Summary Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for global open access clinical use. In the context of the R21 malaria vaccine, in a mouse challenge model, we characterize the efficacy and mechanism of action of four Vaccine Formulation Institute adjuvants: two liposomal (LQ and LMQ) and two squalene emulsion-based adjuvants (SQ and SMQ), containing QS-21 saponin (Q) and optionally a synthetic TLR4 agonist (M). Two R21 vaccine formulations, R21/LMQ and R21/SQ, offer the highest protection (81%–100%), yet they trigger different innate sensing mechanisms in macrophages with LMQ, but not SQ, activating the NLRP3 inflammasome. The resulting in vivo adaptive responses have a different T H 1/T H 2 balance and engage divergent innate pathways while retaining high protective efficacy. We describe how modular changes in vaccine formulation allow for the dissection of the underlying immune pathways, enabling future mechanistically informed vaccine design. Graphical abstract Highlights • Two open access adjuvants offer equally strong protection against malaria in mice • They induce T H 1- or T H 2-skewed response through divergent TLR4 and NLRP3 activation • Modular adjuvant changes can balance cell lytic activity with protective efficacy • Targeting distinct innate immune pathways can be used to polarize adaptive immunity Reinke, Pantazi, et al. describe two safe open access adjuvants that, in combination with the R21 malaria vaccine, offer strong efficacy in mice. The liposome-based LMQ and squalene emulsion-based SQ differentially trigger the TLR4/NLRP3 inflammasome pathway, resulting in divergent Th1/Th2 responses, yet both ultimately lead to equally protective adaptive immunity.
【저자키워드】 Vaccines, TLR4, liposomes, adjuvants, malaria, Inflammasome, NLRP3, Saponin, QS-21, emulsions,