptional analysis of immune cells and systems biology techniques, Moncunill et al. examined blood samples from 24 adult volunteers who received CPS immunization and 255 African children who participated in a phase 3 trial of the RTS,S vaccine. The authors made some surprising findings; for example, children who received the RTS,S vaccine showed few changes in gene expression compared with those who received a nonprotective vaccine. However, the team did identify sets of genes that were linked to a protective response in the trials, observing that the receptor TLR4 and the protein NF-κB both played an important role. Some individuals also showed pre-immunization signatures that were linked to protection, a finding that could help identify non-responders who may benefit from immune priming or other interventions before vaccination.