RTS,S/AS01 is the most advanced malaria vaccine candidate under development. However, very little is understood about how it induces immunity. This article, published in PNAS, uses a systems biology approach to analyze and compare two vaccination regimens of RTS,S: three consecutive vaccinations of RTS,S/AS01 (RRR regimen) versus a primary immunization with an adenovirus 35 vector expressing full-length circumsporozoite protein (ARR regimen), followed by two doses of RTS,S/AS01. The authors found that protective immunity against the malaria parasite Plasmodium falciparum can be achieved through multiple pathways, demonstrating the benefit of a systems biology approach to understanding how vaccination leads in protection from a disease.