A strategy for rational design of fully synthetic glycopeptide conjugate vaccines.
The present study describes a strategy to rationally design fully synthetic glycopeptide conjugate vaccines. Glycopeptide immunogens were constructed by coupling synthetic oligosaccharides comprising repeating units of synthetic 3-beta-D-ribose-(1-1)-D-ribitol-5-phosphate (sPRP) to synthetic peptides containing potent T-helper cell determinants and B-cell epitopes of the Haemophilus influenzae type b (Hib) outer membrane proteins (OMPs) P1, P2, and P6. Rabbit immunogenicity studies revealed that some of these fully synthetic glycoconjugates were capable of eliciting high titers of both anti-PRP and anti-OMP immunoglobulin G antibodies. In addition, we systematically investigated the factors which could influence their immunogenicity. We observed that the magnitude of the anti-PRP antibody response markedly depended on the relative spatial orientation of sPRP and T-cell epitopes, the anti-PRP antibody response was enhanced when a multiple antigenic peptide was used as a carrier, the anti-PRP antibody response was optimal for three PRP repeating units, and lipidation of peptide-PRP conjugates had a minimal effect on the magnitude of the anti-PRP antibody response. The results of this study clearly demonstrate that coupling a carbohydrate hapten to a peptide can provide T-cell help and convert it into a T-cell-dependent antigen. The antisera raised against these conjugates were also found to be protective against Hib infection in the infant rat model of bacteremia.
Chong
P
P
Research Centre, Pasteur Merieux Connaught Canada, North York, Ontario. pchong@ca.pmc-vacc.com
Chan
N
N
Kandil
A
A
Tripet
B
B
James
O
O
Yang
Y P
YP
Shi
S P
SP
Klein
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001428:Bacterial Vaccines; D015195:Drug Design; D006020:Glycopeptides / Q000737:chemistry / Q000276:immunology; D019741:Haemophilus influenzae type b / Q000276:immunology*; D008969:Molecular Sequence Data; D011817:Rabbits; D051381:Rats; D018074:Vaccines, Conjugate; D014614:Vaccines, Synthetic
D001428:Bacterial Vaccines; D006020:Glycopeptides; D018074:Vaccines, Conjugate; D014614:Vaccines, Synthetic