Next-Generation Bio-Reducible Lipids Enable Enhanced Vaccine Efficacy in Malaria and Primate Models

Lipid-based nanoparticles (LNPs) are essential vehicles for mRNA vaccine delivery, with the chemistry of the ionizable lipid determining antigen expression levels and immune activation. In this study, a structure-activity relationship (SAR)-guided optimization is conducted to enhance the potency of bio-reducible ionizable lipids for mRNA vaccination. The chemical architecture of the linker, connecting the amine headgroup to the lipid tails, is identified as a key modifiable feature that affects LNP protonation behavior and performance. In addition, variations in the amine headgroup are shown to impact the type of immune response evoked, reflected by differences in the IgG2a/IgG1 antibody isotype ratio. The strong prophylactic potential of mRNA vaccines based on these optimized LNPs is established in rodent models of Plasmodium infection, the causative agent of malaria. LNP formulations incorporating these lipids exhibit excellent tolerability in non-human primates and evoke potent antigen-specific antibody and T cell responses. These findings underscore the critical role of ionizable lipid chemistry in modulating the magnitude and phenotype of immune responses and support the continued development of bio-reducible ionizable lipids for mRNA vaccine delivery.