Murine immune responses to Neisseria meningitidis group C capsular polysaccharide and a thymus-dependent toxoid conjugate vaccine

Abstract

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.

FIG. 1

Titers of antibodies specific for MCPS, by IgG subclass, in sera of four strains of mice with different H-2 and Igh haplotypes immunized with MCPS or MCPS-TT and then given boosters of the same antigen. Mice were bled prior to immunization (solid bars), 2 weeks (open bars) and 4 weeks (stippled bars) after primary immunization, and 1 week (crosshatched bars) and 3 weeks (striped bars) after secondary immunization. Some titers were below detectable levels (∗).

FIG. 2

Titers of antibodies specific for MCPS, by isotype, in sera of BALB/c mice immunized with MCPS or MCPS-TT and given boosters as indicated. Mice were bled prior to immunization (solid bars), 2 weeks (open bars) and 4 weeks (stippled bars) after primary immunization, and 1 week (crosshatched bars) and 3 weeks (striped bars) after secondary immunization. Some titers were below detectable levels (∗).

FIG. 3

IgG1 antibodies specific for MCPS in sera from irradiated (CBA/N × BALB/c)F₁ male mice that were recipients of B cells from BALB/c mice primed with MCPS or MCPS-TT or from unprimed BALB/c mice. The irradiated hosts were given MCPS or MCPS-TT boosters and bled on day 7 after injection. n, number of mice per group. Data are the geometric means ± 99% confidence intervals (CI). Nonoverlapping confidence intervals indicate a significant difference (P ≤ 0.01).