To generate vaccine mediated protection is a complex challenge. Currently available vaccines have largely been developed empirically, with little or no understanding of how they activate the immune system. Their early protective effcacy is primarily conferred by the induction of antigen-specifc antibodies (Box 2.1). However, there is more to antibodymediated protection than the peak of vaccine-induced antibody titers. The quality of such antibodies (e.g., their avidity, specifcity, or neutralizing capacity) has been identifed as a determining factor in effcacy. Long-term protection requires the persistence of vaccine antibodies above protective thresholds and/or the maintenance of immune memory cells capable of rapid and effective reactivation with subsequent microbial exposure. The determinants of immune memory induction, as well as the relative contribution of persisting antibodies and of immune memory to protection against specifc diseases, are essential parameters of long-term vaccine effcacy.