Pediatric Infectious Disease Journal:
Seroprevalence and Placental Transmission of Maternal Antibodies Specific for Neisseria meningitidis Serogroups A, C, Y and W135 and Influence of Maternal Antibodies on the Immune Response to a Primary Course of MenACWY-CRM Vaccine in the United Kingdom
Blanchard-Rohner, Geraldine MD, DPhil*†; Snape, Matthew D. MB BS, MD*‡; Kelly, Dominic F. MB BS, PhD*‡; O’Connor, Daniel MSc*; John, Tessa BSc (Hons)*‡; Kibwana, Elizabeth MSc*; Parks, Hannah MD*; Ford, Karen BN (Hons)*; Dull, Peter M. MD§; Pollard, Andrew J. MD, PhD*‡
From the *Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom; †Department of Paediatrics, Children’s Hospital of Geneva, University Hospital of Geneva, Geneva, Switzerland; ‡NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom; and §Novartis Vaccines and Diagnostics, Inc., Cambridge, MA.
Accepted for publication January 29, 2013.
This study was funded by Novartis vaccines and supported by the NIHR Oxford Biomedical Research Centre including salary support for M.D.S., D.F.K. and T.J. A.J.P. is a Jenner Investigator and James Martin Senior Fellow.
A.J.P. has conducted clinical trials on behalf of Oxford University, sponsored by Wyeth/Pfizer Vaccines, GlaxoSmithKline Vaccines, Sanofi Pasteur, Sanofi Pasteur MSD and Novartis Vaccines and organized educational meetings at Oxford University with unrestricted grants from these manufacturers, but does not accept any personal payments from vaccine manufacturers. M.D.S. has received assistance to attend scientific meetings from Wyeth Vaccines, Novartis Vaccines and GlaxoSmithKline Vaccines and has had travel and accommodation expenses paid by Novartis Vaccines while working in collaboration with Novartis Vaccines, Siena, Italy. M.D.S. has also conducted clinical trials on behalf of Oxford University, sponsored by Pfizer, Sanofi Pasteur and GlaxoSmithKline. D.F.K. has received assistance from GSK and Wyeth to attend scientific meetings and funding for research from GSK. P.M.D. is an employee of Novartis Vaccines. The authors have no other funding or conflicts of interest to disclose.
Address for correspondence: Geraldine Blanchard-Rohner, MD, DPhil, Center for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford OX3 7LJ, United Kingdom. E-mail: Geraldine.BlanchardRohner@hcuge.ch.
Maternal antibodies give neonates some protection against bacterial infection. We measured antibodies against Neisseria meningitidis serogroups A, C, Y and W135 in mothers and their 2-month-old infants at study enrollment. We also assessed the impact of maternal antibody present at 2 months of age on the immune response to a primary course of quadrivalent meningococcal conjugate vaccine (MenACWY-CRM197) given at 2 and 4 months of age.
This was a single-center, open-label, randomized study undertaken in Oxford, United Kingdom. Two hundred sixteen healthy infants were enrolled in the study and vaccinated with MenACWY-CRM197 at 2 and 4 months of age. Blood was obtained from all mothers, in a subset of infants at 2 months and all infants at 5 months. Antibody and memory B-cell responses at 5 months were correlated with maternal antibodies.
Mothers had low IgG antibodies against serogroups C, W135 and Y polysaccharides, but high serogroup A antibody, whereas 61–78% had protective human complement serum bactericidal activity (hSBA) (≥1:4) for serogroups C, W135 and Y but only 31% for serogroup A. Only 9%, 32%, 45% and 19% of 2-month-old infants had hSBA ≥1:4 for serogroups A, C, W135 and Y, respectively. Maternal antibody had little association on responses to MenACWY-CRM197, except a moderate negative association between MenC-specific bactericidal antibody at 2 and 5 months (r = −0.5, P = 0.006, n = 28) and between carrier-specific IgG antibody at 2 months and MenC-specific hSBA/IgG antibody at 5 months (r = −0.4, P = 0.02 and 0.04, n = 32 and 23). Nonetheless, 90% of infants achieved protective MenC-hSBA titers after vaccination at 2 and 4 months of age.
The levels of serogroup-specific meningococcal antibodies were low in mothers and 2-month-old infants. Immunizing mothers before or during pregnancy with meningococcal conjugate vaccines might increase antibody levels in early infancy and provide protection against infection due to N. meningitidis.
In children, Neisseria meningitidis is one of the leading causes of meningitis and septicemia, with the highest incidence of disease in infants <1 year of age, although an additional peak is observed in adolescents.1 Infants need protection from birth. In the first months of life, infants are protected to some extent by maternal antibodies that are obtained passively (during gestation) across the placenta.2 After 6 months of age, maternal antibodies have waned and are eventually replaced by acquired immunity during childhood, which increases with age and natural exposure to bacterial antigens (other Neisseria or cross-reacting polysaccharides on other colonizing bacteria) or through vaccination. The nature and duration of protection offered by maternal antibody depend on the concentration of specific antibodies in the mother’s serum and the capacity of the placenta to permit transfer of these antibodies to the newborn. This, in turn, depends on a number of other factors, the most important of which is the gestational age of the infant at birth.3,4 Transfer of maternal antibodies is restricted to the IgG class (principally IgG1 and IgG3 and, to a lesser extent, IgG2) and is maximal during the third trimester of gestation.5,6 From a previous study by de Voer et al7 assessing the IgG antibody concentration specific to N. meningitidis serogroup C and various other peptide and polysaccharide antigens at birth in paired samples of maternal and cord blood, it is expected that the concentration of antibody specific for all meningococcal serogroups in the infant at birth is similar to the concentration in mother, indicating good placental transfer of polysaccharide-specific antibodies from mothers to infants. In this study, we assessed the antibody concentrations in maternal blood and infants at 2 months of age, to determine the prevalence of meningococcal antibodies in UK mothers and in infants at 2 months of age and also to assess the effect of these antibodies on the immune response to primary immunization with a MenACWY-CRM197. It has been reported that maternal antibodies may interfere with the immune response to certain vaccines in early infancy.8 The maternal antibodies present in the infant blood during primary immunization may inhibit B-cell activation by forming immune complexes with the vaccine antigen and, therefore, hiding the vaccine epitopes and impairing their recognition by B cells.8 However, the inhibitory effects of maternal antibody depend on the levels of these antibodies present at immunization and are influenced by the “ratio of maternal antibody to antigen.”8–10 In several studies, the effects have been reported to be relatively modest. For example, children with high levels of diphtheria-specific IgG antibodies had lower diphtheria antibody responses to priming immunization; however, a high dose of vaccine antigen was shown to overcome the effect of maternal antibody.10 A recent study has assessed the effect of maternal immunization during pregnancy with pneumococcal polysaccharide vaccine and has reported a slight reduction in the antibody response to primary immunization with a 23-valent pneumococcal plain polysaccharide vaccine given at 7 or 17 weeks for those children with high maternal antibody prepriming.11 In the present study, we assessed the influence of maternal antibody specific to each serogroup of meningococcal polysaccharide and carrier protein on the immune response (antibody and memory B cells) to a 2-dose primary course of MenACWY-CRM197 vaccine given at 2 and 4 months of age.
MATERIALS AND METHODS
A phase II, single-center, open-label, randomized study was conducted in Oxford, United Kingdom, between May 2007 and December 2009. This study was designed to assess the serogroup A-, C-, Y- and W135-specific B-cell responses to a primary and booster course of MenACWY-CRM197 vaccine (Menveo, Novartis Vaccines and Diagnostics, Srl, Siena, Italy) and the influence of maternal antibody on the immune response to a primary course of MenACWY-CRM197 vaccine. This article describes the maternal antibody levels and the immune response among the infant cohort for whom baseline blood draws were obtained (described in ensuing sections). Potential participants were recruited by information letter mailed to all parents in the Thames Valley Region, United Kingdom, whose children were due routine immunizations. Parents interested in enrolling their child in the study contacted the Oxford Vaccine Group. Exclusion criteria included previous meningococcal disease or household contact with meningococcal disease, immune dysfunction and recent receipt of antibiotics or corticosteroids. The participants were then randomly assigned in a 2:1:1 ratio to 1 of the 3 groups described in Table 1 following a randomization list created by the Biostatistics and Clinical Data Management Department, Novartis. Written informed consent was obtained from the mothers of all enrolled infants. Ethical approval was obtained from the Oxfordshire Research Ethics Committees (approval number B07/Q1605/41; EudraCT number 2006-003476-35). The trial was registered with clinicaltrials.gov (identifier NCT 00488683).
In the primary phase of the study, 1 dose of 0.5 mL of the MenACWY-CRM197 vaccine was administered by intramuscular injection into the right anterolateral thigh at 2 and 4 months of age. The 0.5-mL dose consisted of N. meningitidis serogroup A, C, W135, and Y capsular saccharides (10 μg of serogroup A; 5 μg each of serogroups C, Y, and W135) individually conjugated to CRM197 (between 12.5 and 33 μg for serogroup A, 6.5 and 12.5 for serogroup C, 3.3 and 10 μg for serogroups W135 and Y), without adjuvant. The MenACWY-CRM197 was produced by Novartis Vaccines, Siena. Infants also received a heptavalent pneumococcal conjugate vaccine (Prevenar, Pearl River, NY) at 2 and 4 months of age and a combined diphtheria, tetanus toxoid, acellular pertussis, Haemophilus influenzae type b (Hib) and inactivated polio vaccine (DTaP-Hib-IPV, Pediacel, Maidenhead, United Kingdom) at 2, 3 and 4 months of age.
For all children, blood samples were taken at 5 months, following priming with MenACWY-CRM197 at 2 and 4 months of age. In addition, participants had 1 additional blood draw at a time that was determined by their group allocation: group I children were divided into 6 subgroups for the kinetics study, which involved a blood draw either before or at various days after the second dose of MenACWY-CRM197 at 4 months (results not reported here but in Blanchard-Rohner et al submitted to Vaccine); group II had an additional blood draw at the time of enrollment (visit 1–2 months); group III had an additional blood draw 6–7 days following the 12-month dose of MenACWY-CRM197 (results not reported here; see Table 1). Blood samples were obtained from all the mothers at the time of infant enrollment (maternal serum) and from a randomized subset of infants at 2 months of age during the first visit at study enrollment, just before immunization (54 infants). The maternal blood sample at study enrollment was taken on the same day as the infant blood sample at 2 months of age.
Anti-N. meningitidis Serogroup A-, C-, Y- and W135-specific Bactericidal Activity as Measured by hSBA
Serum bactericidal assays using human complement (hSBA) for meningococcal serogroups A, C, Y and W135 were performed at the laboratories of Novartis Vaccines, Marburg, Germany.12 In brief, 2-fold dilutions of heat-inactivated sera were incubated with suspensions of meningococcal strains A, C, Y, and W135 and freshly thawed human complement. The last dilution producing ≥50% reduction in colonies (killing) compared with control wells, containing complement and bacteria, was taken as the endpoint hSBA titer.
Anti-N. meningitidis Serogroups A, C, Y and W135 Antibody Concentration as Measured by Enzyme-linked Immunosorbent Assay
The concentration of serogroups A, C, Y and W135 anticapsular IgG was determined by ELISA following a previously described method.13 In brief, Immulon 2 microtiter plates (Thermo Electron Corporation, Cambridge, England) were coated with serogroup A, C, Y or W135 meningococcal polysaccharide (5 μg/mL; NIBSC, Potters Bar, England) conjugated to 5 μg/mL methylated human albumin (NIBSC) in sterile phosphate buffered saline. Following blocking, eight 2-fold dilutions of the reference serum (Centers for Disease Control and Prevention 1999; starting dilution 1:400 for serogroup A and 1:150 for serogroups C, Y and W135) and test sera (starting dilution 1:25) were made directly in the microtiter plate by well-to-well transfer with a multichannel pipette. The reference serum was assayed in triplicate, and test sera were assayed in duplicate. In addition, an internal quality control (an antimeningococcal adult immune serum) was diluted to yield optical densities approximately on the high, middle and low portions of the reference curve. After overnight incubation at 4°C, microtiter plates were developed with monoclonal pan anti-human Fcγ peroxidase antibody (diluted in serum/conjugate [S/C] buffer; Stratech Scientific Ltd., St. Louis, MO) for 2.5 hours at room temperature, followed by the chromogenic substrate tetramethylbenzidine dihydrochloride monohydrate (Sigma-Aldrich, St. Louis, MO), and the reaction was stopped after 30 minutes with 2 M H2SO4. The optical density of each well was then read at 450 nm.
Anti-CRM197 IgG Concentration
The CRM197 IgG concentration was determined using an ELISA performed in the Oxford Vaccine Group laboratory. In brief, Nunc Immuno Maxisorp microtiter plates (Thermo Fisher Scientific, Waltham, MA) were coated with 5.0 µg/mL of diphtheria toxin mutant CRM197 (Novartis, Siena). Following blocking and washing steps, serial dilutions of sample sera and a reference diphtheria antitoxin serum NIBSC (00/496) were made in duplicate. Following 2 hours of incubation, plates were washed and goat anti-human IgG (Fc-specific)–alkaline phosphatase conjugate antibodies (Sigma-Aldrich) were added for 1 hour. Plates were once more washed and p-nitrophenyl phosphate (Sigma-Aldrich) added; after 21 minutes, the enzymatic reaction was terminated with 3 M NaOH. The optical density of each well was read at 405 nm, and results were reported in International Units per microliter (NIBSC code 00/496).
Preparation of Peripheral Blood Mononuclear Cells
Up to 5-mL heparinized blood was diluted 1:2 with RPMI-1640 medium (Sigma-Aldrich) to which penicillin-streptomycin solution (Sigma-Aldrich) and L-glutamine 200 mM (Sigma-Aldrich) had been added at a dilution of 1:100 (complete medium). The peripheral blood mononuclear cells (PBMCs) were then separated by density gradient centrifugation over Lymphoprep (Axis-Shield Diagnostics, Dundee, Scotland). PBMCs were washed once in complete medium prior to further preparation for ELISpot or cell culture.
Preparation of ELISpot Plates
ELISpot plates (96-well polyvinylidene fluoride membrane; Millipore, Billerica, MA) were coated with serogroups A, C, Y or W135 meningococcal polysaccharide (5 μg/mL; NIBSC) conjugated to methylated human albumin (5 μg/mL; NIBSC), 10 μg/mL CRM197 (Novartis Vaccines, Siena) or 10 μg/mL goat anti-human Ig (Caltag Laboratories, Burlingame, CA) in sterile phosphate buffered saline. Phosphate buffered saline alone was added to the antigen blank wells. The ELISpot plates were stored at 4°C until use.
Detection of Memory B Cells
PBMCs prepared from peripheral blood were resuspended in complete medium with 10% fetal calf serum at a final concentration of 2 × 106 PBMCs/ mL and added to 96-well round-bottomed culture plates (Fisher Scientific, Leicestershire, UK) in 100 μL/well. Culture medium contained a 1/5000 dilution of Staphylococcus aureus (Cowan strain; Calbiochem, Billerica, MA) suspension, 83 ng/mL Pokeweed mitogen (Sigma-Aldrich) and 2.5 μg/mL CpG oligonucleotide (ODN-2006; Invitrogen, Carlsbad, CA). The cells were incubated at 37°C in 5% CO2 for 5.5 days before being resuspended and washed 4 times in complete medium with 10% fetal calf serum. The cultured cells were plated onto precoated ELISpot plates at 2 × 105 cells/well and then incubated and developed as for the ex vivo ELISpot described earlier in the article.
Spots were counted using an AID ELISpot Reader ELR02 (AID) and ELISpot Software, version 3.2.3 (Cadama Medical Ltd, Stourbridge, United Kingdom). Spot-forming cells were counted and confirmed by visual inspection. Identical settings were used for all plates but different settings were used for the different antigens (polysaccharide antigens versus protein antigens). The operator was blinded to which sample was being counted. Antibody forming spots were large, spherical in size with “fuzzy” granular edges.
Intention-to-treat analysis was performed. Stata (version 9.1; StataCorp, College Station, TX) was used for the statistical analysis. Both hSBA titer and ELISA IgG concentrations were summarized using geometric means with corresponding 95% confidence interval (CI). In addition, the proportion of children/mothers with seroprotection (hSBA titer ≥1:4)2,14 for each meningococcal serogroup was given. Antibody results of infants at 2 months and maternal antibody at enrollment were correlated with the immune parameters at 5 months of age, using Spearman’s rank correlation, using the log-transformed ELISA IgG concentration and hSBA titer but untransformed B-cell numbers. The limit of detection of the ELISpot assay was 2.5 cells/million cultured lymphocytes. A memory B-cell frequency of <2.5 cells/million cultured lymphocytes was assigned the value “0.” The primary objective of the study was to assess the relationship between memory B cells at 5 months of age and hSBA titers at 12 and 13 months of age following MenACWY-CRM197 vaccine (Blanchard-Rohner et al submitted to Vaccine). Taking information from previous studies,15–17 a sample size calculation gave 216 participants to achieve a study power of 80% assuming 5% level of significance. There was no statistical correction for multiplicity of endpoints in this study.
A total of 216 children and mothers were enrolled and randomized (108 in group I, 54 in group II and 54 in group III), of whom 205 children (95%) completed this first phase of the study (see Table 1 and Fig. 1). Because of difficulty in blood draws or insufficient sample volumes, not all data points were available for each time point or serogroups of meningococci. Every child was born after 37 weeks of gestation. Mothers were aged between 20 and 44 years.
Seroprevalence of Maternal Antibodies Specific for N. meningitidis Serogroups A, C, Y and W135
The concentration of IgG antibody was assessed in all the mothers, but the hSBA titer was only assessed in a subset of mothers (54), corresponding to the mothers of infants randomly assigned to have a baseline blood draw (group II). The concentration of IgG antibody specific for serogroups C, W135 and Y was lower than that for serogroup A in the maternal blood of all mothers at study enrollment (Fig. 2 and Table 2). Note that there was a tendency to have a higher geometric mean concentration (GMC) for the mothers of children from group II in comparison with the GMC of the totality of mothers (values reported on Table 2); however, the 95% CI were overlapping. In contrast, the hSBA titer was higher for serogroups C, W135 and Y than for serogroup A (Fig. 3 and Table 3). The proportion of mothers who had a protective antibody titer (ie, hSBA titer ≥ 1:4) at study enrollment was 16/52 (31%) for MenA, 35/52 (67%) for MenC, 40/51 (78%) for MenW135 and 31/51 (61%) for MenY. Based on verbal report 24/216 women had been immunized with the serogroup C meningococcal conjugate vaccine (MenCV) previously. In the 52 women for whom there was an hSBA titer for MenC, only 7 women had been immunized with the MenCV. Therefore, it was not possible to test any correlation between the fact of having been immunized previously and the hSBA titer for MenC.
Natural Immunity to N. meningitidis in Infants During the First Months of Life Before Immunization With Meningococcal Vaccines
The IgG-GMC and hSBA-geometric mean titre (GMT) were lower in infant blood at 2 months of age than the corresponding maternal blood sample for each serogroup (see Figs. 1 and 2 and Tables 2 and 3). The ratio between the infant and the maternal antibody (measured by IgG and hSBA) was low for each serogroup (between 1/3 and 1/7; Tables 2 and 3). The proportion of infants who had a protective antibody titer (ie, hSBA titer ≥ 1:4) at study enrollment was 4/43 (9%) for MenA, 12/38 (32%) for MenC, 12/29 (45%) for MenW135, and 4/21 (19%) for MenY.
Influence of Maternal Antibody on the Immune Response to Primary Immunization With MenACWY-CRM197 Vaccine at 2 and 4 Months of Age
There were few associations between the antibody measured in infant blood at 2 months of age and the meningococcal polysaccharide-specific hSBA, IgG and memory B cells at 5 months of age. There was a moderate negative correlation between MenC-specific bactericidal antibody at 2 months and 5 months of age (r = −0.5, P = 0.006, n = 28). There was a moderate positive correlation between MenW135-IgG antibody at 2 months and the MenW135-memory B cells at 5 months of age (r = 0.4, P = 0.03, n = 34; Table 4). There was a negative correlation between carrier-specific IgG antibody measured at 2 months of age and the memory B cells and IgG antibody specific for CRM197 at 5 months of age (Table 4).
Concerning the influence of carrier-specific antibody on the immune response to polysaccharide antigen; there was a moderate negative correlation between CRM197-specific IgG antibody at 2 months of age and the MenC-specific antibody at 5 months of age (both hSBA titer and IgG concentration), but no correlation with MenC-specific memory B cells (Table 5). There was a moderate negative correlation between CRM197-specific IgG antibody at 2 months of age and MenY-specific memory B cells specific to serogroup Y meningococci at 5 months (Table 5).
This is the first study reporting prevalence of serum bactericidal antibody against meningococcal serogroups A, W135 and Y in mothers of childbearing age (between 20 and 44 years) in the United Kingdom. The prevalence of bactericidal antibody (assessed by hSBA) was moderately high for serogroups C, W135 and Y but low for serogroup A. In contrast, the prevalence of meningococcal IgG antibody in the mothers of the study children was low for serogroups C, Y and W135 but high for serogroup A. A Dutch study assessed serogroup C–specific meningococcal IgG antibody and SBA titer at the time of delivery in maternal blood and cord blood. They reported a MenC-IgG-concentration of 0.2 (95% CI: 0.16–0.24) and 0.23 (95% CI: 0.18–0.28) in mothers and infants respectively and SBA titer of 29 (95% CI: 16–52), and 41 (95% CI: 25–67) in mothers and infants respectively in a rabbit complement assay. The authors reported a poor correlation between MenC-specific IgG and SBA titers (only 10% had a concentration of IgG antibodies ≥2 µg/mL whereas some 64% had a protective rSBA titer ≥8).7 Moreover, another study in toddlers reported a poor positive correlation between total IgG antibody and bactericidal antibody for MenC, although there was a strong positive correlation between high avidity-IgG antibody and bactericidal antibody.18 In that study, there were no data on the other serogroups of meningococci. The poor positive correlation between IgG antibody levels and the hSBA titer indicate that a large proportion of the polysaccharide-specific IgG antibody may not be protective, probably because of suboptimal specificity (low-avidity).19 These results suggest that a small amount of IgG antibody may be sufficient if those are bactericidal. The most reliable correlate for protection against meningococcal disease relies on serum bactericidal antibody titer.2 Furthermore, it was reported that the level of IgG antibody against serogroup A meningococci is elevated in comparison to the other serogroups in many “naïve individuals,” although these MenA-IgG antibodies were not bactericidal.19 Possible explanations for the high levels of MenA-IgG antibody in the population may be natural exposure to nonpathogenic Neisseria and other cross-reacting species in the nasopharynx.20,21 It is also known that cross-reactive antigens present in the gut microflora, induced antibody against serogroup A meningococci.22,23
Most women (192/216 [89%]) in this study had not been immunized with protein polysaccharide meningococcal conjugate vaccines previously. In the United Kingdom, in 1999 to 2000 in conjunction with the introduction of MenCV into the routine infant immunization schedule, a mass immunization campaign with MenCV targeted all children aged between 1 and 18 years with a further catch up to 24 years of age. A study comparing the prevalence of meningococcal antibodies before and after the introduction of MenCV in the United Kingdom has shown an increase in the prevalence of people with protective bactericidal antibody for serogroup C meningococci in the postvaccination eras, but only for the age groups targeted by the MenCV vaccination.24 In adults aged 25 years and older, including women of childbearing age, the prevalence of protective bactericidal antibodies were similar in the pre and postvaccine eras (10–20%) showing evidence of seroprotection against MenC.24 Currently, the UK immunization schedule includes 3 doses of MenCV at 3, 4 and 12 months of age, but this schedule does not induce long-term immunity to childbearing age.25 To sustain immunity through the fertile period in adulthood the use of booster doses of vaccine in adolescence26–28 or during pregnancy are necessary. In the present study, there are insufficient data to assess any association between prior maternal vaccination and antibody levels in mothers or their infants. Even if the transfer of maternal antibody in cord blood is efficient, antibody concentrations are low in the mothers, resulting in low concentrations of maternally derived antibodies in the infants during the first months of life leaving them susceptible to infection. Previous studies on immunization with plain polysaccharide pneumococcal or Hib-conjugate vaccine during pregnancy have shown an increase in the levels of IgG antibodies in infants during the first months of life after maternal immunization.11,29 There are no data on the use of the meningococcal vaccines during pregnancy. It is well known that IgG antibodies cross the placenta via active transport from the mother to the fetus.8 Consequently, antibody titers are even higher at birth in full-term newborns than in the mothers.30 The active transfer of IgG antibody across the placenta is variable; cord blood levels can be as low as 20% of maternal levels or exceed maternal levels by 200%.31 The lack of serological measurement at birth is a limitation of this study, however, maternal and infant levels of serogroup C–specific meningococcal IgG and SBA antibodies have been shown to be similar at delivery in a previous study.7 It is expected that the levels of antibodies in mothers are the same at delivery and again at 2 months after delivery, as it has been shown in adults that the levels of antibodies reach a steady state 6–9 months postimmunization which last for several years.32 There are no data on physiological changes that would occur in mothers after delivery that would modify this steady state. In the present study, maternal antibodies in the infants appeared to wane rapidly after birth; at 2 months of age, only one third to one seventh of the maternal antibody levels were detectable in infants, depending on the serogroup, and only a small proportion of children were still protected with an hSBA ≥ 1:4. The duration of passively acquired antibody in infants depends on the initial cord blood concentration, and lasts from 2 to 4 months.33–35
It has been reported previously that the presence of maternal antibodies in infant blood prepriming may inhibit further antibody increase following primary immunization in the first months of life.8,11 Several previous studies have reported that most children with high maternal antibody levels prepriming had a lower increase in antibody levels postpriming but they still had high levels of antibodies.10,29,36,37 A study assessing the influence of preimmunization antibody on the antibody response to priming immunization with an acellular pertussis, diphtheria, tetanus vaccine mixed with H. influenzae type b (Hib) vaccine (PRP-T) reported significant decrease in antibody response to tetanus but not to other vaccine antigens. Regression analysis suggested that the variation in preimmunization antibody explained only a small proportion of the variation in antibody at 5 months.38 Another study assessing the effect of tetanus toxoid (TT)-specific maternal antibodies (after immunization during pregnancy) on the immune response to a Hib-TT vaccine reported no interference with Hib-specific antibody, however, a reduction in the TT-specific antibody response for those with concentrations of TT-antibodies ≥1 International Units/mL.37 One possible explanation is that antibodies do not increase above a certain threshold as a result of a feedback mechanism which limits the antibody level.16 It is not clear whether this mechanism still allows activation of memory B cells and long-lived plasma cells that can sustain long-term antibody production. In the present study, the levels of antibodies were very low in the infants at 2 months of age for all serogroups of meningococci and for the carrier protein. A negative association between the polysaccharide-specific antibody at 2 months and the immune parameters at 5 months was not observed, except for MenC-specific bactericidal antibody at 2 months and 5 months (r = −0.5, P = 0.006, n = 28). In comparison, a moderate negative correlation was observed between carrier-specific IgG antibody at 2 months and carrier-specific IgG antibody/memory B cells at 5 months (r = −0.6 and −0.5 respectively), although the GMC of carrier-specific antibody at 2 months was very low. Previous studies have shown that high levels of carrier-specific maternal antibody inhibit antibody responses to the carrier protein but do not interfere with T-cell helper responses and with the antibody response to polysaccharide.9,37 In the present study there was a moderate negative correlation between CRM197-specific IgG antibody at 2 months of age and the MenC-specific antibody at 5 months of age (both hSBA titer and IgG concentration; r = −0.4), but not with MenC-specific memory B cells. There was also a positive association between the CRM197 IgG at 2 months and the memory B cells specific to serogroup Y meningococci at 5 months (r = 0.5, P = 0.02, n = 26). In summary, similarly to previous reports,10,36,38–40 these data suggest that there is no consistent negative effect of preimmunization polysaccharide or carrier-specific antibody on the immune response to primary immunization with a quadrivalent meningococcal protein polysaccharide conjugate vaccines. However, these data should be taken with caution, as the levels of maternal antibodies for meningococcal polysaccharides and for the carrier proteins were very low in this study. Further research should be carried out in a vaccinated group of mothers with higher levels of meningococcal antibodies and carrier proteins, for example adolescents who were vaccinated during the MenC campaign and are now of childbearing age (this should include the majority of pregnant women in the United Kingdom) or in further vaccine trials which involve immunization of pregnant women with meningococcal conjugate vaccines, to assess potential interference of maternal antibody specific to the polysaccharides but also to the carrier proteins on the immune response to primary immunization with meningococcal vaccines in young infants. It would be important to understand if there is a levels of protective antibody above which there is no more increase in response, but activation of memory B cells and long-lived plasma cell production is still possible. The kinetics of decrease of the meningococcal- and carrier-specific maternal antibodies in the first months of life in infants born from vaccinated mothers should also be assessed in order to define the best timing for infant primary vaccination to offer the best protection against infection by N. meningitidis in the first months of life.
In conclusion protection against invasive bacterial infection in the first months of life relies principally on placental transfer of maternal antibodies, herd immunity and vaccine-induced immunity. Most mothers in the present study had low levels of circulating meningococcal-specific antibody to provide early protection to their infants. Immunizing all adolescents or women of childbearing age with meningococcal vaccines could increase maternal antibody and improve direct protection of young infants, apparently without substantially inhibiting the response of their infants to primary immunization, although further research is needed to confirm this.
We thank all the children and families who participated in the study, and the research nurses and research doctors of Oxford Vaccine Group (University of Oxford, Oxford, United Kingdom), in particular Brigitte Ohene-Kena and Chaam Klinger, who undertook the clinical procedures. We also would like to thank Elizabeth Clutterbuck for help and advices in the laboratory procedures.
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human; maternal antibodies; Neisseria meningitidis
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