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Infection and Immunity, February 2005, p. 956-964, Vol. 73, No. 2
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.2.956-964.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Protective Levels of Polysaccharide-Specific Maternal Antibodies May Enhance the Immune Response Elicited by Pneumococcal Conjugates in Neonatal and Infant Mice

Margret Y. Richter,1 Havard Jakobsen,1 Jean-François Haeuw,2 Ultan F. Power,2,{dagger} and Ingileif Jonsdottir1,3*

Department of Immunology, Landspitali-University Hospital,1 Faculty of Medicine, University of Iceland, Reykjavik, Iceland,3 Centre d'Immunologie Pierre Fabre, St. Julien en Genevois, France2

Received 6 April 2004/ Returned for modification 3 June 2004/ Accepted 6 October 2004


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ABSTRACT
 
Maternal antibodies (MatAbs) may protect the offspring against infections but may also interfere with their immune responses to vaccination. We have previously shown that maternal immunization with pneumococcal polysaccharides (PPS) conjugated to tetanus protein (Pnc-TT) protected the offspring against infections caused by three important pediatric serotypes. To study the influence of MatAb on the immune response to Pnc-TT early in life, adult female mice were immunized twice with Pnc-TT of serotype 1 (Pnc1-TT), and their offspring received Pnc1-TT subcutaneously three times at 3-week intervals starting at 1 week (neonatal) or 3 weeks (infant) of age. High levels of PPS-1-specific MatAb (>3 log) in offspring of Pnc1-TT-immunized dams completely inhibited their anti-PPS-1 response elicited by Pnc1-TT. In contrast, low or moderate (~1 to 2 log) levels of MatAb did not interfere with and even enhanced the immune response of the offspring, and a booster response to a second Pnc1-TT dose was observed. Carrier-specific MatAbs had little effect on the response of offspring to the conjugate. All Pnc1-TT-immunized offspring were protected against pneumococcal bacteremia and had reduced lung infection. These results demonstrate that in the presence of MatAb, Pnc1-TT may elicit a protective PPS-1-specific antibody response and prime for PPS-1-specific memory in young offspring. Importantly, low or moderate levels of PPS-1-specific MatAb not only provided protection against pneumococcal infections but also enhanced the immune response elicited by Pnc1-TT in neonatal and infant mice. This murine model will be used to develop novel strategies combining maternal and neonatal immunization to protect against infections caused by encapsulated bacteria in early life.


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INTRODUCTION
 
Streptococcus pneumoniae (pneumococcus) causes severe infections like pneumonia, bacteremia, and meningitis (4, 29) as well as otitis media, particularly in infants and young children (41, 47). Induction of protective immunity by vaccination in the neonatal period is hampered by the immaturity of the immune system (61). Whereas pneumococcal polysaccharides (PPS) are immunogenic and protective in healthy adults (6, 58), they are not immunogenic and protective at an early age (14, 30, 34, 69). A marked improvement in the immunogenicity of polysaccharide (PS) antigens has been achieved by conjugation to protein carriers (15, 51), and several multivalent PPS-protein conjugate vaccines have proven immunogenic and efficacious against both invasive disease and acute otitis media in infants (3, 5, 12, 16, 59, 64, 65). Indeed, these vaccines induce immunological memory (2, 45) and reduce nasopharyngeal carriage of pneumococci (11, 44).

To protect the very young against pneumococcal diseases, two strategies may be developed: neonatal and/or maternal immunization. Maternal immunization is particularly attractive against infections caused by encapsulated bacteria, as infants do not respond to polysaccharides. Pregnant women can mount an effective response to vaccination, and pathogen-specific maternal antibodies (MatAbs) of the immunoglobulin G (IgG) isotype are actively transported to the fetus during the third trimester of pregnancy. Serum IgG levels of a full-term human neonate equal or exceed maternal IgG levels, particularly IgG1, and the levels of pathogen-specific protective antibodies (Abs) present early after birth determine the duration of protection provided by MatAbs. (reviewed in reference 39). In clinical trials on maternal immunization with PPS vaccines in the third trimester of pregnancy, safety and effective transfer of vaccine-specific antibodies have been demonstrated in both developing and industrialized countries (33, 40, 43, 46, 49, 57). In a trial of maternal immunization with 9-valent pneumococcal conjugate vaccine, the protective effect against otitis media as well as possible interference of MatAbs with infant responses to a 7-valent pneumococcal conjugate vaccine are being studied (13).

Vaccine-specific MatAb may confer protection against infections but may also interfere with offspring immune responses to vaccination at an early age, but this depends on the ratio of the vaccine and the vaccine-specific MatAb (61). In mice, as in humans, the main determinant of MatAb-mediated inhibition of immune responses in offspring is the level of maternal antibody present at the time of immunization (17, 36, 60, 62, 63). The effect may also vary depending on the vaccine. Administration of vaccine to a host with preexisting antibodies may result in the formation of antigen-antibody complexes. There are several hypotheses of the mechanism of MatAb interference with offspring responses to nonlive vaccines. First, MatAb-antigen complexes can, by coligation of the B-cell receptor (BCR) and the Fc receptor Fc{gamma}RIIB, induce a negative signal in B cells of the offspring and thus inhibit their activation. Second, enhanced internalization of antigen by antigen-presenting cells (APC) through targeting of MatAb-antigen complexes via Fc and complement receptors may enhance antigen processing and presentation of peptides and thus enhance T-cell help. Third, epitope-specific masking of B-cell epitopes by MatAb may prevent B cells of the offspring from accessing the vaccine antigen (reviewed in reference 60). Fourth, anti-idiotype antibodies that are transferred from mother to offspring could either enhance the Ab response of the offspring by acting as immunogens or inhibit the responses, as anti-idiotype-idiotype-antigen complexes could be cleared by phagocytes (18, 20, 68, 70).

Using a murine model of pneumococcal infections caused by intranasal (i.n.) challenge (53), we have shown that passive immunization with sera from infants vaccinated with pneumococcal conjugate vaccines can protect mice from bacteremia and pneumonia and that protection was related to infant serum antibody levels and opsonic activity (27, 52). This pneumococcal infection model was adapted to early life, and pneumococcal immune responses to PPS conjugated to tetanus protein (Pnc-TT) were shown to induce protective immunity against lethal pneumococcal infections in neonatal and infant mice (24). We have recently demonstrated that MatAbs elicited by immunization of adult female mice with Pnc-TT of three important pediatric serotypes were able to protect their offspring against pneumococcal infections caused by i.n. challenge with a lethal dose of the homologous pneumococcal serotype (50).

This early-life murine model was used to study whether MatAbs elicited by immunization of adult female mice with native PPS or Pnc-TT of serotype 1 (Pnc1-TT) or the carrier protein TT interfere with the immune responses of their offspring to the conjugate. Our results show that immunization of neonatal and infant mice with Pnc1-TT may, in the presence of MatAb, elicit high vaccine-specific Ab response, prime for memory cells, and protect against pneumococcal bacteremia and lung infection. Importantly, immune responses elicited by Pnc1-TT in neonatal and infant offspring were enhanced by low or moderate levels of PPS-1-specific MatAbs that were still protective against pneumococcal infections.


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MATERIALS AND METHODS
 
Mice. Adult NMRI mice were obtained from M&B AS (Ry, Denmark) or Charles River Wiga (Sulzfeld, Germany). The mice were kept in microisolator cages with free access to commercial food pellets and water and housed under standardized conditions at the Institute of Experimental Pathology at Keldur (Reykjavik, Iceland) with regulated daylight, humidity, and temperature. Breeding cages were checked daily for new births, and the pups were kept with their mother until weaning at the age of 4 weeks. The animal experiments were authorized by the Experimental Animal Committee of Iceland and complied with animal welfare act 15/94.

Vaccines and adjuvant. PPS of serotype 1 (PPS-1) was purchased from the American Type Culture Collection (ATCC; Manassas, Va.). Pnc1-TT was produced by the Centre d'Immunologie Pierre Fabre. Pnc1-TT conjugate was synthesized with adipic acid dihydrazide as the linker. PPS-1 was conjugated to activated TT (31). Conjugate was purified by gel filtration and stored at 4°C after addition of thimerosal at a final concentration of 100 µg/ml. Conjugate was analyzed for carbohydrate and protein with the anthrone and bicinchoninic assays, respectively. Covalence and absence of uncoupled protein were assessed by gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses. The PPS-to-TT (wt/wt) ratio was determined to be 3.84.

Immunization and blood sampling. Adult (6-week-old) female mice were immunized subcutaneously with 5.0 µg of PPS (ATCC) or 0.5 µg of Pnc-TT (Centre d'Immunologie Pierre Fabre) of serotype 1 or with 1.0 µg of the carrier protein TT (Aventis Pasteur, Marcy l'Etoile, France) and boosted with the same vaccine and dose 2 weeks later. Unimmunized mice were used as controls.

The offspring of each dam (n = 8) were immunized at 1 week (neonatal experiment) or 3 weeks (infant experiment) of age with 0.5 µg of Pnc1-TT and boosted twice at 3-week intervals at 4 and 7 weeks or 6 and 9 weeks of age, respectively. One group of offspring (infant experiment) of a Pnc1-TT-immunized mother was first immunized at 6 weeks of age and boosted once 3 weeks later. Unimmunized offspring from Pnc1-TT- or PPS-1-immunized mothers were used as controls. Pnc1-TT-immunized offspring of an unimmunized mother were used as positive controls, and unimmunized offspring of an unimmunized mother were used as negative controls. Two experiments were performed for each protocol, i.e., two neonatal and two infant experiments, and one of each experiment are shown.

One week after the second dose, the mice were bred. Mothers were bled from the tail vein 1 week after delivery, and offspring were bled weekly from 3 weeks until 9 weeks of age (neonatal experiment) or until 11 weeks of age (infant experiment) for measurements of PPS-1- or TT-specific antibodies by enzyme-linked immunosorbent assay (ELISA).

ELISA. Specific IgG antibodies to PPS-1 were measured by ELISA as described previously (23). In brief, microtiter plates (MaxiSorp; Nunc AS, Roskilde, Denmark) were coated with 5 µg of PPS-1 (ATCC) per ml of phosphate-buffered saline (PBS) and incubated for 5 h at 37°C. For neutralization of antibodies to cell wall PS, serum samples and standard were diluted 1:50 in PBS with 0.05% Tween 20 (Sigma, St. Louis, Mo.) and incubated in 500 µg of cell wall PS (Statens Serum Institute, Copenhagen, Denmark) per ml for 30 min at room temperature. The neutralized sera were serially diluted and incubated in duplicate in PPS-1-coated microtiter plates at room temperature for 2 h. Horseradish peroxidase-conjugated goat anti-mouse IgG antibodies (Southern Biotechnology Associates Inc., Birmingham, Ala.) were diluted 1:5,000 in PBS-Tween and incubated for 2 h at room temperature for detection of bound antibodies. For development of the enzyme reaction, 3,3',5,5'-tetramethylbenzidine peroxidase substrate (Kirkegaard & Perry Laboratories, Gaithersburg, Md.) was incubated for 10 min according to the manufacturer's instructions, and the reaction was stopped by adding 0.18 M H2SO4. The absorbance was measured at 450 nm in an ELISA spectrophotometer (Titertek Multiscan Plus MK II; ICN Flow Laboratories, Irvine, United Kingdom).

For detection of TT-specific antibodies, microtiter plates (MaxiSorp) were coated with 5.0 µg of purified TT (Aventis Pasteur) per ml of 0.10 M carbonate buffer (pH 9.6) and incubated overnight at 4°C. After blocking of coated plates with PBS containing 1% bovine serum albumin (Sigma), duplicates of samples and standard were serially diluted in PBS-Tween, added to TT-coated plates, and incubated for 2 h at room temperature. The detection of TT-specific antibodies and the development of the enzyme reaction were performed as described above.

Reference sera obtained by hyperimmunization of adult mice with Pnc1-TT were included on each microtiter plate. The titer of the reference serum in ELISA units (EU) corresponded to the inverse of the serum dilution giving an optical density of 1.0. The titers of the test serum samples were calculated from the reference sera based on a minimum of four data points and parallelism between the serum samples and the reference curve. The interassay coefficient of variation was less than 10%, and the detection limit was 1.0 EU/ml. Results are expressed as mean log10 ELISA units per milliliter. For each group of mice (usually eight mice per group), PBS-Tween was used for dilutions and washing, and 100-µl volumes were used in all incubation steps with three washings in between.

Pneumococci and challenge of mice. The bacteria were maintained in Tryptoset broth (Difco Laboratories, Detroit, Mich.) plus 20% glycerol (BUFA B.V., Uitgeest, The Netherlands) at –70°C. The day before challenge, stocks were plated onto blood agar (Difco) and incubated at 37°C in 5% CO2 overnight. Isolated colonies were transferred to a heart infusion broth (Difco) with 10% horse serum, cultured at 37°C to log phase for 3.5 h, and resuspended in 0.9% sterile saline. Serial 10-fold dilutions were plated onto blood agar to determine the density of the inoculum. Two weeks after the third immunization, the offspring were challenged intranasally with 50 µl of virulent pneumococci, ~6 x 105 to 8 x 105 CFU of serotype 1 (ATCC 6301), as previously described (25, 27, 52, 53). The mice were sacrificed 24 h later, and pneumococcal bacteremia was determined as CFU per milliliter of blood and lung infection was determined as CFU per milliliter of lung homogenate. Depending on the first dilution used, the detection limit was 2.0 CFU/ml of lung homogenate and 1.3 CFU/ml of blood.

Statistical analysis. Student's t test and nonparametric test (Mann-Whitney) were used to compare log antibody titers and numbers of CFU (log10) between groups and time points. Pearson's correlation test was used. A P value of <0.05 was considered statistically significant.


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RESULTS
 
Immune response of offspring in the presence of maternal PPS-1-specific antibodies. To study the interference of vaccine-specific IgG Abs on the immune response of offspring of immunized dams, adult female mice were immunized twice before pregnancy with Pnc1-TT, native PPS-1, or the carrier protein TT. Their offspring were immunized with Pnc1-TT as neonatal (1-week-old) or infant (3-week-old) mice and received two additional doses at the 3-week interval. Two experiments were performed for neonatal mice and two were performed for infant immunization, and results from one experiment each are shown in Fig. 1. For clarification, panels A and B of Fig. 1 show control groups only, and experimental groups are added in panels C to F. In the experiments shown, the Pnc1-TT-immunized dams showed higher PPS-1-specific antibodies (~1 to 3 log) than those of dams immunized with native PPS-1 (Fig. 1). PPS-1-specific IgG levels in 3-week-old offspring of conjugate-immunized mothers were similar or higher than maternal Ab levels 1 week postdelivery (Fig. 1C and D), and there was a highly significant correlation between maternal and offspring antibody levels in the neonatal (r = 0.984; P = 0.002) and infant (r = 0.998; P < 0.001) experiments shown. These results demonstrate effective transmission of MatAb to the offspring, in agreement with our previous results for pneumococcal and meningococcal PS-specific antibodies (50).



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  		FIG. 1. PPS-1-specific antibodies in mothers and offspring. PPS-1-specific IgG levels (mean log10 ELISA units per milliliter) in mothers (first data point) and offspring of each dam (n = 8 mice per group) are shown. Filled symbols represent Pnc1-TT-immunized offspring, and open symbols represent unimmunized offspring. Dams were immunized twice before pregnancy with Pnc1-TT ({blacksquare}) (C and D) or PPS-1 (•) (E and F). The neonatal offspring were immunized with Pnc1-TT at 1, 4, and 7 weeks of age (A, C, and E), and infant offspring were immunized with Pnc1-TT at 3, 6, and 9 weeks of age (B, D, and F). One group of offspring of a Pnc1-TT-immunized mother was first immunized at 6 weeks of age and boosted once 3 weeks later ({square}/{blacksquare}) (D). Unimmunized offspring of Pnc1-TT-immunized mothers ({square}) (A to D) or PPS-1-immunized mothers ({circ}) (A, B, E, and F) are shown. Unimmunized offspring of Pnc1-TT- or PPS-1-immunized mothers and controls (A and B), Pnc1-TT-immunized offspring of Pnc1-TT-immunized mothers and controls (C and D), and Pnc1-TT-immunized offspring of PPS-1-immunized mothers and controls (E and F) are also shown. Negative controls, unimmunized offspring of an unimmunized mother ({diamond}); positive controls, Pnc1-TT-immunized offspring of an unimmunized mother ({diamondsuit}). Arrows indicate times of immunization.

The high levels of maternal PPS-1-specific IgG in unimmunized offspring of the Pnc1-TT-immunized mothers declined slowly, ~1 log until 9 weeks of age in the neonatal experiment shown and ~1 to 1.5 log until 11 weeks of age in the infant experiment. At the time of challenge, Ab levels were comparable to those of Pnc1-TT-immunized offspring of the unimmunized mother (positive control) which were immunized as infants (P = 0.234) but significantly lower (P < 0.001) in offspring immunized as neonates (Fig. 1A and B). Compared to previous experiments, the immune response of the Pnc1-TT-immunized infant offspring of unimmunized dams (positive control) was low.

The maternal PPS-1-specific IgG levels in offspring of Pnc1-TT-immunized dams varied (~1, 2, or 3 log) between offspring groups at the time of the first Pnc1-TT immunization (Fig. 1C and D). When the PPS-1-specific MatAb levels in the offspring were high (~3 log), they interfered with the offspring immune response, and the PPS-1-specific IgG levels continued to decline and did not exceed those of unimmunized offspring of the Pnc1-TT-immunized mother throughout the experimental period. Two weeks after the third immunization, both groups of neonates immunized in the presence of high levels of MatAb (~3 log) had lower PPS-1-specific antibodies (P < 0.001) than Pnc1-TT immunized offspring of the unimmunized mother (positive control). This difference was already >1 log 1 week after the third immunization (Fig. 1C). In the infant experiment, Ab levels were comparable in Pnc1-TT-immunized and unimmunized offspring of dams with high levels of MatAb (P = 0.574) (Fig. 1D), which may partly be explained by low response in the infant group immunized in the absence of MatAb compared to previous results (reference 24 and unpublished data). In fact, the curves showing Ab levels of unimmunized and Pnc1-TT-immunized offspring of dams with high levels of MatAb were superimposable in both neonatal (Fig. 1C) and infant (Fig. 1D) experiments shown. In contrast, when MatAb levels were moderate (~2 log) or low (~1 log) at the time of the first immunization, offspring of Pnc1-TT-immunized dams mounted a comparable (neonates, P = 0.318 and P = 0.694, respectively) or higher (infants, P < 0.001 and P = 0.008, respectively) booster response to the second dose of Pnc1-TT compared to Pnc1-TT-immunized offspring of unimmunized dams. Similar results were observed in another infant experiment, where the MatAb levels were moderate (~2 log) (data not shown). Thus, effective conjugate priming for PPS-specific memory occurred in neonatal and infant mice in the presence of low or moderate MatAbs.

In the infant experiment, offspring of one Pnc1-TT-immunized dam received the Pnc1-TT only at 6 and 9 weeks of age; i.e., the first dose at 3 weeks of age was omitted, and the PPS-1-specific IgG levels declined similarly to those in immunized infant offspring of the Pnc1-TT-immunized mother with high MatAb levels (~3 log) and unimmunized offspring of the Pnc1-TT-immunized mother (Fig. 1D).

Neonatal offspring of mothers immunized with native PPS-1 had low PPS-1-specific MatAb levels. Importantly, one group of Pnc1-TT-immunized neonatal offspring mounted a significantly higher antibody response (P = 0.029) than Pnc1-TT-immunized offspring of the unimmunized mother (positive control), but two groups mounted similar or lower responses (P = 0.273 and P = 0.036) (Fig. 1E). Accordingly, there was a significant difference between the Pnc1-TT-immunized offspring of the three PPS-1-immunized dams, the highly responding group versus the two groups with a weaker response (P = 0.001 and P = 0.011).

When the offspring of PPS-1-immunized mothers were immunized as infants, the Pnc1-TT elicited significantly higher PPS-1-specific IgG levels (~1 to 1.5 log higher; P < 0.001) than the positive controls immunized in absence of MatAbs (Fig. 1F). The difference between the Pnc1-TT-immunized offspring groups of the two PPS-1-immunized mothers was not significant (P = 0.096).

In another infant experiment, the offspring of PPS-1-immunized mothers already showed antibody levels that were ~0.5 to 1 log higher than those of the immunized offspring of the unimmunized mother (positive control) after the first Pnc1-TT immunization, although the differences were not significant (P = 0.089 and P = 0.234), and at the time of challenge at 11 weeks of age, levels for one of the two groups were similar to those of the positive control (data not shown). Thus, high levels of PPS-1-specific MatAb seemed to completely prevent the induction of Ab response by conjugates in young offspring, whereas low or moderate MatAb levels significantly enhanced the immune response of both neonatal and infant offspring, although to a varying degree.

Effect of maternal carrier-specific antibodies on PPS-1-specific antibody response of offspring to conjugate. Adult female mice mounted a high (~3 log) TT-specific IgG response after immunization with two doses of TT. At 3 weeks of age, the offspring had levels similar to those of their mothers which declined slowly during the experimental period (~1 to 1.5 log) and were comparable to those of Pnc1-TT-immunized offspring of the unimmunized mother (positive control) (Fig. 2B). Neonatal offspring of TT-immunized dams immunized with Pnc1-TT mounted a high PPS-1-specific IgG response (~2 to 2.5 log after three doses) which was comparable to that of Pnc1-TT-immunized offspring of the unimmunized mother (positive control) (Fig. 2A) for one group (P = 0.128) but lower for two groups (P = 0.026 and P = 0.04). The PPS-1-specific Ab levels varied between the Pnc1-TT-immunized offspring groups of TT-immunized mothers, but the difference was not significant (P = 0.054, P = 0.336, and P = 0.31) at the age of 9 weeks (although the difference between two out of three groups was significant [P = 0.009] at 6 weeks of age). When infant offspring of TT-immunized dams were immunized with Pnc1-TT, they also mounted high (~2 to 2.5 log) PPS-1-specific IgG responses after three doses (Fig. 2C) which were similar or higher than that in Pnc1-TT-immunized offspring of the unimmunized dam (P = 0.195 and P = 0.002). Accordingly, there was not a statistical difference between two offspring groups of TT-immunized mothers (P = 0.829).



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  		FIG. 2. PPS-1- and TT-specific IgG in Pnc1-TT-immunized offspring of TT-immunized mothers and controls. IgG antibodies (mean log10 ELISA units per milliliter) to PPS (A and C) or TT (B and D) in mothers (first data point) and offspring of each dam (n = 8 mice per group) are shown. Dams were immunized with TT twice before pregnancy. Offspring (n = 8 mice per group) were immunized with Pnc1-TT at 1 week of age (neonatal mice) (A and B) or 3 weeks of age (infant mice) (C and D) and boosted twice at 4 and 7 weeks (neonates) or 6 and 9 weeks (infants), respectively ({blacksquare}). Negative controls, unimmunized offspring of an unimmunized mother ({triangleup}); positive controls, Pnc1-TT-immunized offspring of an unimmunized mother ({circ}). Arrows indicate times of immunization.

In another comparable experiment, the PPS-1-specific IgG levels of the offspring of TT-immunized mothers were similar to those of the positive control (P = 0.426 and P = 0.934).

Offspring of the TT-immunized dams which were immunized as infants had high TT-specific IgG maternal antibodies (~3.5 log) that declined by ~1.5 log during the experimental period (Fig. 2D) and were comparable (P = 0.065 and P = 0.105) to those of Pnc1-TT-immunized offspring of the unimmunized mother (positive control).

Thus, carrier-specific MatAbs have little or no influence on the immune responses of young offspring to conjugates.

Protection against pneumococcal bacteremia and pneumonia. Two weeks after the third dose of Pnc1-TT, the offspring of dams immunized with Pnc1-TT, PPS-1, or TT and the controls were challenged intranasally with virulent pneumococci of serotype 1, and bacteremia and lung infection were evaluated 24 h later (53). Results for one of two infant and neonatal immunization experiments each are shown (Fig. 3), i.e., the same experiment as Ab responses (Fig. 1 and 2). The intranasal challenge (Fig. 3) caused severe bacteremia and lung infection in unimmunized offspring of unimmunized mice (negative control).



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  		FIG. 3. Protection of offspring of immunized mothers against pneumococcal bacteremia and lung infection caused by serotype 1. CFU (mean log10 CFU per milliliter ± standard deviation) in blood (A and C) and lung homogenate (B and D) 24 h after challenge of offspring (n = 8 offspring of each dam per group) with pneumococci of serotype 1 are shown. Detection limits are indicated with dotted lines (1.3 for bacteremia and 2.0 for lung infection). Dams were immunized twice before pregnancy with Pnc1-TT, PPS-1, or TT. The 1-week-old (A and B) and 3-week-old (C and D) offspring were immunized with Pnc1-TT three times at 3-week intervals. Filled bars represent Pnc1-TT-immunized offspring, and open bars represent unimmunized offspring. One group of offspring of a Pnc1-TT-immunized mother was immunized twice, first at 6 weeks of age and boosted 3 weeks later ({cjs2113}). The following controls were included: unimmunized offspring of Pnc1-TT- or PPS-1-immunized mothers, Pnc1-TT-immunized offspring of an unimmunized mother (positive control), and unimmunized offspring of an unimmunized mother (negative control).

Complete protection against pneumococcal bacteremia was observed in all offspring immunized with Pnc1-TT as infants or neonates in the presence or absence of maternal antibodies (Fig. 3A and C). Furthermore, significantly reduced pneumococcal CFU in lungs was observed in all Pnc1-TT-immunized offspring when immunized as neonates (P < 0.001) or infants (P = 0.007) compared to unimmunized offspring of PPS-1-immunized mothers or unimmunized offspring of unimmunized mothers (Fig. 3B and D). Thus, lung infection was undetectable in the majority of Pnc1-TT-immunized neonatal offspring of dams immunized with Pnc1-TT (83.3%), PPS (95.7%), TT (95.7%), or saline (100%) and of Pnc1-TT-immunized infant offspring of dams immunized with Pnc1-TT (66.7%), PPS (56.3%), TT (53.9%), or saline (25%). The protective efficacy in offspring immunized with Pnc1-TT in presence of MatAb and Pnc1-TT-immunized offspring of unimmunized mothers (absence of MatAb) is in agreement with high PPS-1-specific IgG levels at the time of challenge (Fig. 1).


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DISCUSSION
 
Maternal antibodies may interfere with responses to vaccines administered in early infancy, but this depends on the vaccine (55, 60). Immunization of mothers during pregnancy is particularly attractive to protect the newborn against infections caused by encapsulated bacteria because infants do not respond to PS antigen, and Ab responses to PS tend to be short-lived (38). Maternal immunization with conjugate against Haemophilus influenzae type b (Hib) before pregnancy has been shown to significantly increase the proportion of infants who had protective Hib Ab levels at birth and 2 months of age (54). Interference of MatAb with Hib vaccine responses has been reported (8). However, the persistence of protective Hib Abs without interference with the active Ab response has been shown in infants following combined passive and active immunization with high titers of bacterial PS immunoglobulins and Hib conjugate vaccine, also resulting in a dramatic decline in Hib disease (35, 67). A recent study suggested that MatAbs may interfere with infant responses to primary immunization with pneumococcal conjugate vaccine, but the booster response was not affected. Those authors concluded that a high preimmunization Ab titer did not interfere with the development of immunological memory (1).

In the present study, we used an early-life murine model of pneumococcal immunization and infections previously shown to reproduce the main features of infant responses to pneumococcal conjugates (24). We assessed whether MatAbs elicited by immunization of adult female mice with Pnc1-TT, native PPS-1, or the carrier protein TT interfere with the immune responses of their offspring to the conjugate Pnc1-TT. As expected, adult female mice immunized with two doses of Pnc1-TT developed higher PPS-1-specific Abs than mice immunized twice with native PPS-1. PPS-1-specific IgG MatAbs in Pnc1-TT-immunized dams were effectively transmitted to the offspring. Also, as previously demonstrated for several pneumococcal serotypes (50), PPS-1-specific IgG MatAbs in offspring of Pnc1-TT-immunized dams were above protective levels in infancy, when the offspring were unable to produce sufficient Abs in response to conjugate vaccination. High levels of MatAb (>3 log) protected the offspring during the first weeks of life but completely inhibited their Ab responses to Pnc1-TT. Importantly, low or moderate (~1 to 2 log) levels of PPS-1-specific MatAbs did not interfere with but even enhanced the Pnc1-TT-induced immune responses of neonatal and infant offspring, which also mounted a significant booster response to the second dose of Pnc1-TT. When offspring of the Pnc1-TT-immunized mother received their first Pnc1-TT dose as late as 6 weeks of age (the first dose at 3 weeks of age was omitted) and the PPS-1-specific IgG MatAb levels at that time of immunization were moderate (~2 log), the PPS-1-specific IgG levels 3 weeks later were comparable to those of unimmunized offspring of Pnc1-TT mothers and offspring immunized in the presence of high MatAb levels (~3 log). These results indicate that even in the presence of MatAbs, the first Pnc1-TT dose administered to the infant mouse (at 3 weeks of age) is important for priming B cells to become memory cells that are able to respond to the second dose of Pnc1-TT. However, in the presence of very high MatAb levels, the priming of B cells seems to be inhibited, as Ab levels continued to decline even after the third dose of Pnc1-TT.

According to the epitope-specific masking hypothesis (22), the MatAbs mask or hide B-cell epitopes from the infant B cells and thus prevent them from responding properly to the antigens. This mechanism is consistent with preclinical and clinical observations of infant Ab responses to vaccination, and MatAb titers at the time of vaccination correlated with the inhibitory effect on infant Ab responses. In contrast, T-cell priming was not inhibited. Therefore, increasing the vaccine dose could circumvent such epitope-specific inhibition (reviewed in reference 60). The epitope-specific masking hypothesis could explain the complete inhibition of offspring responses observed in our experiments when the PPS-1-specific MatAb levels were high (~3 log) as well as the lack of inhibition when the MatAb levels were lower (~1 to 2 log), and thus, the masking of PPS-1 epitopes by MatAb would be incomplete, allowing effective priming of the offspring PPS-1-specific B cells which respond to the second and third doses of the Pnc1-TT conjugate. Similar results were obtained for the effect of MatAb on response to a protein antigen, since in 2-week-old mice immunized with TT in the presence of high (>5 log10) levels of passively transferred TT-specific MatAbs, their immune responses to one dose of TT were totally inhibited, whereas lower MatAb levels had no effect or delayed their Ab responses to TT (63). However, enhancement of offspring immune response by MatAbs has not been reported previously. The importance of the ratio of MatAb to vaccine at the time of vaccination was demonstrated in a recent study, where Israeli infants were immunized with a nonlive hepatitis A vaccine. The B-cell immune responses of infants were inhibited in the presence of MatAbs until the MatAb titer had fallen below a specific threshold. However, the infants' responses showed that they had been primed by the initial vaccination despite the interference, indicating unaffected T-cell priming (10). Based on our results, it is conceivable that in the presence of the high MatAb levels, the Pnc1-TT-immunized offspring might respond to a booster dose of Pnc1-TT when the MatAbs have fallen below a critical threshold.

In accordance with the MatAb-antigen complex hypothesis, immunization in the presence of MatAb leads to enhanced uptake of antigen as MatAb-antigen complexes by APC, mainly dendritic cells, via Fc{gamma}R, complement receptors, or other scavenger receptors. Internalized immune complexes are transported to the lymph nodes and processed, and their peptides are presented by APC. This mechanism could result in the inhibition of infant B-cell responses but not T-cell responses, as has been shown both in humans and in experimental animals (7, 28, 37, 56, 66, 71). It is also known that when the concentration of MatAb-antigen complexes is very high, they can simply be cleared from circulation by phagocytes (9).

Interestingly, internalization of MatAb-antigen complexes by APC could, under certain conditions, even enhance T-cell responses in infants immunized in the presence rather than in the absence of MatAb due to enhanced peptide presentation and T-cell priming (reviewed in reference 60). This could explain the enhanced anti-PPS-1 responses observed in our experiments when offspring of PPS-1- or Pnc1-TT-immunized dams were immunized with Pnc1-TT in the presence of low or moderate titers of PPS-1-specific MatAb. The low PPS-1-specific MatAb titer would not lead to masking of the PPS-1 epitopes or coligation of the BCR and the Fc{gamma}RIIB receptor, and therefore, B-cell responses would not be inhibited. However, enhanced internalization of MatAb-Pnc1-TT complexes by the APC, processing, and presentation of TT epitopes could enhance TT-specific T-cell priming and thus provide increased help to PPS-1-specific B cells by cognate recognition of Pnc1-TT (19).

In our study, adult female mice immunized only with TT mounted high (~3 to 3.5 log) TT-specific IgG Ab responses, and their offspring had similar levels at the time of the first immunization in both neonatal and infant experiments. The TT-specific MatAb had some inhibitory effects on the Ab response of neonatal offspring but showed no effect or even enhanced the responses in the two infant experiments resulting in similar or higher PPS-1-specific IgG levels after three doses of the conjugate compared to those of responses in the absence of TT-specific MatAb. The offspring mounted a better PPS-1 Ab response when immunized first as infants in presence of high (>3.5 log) levels of TT-specific MatAb than when immunized as neonates in presence of ~3 log TT-specific MatAb. These results may indicate that clearance of TT-specific MatAb-Pnc1-TT complexes lowering the effective vaccine dose may have more effect on the responses of immature immune systems of the neonatal mice than on those of the infant mice. Immature B cells may also become anergic upon encountering antigen or via coligation of the BCR and Fc{gamma}RIIB. Importantly, high TT-specific MatAb levels had little or no effect on PPS-1 Ab responses of offspring immunized with Pnc1-TT. These results are consistent with the lack of masking of PPS-1 epitopes by TT-specific MatAb and therefore negligible interference with the B-cell responses to the PPS-1 moiety of the vaccine.

Our results are consistent with results from a previous study of human infants immunized with Hib-TT conjugate, suggesting that the influence of MatAb on the immune responses was due to epitope masking. Carrier-specific MatAbs mediated a specific inhibitory influence on the infant Ab responses to TT but not to the Hib PS moiety (32, 42, 48). These findings are further supported by murine studies indicating that the MatAbs do affect the B cells more than the T-cell responses, whereas very high (>5 log10) levels of carrier-specific MatAb (i.e., to TT) totally inhibited Ab responses to TT but not to the B-cell epitope moiety of a conjugate (a B-cell peptide epitope conjugated to TT), even though the immunogenicity of the conjugate is dependent on the T-cell help provided by the TT component of the conjugate (63).

The protective efficacy of maternal immunization was evaluated against pneumococcal infections caused by the homologous serotype 1, an important pediatric serotype (21) previously shown to be virulent in this i.n. pneumococcal infection model (24-26, 53). All offspring immunized with Pnc1-TT in the absence or presence of MatAb were completely protected against pneumococcal bacteremia, and a great majority were protected against lung infection. As protection against pneumococcal infections is mediated by Abs only, it is important during the time when the offspring are unable to mount adequate Ab responses that MatAbs are above the levels known to be protective (50). Whereas high levels of PPS-1-specific MatAb may protect the offspring during the most vulnerable period, they may also be detrimental, as they can completely inhibit the offspring immune response to the conjugate. In contrast, moderate MatAb levels are clearly beneficial, as they can protect the offspring without interfering with their immune response to the conjugate, and importantly may even enhance the offspring PPS-specific Ab response and allow effective priming of PPS-specific memory cells that will provide long-term protection against pneumococcal infections.

We have previously shown that MatAb elicited against three important pediatric serotypes can protect neonatal and infant offspring from pneumococcal infections (50), but the effect of MatAb on offspring responses to conjugates of other serotypes was not assessed. For highly versus poorly immunogenic serotypes, it is difficult to predict which levels of MatAb are optimal to provide protection without interfering with the offspring responses. This will have to be studied for each multivalent conjugate vaccine given at various doses and time schedules in relation to the time of delivery. Clinical trials combining maternal and neonatal vaccination against pneumococcal infections are needed.

Our results demonstrate that this murine model of lethal pneumococcal infections is suitable to study maternal immunization and the influence of MatAb on offspring immune responses to conjugate vaccines. It allows one to dissect the components of the maternal and offspring immune responses that are important for protective immunity and consequently can provide an understanding of how both strategies may be maximally exploited to protect against infections caused by encapsulated bacteria and reduce disease burden.


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ACKNOWLEDGMENTS
 
We kindly thank Claire-Anne Siegrist for critical reading of the manuscript.

We thank Aventis Pasteur, Marcy l'Etolie, for providing pneumococcal polysaccharides and tetanus protein for the preparation of Pnc-TT conjugates.

The study was supported by the Icelandic Research Council, Reykjavik, Iceland, and the European Union (QLK2-CT-1999-00429-Neovac-EC).


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Immunology, Landspitali-University Hospital, Hringbraut, 101 Reykjavik, Iceland. Phone: 354-543 5812. Fax: 354-543 4828. E-mail: ingileif{at}landspitali.is. Back

Editor: J. N. Weiser

{dagger} Present address: Queen's University Belfast, Belfast, Northern Ireland, United Kingdom. Back


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Infection and Immunity, February 2005, p. 956-964, Vol. 73, No. 2
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.2.956-964.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.




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