Vaccination against encapsulated bacteria in humans: paradoxes

Infection with encapsulated bacteria can be prevented by vaccination with capsular polysaccharides, either plain or conjugated to a protein carrier. However, results concerning these vaccinations raise several paradoxes. Polysaccharides from encapsulated bacteria are generally considered to be T cell-independent antigens which are unable to trigger a T cell-dependent germinal center reaction, but, strikingly, anti-polysaccharide antibodies are often mutated in humans. Polysaccharide–protein conjugate vaccines are able to induce a true T cell-dependent memory response with a rise in antibody titers and a switch to high-affinity IgG antibodies in children below two years of age, but neither the plain nor the conjugated vaccine can induce memory in older infants and adults. We propose some explanations for these paradoxes based on our recent observation that humans display a circulating splenic marginal zone B-cell population with a pre-diversified immunoglobulin repertoire in charge of the immune response to T cell-independent antigens.