Immunization of female mice with glycoconjugates protects their offspring against encapsulated bacteria

Abstract

The immune system of the newborn is immature, and therefore it is difficult to induce protective immunity by vaccination in the neonatal period. Immunization of mothers during pregnancy against infections caused by encapsulated bacteria could thus be particularly attractive, as infants do not respond to polysaccharide (PS) antigens. Transmission of maternal vaccine-specific antibodies and protection of offspring against pneumococcal bacteremia and/or lung infection were studied in a neonatal murine model of pneumococcal immunization and infections. Adult female mice were immunized with native pneumococcal PS (PPS) of serotypes 1, 6B, and 19F or PPS conjugated to tetanus protein (Pnc-TT), and PPS-specific antibodies were measured in sera of mothers and their offspring. Effective transmission of maternal antibodies was observed, as PPS-specific immunoglobulin G levels in 3-week-old offspring of immunized mothers were 37 to 322% of maternal titers, and a significant correlation between maternal and offspring antibody levels was observed. The PPS-specific antibodies persisted for several weeks but slowly decreased over time. Offspring of Pnc-TT-immunized mothers were protected against pneumococcal infections with homologous serotypes, whereas PPS immunization of mothers did not protect their offspring, in agreement with the low titer of maternal PPS specific antibodies. When adult female mice were immunized with a meningococcal serogroup C conjugate vaccine (MenC-CRM), antibody response and transmission were similar to those observed for pneumococcal antibodies. Importantly, bactericidal activity was demonstrated in offspring of MenC-CRM-immunized mothers. These results demonstrate that this murine model of pneumococcal immunization and infections is suitable to study maternal immunization strategies for protection of offspring against encapsulated bacteria.

FIG. 1.

Vaccine-specific IgG titers in mothers (1 week after delivery) and offspring from 3 to 6 weeks of age. Mothers were immunized twice with PPS-1, Pnc1-TT, PPS-6B, Pnc6B-TT, PPS-19F, Pnc19F-TT, MenC-PS, or MenC-CRM. Offspring from unimmunized adult mice were controls. Dams immunized with conjugates and their offspring (•), dams immunized with PS and their offspring (▵) and unimmunized dams and their offspring as controls (▪) (n = 8/group) were evaluated. Individual lines with the same symbol represent offspring of individual dams.

FIG. 2.

Relationship between IgG antibodies to PPS for serotypes 1, 6B, and 19F and PS-IgG antibodies to MenC in sera from immunized mothers and their offspring. The mothers were immunized twice before pregnancy with PPS or Pnc-TT of serotype 1, 6B, or 19F. LT-R72 was coadministered with the conjugates of serotypes 6B and 19F. For meningococcus group C, mothers were immunized with MenC-PS or MenC-CRM. Offspring of unimmunized adult mice were controls. Samples were taken from dams 1 week after delivery and from 4-week-old offspring. Dams immunized with conjugates and their offspring (•), dams immunized with PS and their offspring (▵), and controls (▪) (n = 8/group) were evaluated. Individual lines with the same symbol represent offspring of individual dams. Error bars, standard deviations (SDs).

FIG. 3.

Transmission of maternal PPS-specific antibody isotypes in sera from immunized mothers to their offspring. The percent transmission was determined by calculating for each isotype the EU per milliliter for each offspring (4 weeks of age) as the percentage of the EU per milliliter of the respective Pnc19F-TT-immunized mother (1 week after delivery). The results are shown as means + SDs (error bars) of percent transfer of each antibody isotype to offspring of each of two mothers. The mothers were immunized twice before pregnancy with Pnc19F-TT with LT-R72.

FIG. 4.

Protection of offspring (6 weeks old) of dams immunized with native (PPS) or conjugated (Pnc-TT) PS against bacteremia and pneumonia following i.n. challenge of pups with the homologous serotype. Dams were immunized twice before pregnancy with PPS-1 or Pnc1-TT (A and B), PPS-6B or Pnc6B-TT (C and D), and PPS-19F or Pnc19F-TT (E), and offspring of unimmunized mice were used as controls. Each bar represents results for offspring of a given dam, as the mean ± SD of numbers of CFU/ml (log₁₀) in blood (A and C) and lungs (B, D, and E) of offspring (n = 8/group) of PPS-immunized dams (white bars), Pnc-TT-immunized dams (black bars), or unimmunized dams (gray bars), 24 h after challenge with virulent pneumococci of homologous serotype. Detection limits are 1.3 for bacteremia and 2.0 for lung infection. Symbols: *, P < 0.05; **, P < 0.01; ***, P < 0.001 (compared to results for offspring of unimmunized dams).