SYNTHETIC PEPTIDES REPRESENTING T-CELL EPITOPES ACT AS CARRIERS IN PNEUMOCOCCAL POLYSACCHARIDE CONJUGATE VACCINES

Improvement of antibody responses to polysaccharides through their lin kage to proteins is thought to be mediated by protein-specific T helpe r (Th) cells. To investigate whether the carrier protein of a conjugat e could be substituted by a Th epitope, Streptococcus pneumoniae type 17F polysaccharide (PS) was bromoacetylated and coupled to different p eptides via their carboxy-terminal cysteines. Two peptides, one from t he mycobacterial 65-kDa heat shock protein (hsp65) and the other from influenza virus hemagglutinin, are well-known Th epitopes. Two other p eptides were selected from the pneumolysin sequence by Th epitope pred iction methods; one of them was synthesized with cysteine either at th e carboxy or the amino terminus. Three conjugates consistently elicite d in mice anti-PS immunoglobulin M (IgM) and IgG responses that were n ot observed upon immunization with derivatized PS without peptide. The same conjugates induced no anti-PS antibody responses in athymic (nu/ nu) mice, whereas clear responses were elicited in euthymic (nu/+) con trols, demonstrating the thymus-dependent character of these conjugate s. Only the three conjugates inducing anti-PS responses were capable o f eliciting antipeptide antibodies. One of the immunogenic conjugates was studied in more detail. It induced significant protection and an a nti-PS IgG response comprising all subclasses. Od the basis of these r esults and proliferation studies with peptide and conjugate-primed cel ls, it is concluded that linkage of Th epitopes to PS in the right ori entation enhances its immunogenicity in a thymus-dependent manner. Fut ure possibilities for using peptides as carriers for inducing antibody responses to poorly immunogenic saccharide antigens are discussed.