Many adjuvants are known to enhance expression of co-stimulatory and adhesion molecules secondarily to the activation of immune cells. Whether interactions via these molecules are obligatory in adjuvants' ability to potentiation vaccine immunogenicity is less clear. We investigated the ability of eight adjuvant formulations to potentiate the immunogenicity of a malaria vaccine in mice deficient in the prominent co-stimulatory molecules, CD80 and CD86; and the adhesion ligand, ICAM-1. While no adjuvants could bypass co-stimulatory requirements, more formulations exhibited dependency for CD86 than for CD80. In CD80 or CD86 KO mice, formulations with the saponin derivative, QS21 could efficiently default to the other B7 molecule. This effect was dominant over other adjuvant constituents. The requirement for ICAM-1 could be readily bypassed using adjuvant formulations containing immunomodulators; whereas this was not the case with emulsion-type adjuvants in which reduction in adjuvanticity was associated with decreases in antigen-specific IFN-gamma responses. These studies may help to guide the formulation of vaccine adjuvants to maintain effectiveness in hosts with altered immunological environment that often result from infections.