To develop a cost-effective pneumococcal vaccine, we compared the effects of a panel of Toll-like receptor (TLR) agonists on a low dose pneumococcal surface protein A (PspA) nasal vaccine in a fatal pneumococcal pneumonia model using a serotype 3 strain. The mice were nasally immunized with 10 µg of the TLR agonist (TLR 2, 3, 4 and 9) and 0.1µg of PspA once per week for three weeks. A high level of PspA-specific immunoglobulin G (IgG) was detected in sera of mice that were nasally administered a low dose of PspA plus each TLR agonist, while no PspAspecific IgG were detected in sera of mice that had been nasally administered a low dose of PspA. A relatively low level of PspA-specific IgG was also detected in the airway of mice that had been nasally administered a low dose of PspA plus each TLR agonist. The binding of PspA-specific IgG increased the deposition of C3 on the bacterial surface. Bacterial density in the lung and blood was significantly decreased in mice that had been administered a low dose of PspA plus each TLR agonist, compared with mice that received a low dose of PspA alone 24 h after a bacterial challenge. Furthermore, significant increases in survival rate were found in a murine model of fatal pneumonia that had been nasally administered a low dose of PspA plus each TLR agonist, compared with mice that received a low dose of PspA alone. The rank order of TLR agonists on the effect of increasing survival rate was LPS > Pam3CSK4 > Poly (I:C) and CpG 1826. These data suggest a potentially new strategy for the development of a cost-effective intranasal vaccine with a low dose PspA plus TLR agonist that would be effective against lifethreatening bacteremic pneumococcal pneumonia.