The polysaccharide (PS) capsules of many pathogenic bacteria are poor immunogens in infants and young children as a result of the delayed response to PS antigens during ontogeny. The development of polysaccharide-protein conjugate vaccines for Haemophilus influenzae type b, which have proven to be efficacious in this age group, has led to active development by a number of investigators of conjugate vaccines for other diseases. We describe here the response of several mouse strains to the capsular PS of Neisseria meningitidis group C (MCPS) conjugated to tetanus toxoid (MCPS-TT) and the same response in BALB/c mice as a model of the immune consequences of conjugate vaccine immunization. The use of a conjugate vaccine results in a shift in the isotype elicited in response to the MCPS, from immunoglobulin M (IgM) and IgG3 to primarily IgG1. A response to MCPS-TT is seen even among mouse strains which respond poorly to MCPS itself, emphasizing the importance of a strain survey when choosing a mouse model for a vaccine. The marked increase in IgG1 antibody titer was accompanied by a large increase in bactericidal activity of sera from these animals. Animals primed with the conjugate vaccine demonstrated a booster response after secondary immunization with either the MCPS or the conjugate. The ability to produce a boosted IgG1 anti-MCPS response to the MCPS can be transferred to adoptive recipients by B cells alone from mice primed with MCPS-TT but not mice primed with MCPS alone. These data indicate that in BALB/c mice a single immunization with MCPS-TT is sufficient to induce a shift to IgG1 and generate a memory B-cell population that does not require T cells for boosting.

Antibody (Ab) responses to polysaccharides (PSs) such as Neisseria meningitidis group C PS (MCPS) are characterized as being thymus independent (TI) and are restricted with regard to clonotype and isotype expression. PS conjugated to proteins, e.g., MCPS coupled to tetanus toxoid (MCPS-TT), elicits a thymusdependent (TD) response. In order to understand the influence of the form of a vaccine (TI versus TD) on the Ab repertoire, we generated monoclonal antibody (MAb) panels from mice immunized and boosted with MCPS or MCPS-TT in different ways. The panels of MAbs were examined for isotype, fine specificity, affinity, and V H gene family usage. The use of MCPS-TT resulted in a shift in the isotype from immunoglobulin M (IgM) and IgG3 elicited in response to the MCPS to primarily IgG1. This isotype shift was accompanied by a change in the fine specificity of the response to the conjugate compared to that of PS. New fine specificities and increased affinity were observed in response to the TD antigen (Ag). Dot blot and Northern analyses of MCPS MAbs revealed that V H gene family usage is dominated by V H J558, used by 23 of 39 MAbs. V H 3609 was seen in three MAbs of restricted fine specificity. V H Q52, V H 7183, and V H VGAM3-8 were seen in more than one MAb across these panels, while V H 10 and V H X24 were detected only once in response to the TI-2 Ag. All MAbs in the panels utilized kappa light chains, and all functional J genes were expressed.The capsular polysaccharide (PS) constitutes the major virulence factor of many pathogenic bacteria that cause invasive diseases. Antibodies (Abs) against these PSs are protective (27,28). PSs are classified as thymus-independent-2 (TI-2) antigens (Ags) because they do not require mature T cells to elicit a humoral response in vivo. These PS Ags are immunogenic in adults but are only poorly or nonimmunogenic in infants and young children who are highly susceptible to infection caused by encapsulated bacteria (28,31,44,65).The response to capsular PS is markedly different from the response to most protein Ags (thymus-dependent [TD] Ags). The Ab response to TI-2 Ag develops late in ontogeny (25,44,50) and in mice utilizes a particular late-developing subset of B cells that is defined by the expression of Lyb5 and other cell markers (39, 60). TI Ags also generally fail to elicit a memory response or show affinity maturation. In contrast, the ability to respond to a TD Ag is present at birth and results in the formation of memory cells, and the Ab response undergoes subsequent affinity maturation upon reimmunization (61). For TI Ag, immunoglobulin G3 (IgG3) and IgM are the major isotypes expressed in mice, even after secondary immunization (45), whereas for TD Ag, the ratio of IgG to IgM increases after secondary immunization, with IgG1 being the major subclass (52,59,60).The majority of the anti-PS responses are oligoclonal and encoded by a few variable regions of the heavy chain (V H ) gene families (10). The anti-␣(133) dextran Ab, for example, expresses mainly the V H J55...

Antibody (Ab) responses to polysaccharides (PS), such as

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