Twenty years ago we reported the first synthetic peptide-based anti-malarial vaccine named SPf66, which conferred limited protective efficacy in large-scale human field-trials. Our efforts towards a second vaccine generation based on the rational selection of conserved high activity binding peptides (HABPs) whose critical binding residues have to be precisely replaced by others. Introducing peptide bond isosters on these HABPs' critical binding residues constitutes also an important approach. Our results suggest that knowing a parasite's immunologically active peptides, their 3D structure, and their interaction for properly stabilizing MHC-II peptide-TCR complexes constitutes the basis for rationally designing a fully effective, multi-component, multistage subunit-based anti-malarial vaccine.