Immunization of Aged Mice with a Pneumococcal Conjugate Vaccine Combined with an Unmethylated CpG-Containing Oligodeoxynucleotide Restores Defective Immunoglobulin G Antipolysaccharide Responses and Specific CD4+-T-Cell Priming to Young Adult Levels

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Abstract
Polysaccharide (PS)-protein conjugate vaccines, in contrast to purified PS vaccines, recruit CD4+-T-cell help and restore defective PS-specific humoral immunity in the immature host. Surprisingly, in the immunocompromised, aged host, anti-PS responses to conjugate vaccines are typically no better than those elicited by purified PS vaccines. Although aging leads to defects in multiple immune cell types, diminished CD4+-T-cell helper function has recently been shown to play a dominant role. We show that in response to immunization with purified pneumococcal capsular PS serotype 14 (PPS14) in saline, the T-cell-independent immunoglobulin G (IgG) anti-PPS14 response in aged mice was comparable to that in young mice. In contrast, the T-cell-dependent IgG anti-PPS14 response to a soluble conjugate of PPS14 and pneumococcal surface protein A (PspA) (PPS14-PspA) in saline was markedly defective. This was associated with defective priming of PspA-specific CD4+T cells. In contrast, immunization of aged mice with PPS14-PspA combined with an unmethylated CpG-containing oligodeoxynucleotide (CpG-ODN) restored IgG anti-PPS14 responses to young adult levels, which were substantially higher than those observed using purified PPS14. This was associated with enhanced PspA-specific CD4+-T-cell priming. Similarly, intactStreptococcus pneumoniaecapsular type 14, which contains Toll-like receptor (TLR) ligands, also induced substantial, though modestly reduced, T-cell-dependent (TD) IgG ant-PPS14 responses in aged mice. Spleen and peritoneal cells from aged and young adult mice made comparable levels of proinflammatory cytokines in response to CpG-ODN, although cells from aged mice secreted higher levels of interleukin-10. Collectively, these data suggest that inclusion of a TLR ligand, as an adjuvant, with a conjugate vaccine can correct defective TD IgG anti-PS responses in elderly patients by augmenting CD4+-T-cell help.