Third, our results support the hypothesis that although interclonal variation in VAR2CSA is the result of antibodydriven positive selection, the diversity of functionally important antibody epitopes in the molecule is constrained (21) . Thus, some parasites can express VAR2CSA without being vulnerable to recognition by certain VAR2CSAreactive antibodies, because of variation in defined parts of VAR2CSA. The persistent nonrecognition by PAM8·1 of VAR2CSA-expressing 3D7 is a case in point. At the same time, the PAM8·1 antibody, originally identified by its reactivity with VSA PAM -expressing FCR3-IEs (3), was effectively selected for VSA PAM expression in the genetically unrelated HB3 clone. The significance of these findings is underscored by the fact that PAM8·1 efficiently opsonizes IEs for phagocytosis as well as interferes with IE adhesion to CSA (Barfod et al. in preparation) . Our study also corroborates existing evidence that PAM1·4 recognizes most if not all VSA PAM -expressing parasites by recognizing a functionally highly constrained and conformation-dependent discontinuous epitope in VAR2CSA (3). Like PAM8·1, PAM1·4 is an opsonin and capable of interfering with IE adhesion to CSA (Barfod et al. in preparation) . Therefore, the PAM1·4 epitope is a highly attractive candidate for development of a PAM-specific vaccine, and its characterization is a matter of the highest priority in our current research. Although the theoretical possibility of another, non-PfEMP1 target of PAM1·4 remains, available evidence point to VAR2CSA.