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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e3182787bff
Vaccine Reports

Three-year Antibody Persistence and Safety After a Single Dose of Combined Haemophilus influenzae Type b (Hib)–Neisseria meningitidis Serogroup C-tetanus Toxoid Conjugate Vaccine in Hib-primed Toddlers

Booy, Robert MB BS, MSc, MD*; Richmond, Peter MB BS; Nolan, Terry MB BS, PhD; McVernon, Jodie MB BS, PhD; Marshall, Helen MB BS, MPH§; Nissen, Michael MB BS; Reynolds, Graham MD; Ziegler, John B. MD**; Stoney, Tanya MB BS††; Heron, Leon MB ChB, MPH*; Lambert, Stephen MB BS, PhD; Mesaros, Narcisa MD‡‡; Peddiraju, Kavitha MSc§§; Miller, Jacqueline M. MD¶¶

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From the *National Centre for Immunisation Research and Surveillance (NCIRS), The Children’s Hospital at Westmead, Sydney; School of Paediatrics and Child Health, University of Western Australia and Princess Margaret Hospital for Children, Perth; Murdoch Children’s Research Institute and Melbourne School of Population Health, University of Melbourne, Parkville; §Women’s and Children’s Hospital and University of Adelaide, Adelaide; Royal Children’s Hospital, Brisbane; Canberra Hospital, Woden; **Sydney Children’s Hospital, Randwick; ††Vaccine Trials Group, Telethon Institute for Child Health Research, Perth, Australia; ‡‡GlaxoSmithKline Biologicals, Wavre, Belgium; §§GlaxoSmithKline Biologicals, Bangalore, India; and ¶¶GlaxoSmithKline Biologicals, King of Prussia, PA.

Accepted for publication September 18, 2012.

Study number: 106449/106450; www.ClinicalTrials.gov: NCT00326118.

Funding and conflicts disclosures are listed in the Acknowledgments.

Address for correspondence: Robert Booy, MB BS, MSc, MD, National Centre for Immunisation Research and Surveillance (NCIRS), The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia. E-mail: robertb2@chw.edu.au.

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Abstract

Background: Persistence of seroprotective bactericidal antibody titers is important for long-term protection against meningococcal serogroup C disease in young children. Antibody persistence values were determined in children up to 3 years after vaccination with a single dose of the combined Haemophilus influenzae type b (Hib)–Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine (Hib-MenC-TT; www.ClinicalTrials.gov: NCT00326118).

Methods: The children had been randomized at ages 12–18 months to receive either 1 dose of Hib-MenC-TT (Hib-MenC group) or separately administered Hib-TT conjugate vaccine and MenC-CRM197 (MCC) vaccine (Hib plus MCC group). All children had been primed in infancy with a Hib vaccine. Antibodies against MenC were measured by a serum bactericidal assay using rabbit complement (rSBA-MenC) and antibodies against Hib polyribosylribitol phosphate were assessed by enzyme-linked immunosorbent assay.

Results: The rSBA-MenC titers ≥1:8 were demonstrated 3 years after vaccination in 64.2% and 53.2% of participants in the Hib-MenC group and in the Hib plus MCC group, respectively. Antipolyribosylribitol phosphate concentrations ≥0.15 µg/mL persisted in >98% of participants in both groups. The rSBA–MenC geometric mean titers and antipolyribosylribitol phosphate geometric mean concentrations remained higher 3 years after vaccination than before vaccination. No serious adverse events assessed by the investigator as being related to vaccination were reported.

Conclusion: In this antibody persistence study of Hib-primed but MenC-naïve toddlers who received a single dose of Hib-MenC-TT, protective antibody levels against Hib and MenC were maintained in the majority of children 3 years after vaccination.

Australia’s National Immunization Program schedule includes Haemophilus influenzae type b (Hib) priming in infancy plus a Hib booster and 1-dose meningococcal serogroup C (MenC) vaccination in the second year of life. Observations with MenC conjugate vaccine programs suggest that persistence of seroprotective bactericidal antibody titers is important for long-term protection against MenC disease in young children.1–3

In a randomized study of 433 Hib-primed but MenC-naïve Australian toddlers, 1 dose of the combined Hib–Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine (Hib-MenC-TT; Menitorix, GlaxoSmithKline Biologicals, Rixensart, Belgium) was not inferior to separately administered Hib-TT conjugate vaccine (Hiberix, GlaxoSmithKline Biologicals) and MenC-CRM197 vaccine (Meningitec, Pfizer, New York, NY) in terms of proportions of children seroprotected against both components of the vaccine at 1 month after vaccination.4 One year after vaccination, seroprotective bactericidal antibody titers against MenC persisted in 86.7% of Hib-MenC-TT recipients and 76.4% of the control group, and >98% in both groups had seroprotective antibody concentrations against Hib polyribosylribitol phosphate (PRP).4 Assessments of long-term protection are planned at yearly intervals up to 5 years after vaccination. This report presents antibody persistence levels in children up to 3 years after vaccination.

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METHODS

The design of this open, randomized, controlled, multicenter vaccination study in Australia was described previously.4 Briefly, children aged 12–18 months were randomized (ratio 3:1) to receive either 1 dose of Hib-MenC-TT (Hib-MenC group) or Hib-TT plus MenC-CRM197 vaccine (Hib plus MCC group). Both groups were coadministered measles, mumps and rubella live attenuated vaccine (Priorix; GlaxoSmithKline Biologicals). A pneumococcal conjugate vaccine was not coadministered because a booster dose is not recommended in healthy children at ages 12–18 months after a 3-dose primary course in the Australian National Immunization Program schedule. All children had been primed in infancy with a Hib vaccine: either 2 doses of a vaccine containing PRP conjugated to outer membrane protein (Hib-OMP) or 3 doses of a diphtheria-tetanus-acellular pertussis/Hib vaccine containing PRP conjugated to TT (DTPa/Hib-TT). Two Hib priming vaccines were permitted to reflect regional differences in vaccination regimens. This study was conducted according to the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol and informed consent forms were approved by local Institutional Review Boards for each study center.

Antibody persistence was determined from blood samples collected 24 and 36 months after vaccination (between 2008 and 2010), when the children were 3 and 4 years of age, respectively. Results are presented for the according-to-protocol (ATP) immunogenicity cohorts for antibody persistence at years 2 and 3, defined as vaccinated children who complied with all protocol-defined procedures and for whom antibody results were available at the given persistence time points. Because the percentage of subjects enrolled in each persistence phase (but excluded from the ATP cohorts for persistence) was >5%, additional analyses also were performed on the total enrolled cohorts at years 2 and 3.

Antibodies against MenC were measured by a serum bactericidal assay using rabbit complement (rSBA-MenC), for which titers ≥1:8 are considered indicative of seroprotection.1,2 Antibodies against Hib PRP were assessed by enzyme-linked immunosorbent assay for which levels ≥0.15 µg/mL are considered indicative of protection.5,6 For each group, seroprotection rates and antibody geometric mean titers (GMTs) and geometric mean concentrations (GMCs) were calculated with 95% confidence intervals (CIs).

Comparability of groups (Hib-MenC group versus Hib plus MCC group) was evaluated with exploratory analyses of the percentage of children with rSBA-MenC titers ≥1:8 or anti-PRP concentrations ≥0.15 µg/mL; 95% CIs of differences not including 0 were regarded as indicative that a significant difference might exist between groups. GMT-to-GMC ratios (Hib-MenC group over Hib plus MCC group) with 95% CIs not including 1 also indicated a potentially significant difference. Exploratory subgroup analyses also were performed by primary Hib vaccination (DTPa/Hib-TT or Hib-OMP). The results of all exploratory group comparisons should be interpreted with caution considering that there was no adjustment for multiplicity for these comparisons and the clinical relevance of the differences is unknown.

Each subject’s parent or guardian was asked if any serious adverse event had occurred since the previous visit. Serious adverse events considered by the investigator to be related to vaccination were recorded.

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RESULTS

Of the 433 children who were enrolled and vaccinated,4 362 (83.6%) participated in the year 2 study and 345 (79.7%) participated in the year 3 study. Reasons for nonparticipation in the persistence studies and for elimination from the ATP cohorts for antibody persistence at years 2 and 3 are listed in Figure 1. The ATP cohort for antibody persistence at year 2 included 243 children in the Hib-MenC group and 87 in the Hib plus MCC group; mean ages were 36.6 and 36.5 months, respectively (range, 35–40 months in both groups), 54.7% and 59.8% were male, respectively, and the majority (88.2%) was white or Caucasian or of European heritage. The ATP cohort for antibody persistence at year 3 included 235 children in the Hib-MenC group and 80 in the Hib plus MCC group; mean ages were 48.5 and 48.4 months, respectively (range, 47–52 months in both groups) and 54.9% and 65.0% were male, respectively.

Figure 1
Figure 1
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Three years after vaccination, rSBA–MenC titers ≥1:8 were observed in 64.2% of the Hib–MenC group and in 53.2% of the Hib plus MCC group, and the percentage of children with anti–PRP concentrations ≥0.15 μg/mL remained high (>98%) in both groups (Table 1). At the year 2 and year 3 persistence time points, there were no statistically significant differences between groups in percentage of children with rSBA–MenC titers ≥1:8 or GMT, or in percentage of children with anti–PRP concentrations ≥0.15 μg/mL or GMC (Table 2).

Table 1
Table 1
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Table 2
Table 2
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Exploratory analysis by Hib primary vaccination history showed that in DTPa/Hib-TT–primed children, the anti-PRP GMC was statistically significantly lower in the Hib-MenC group than in the Hib plus MCC group at year 2 (95% CI on GMC ratio: 0.46–0.94) but not at year 3 (95% CI on GMC ratio: 0.54–1.12). At all antibody persistence time points, anti-PRP GMCs tended to be higher in Hib-OMP–primed children compared with DTPa/Hib-TT–primed children in both treatment groups, as indicated by nonoverlapping 95% CIs (post hoc comparison; Table 3). In the exploratory analysis of rSBA-MenC GMTs by Hib-priming vaccination history, no statistically significant differences were detected between groups and 95% CIs for Hib-OMP–primed and DTPa/Hib-TT–primed children overlapped (data not shown).

Table 3
Table 3
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In both treatment groups, rSBA–MenC GMTs and anti–PRP GMCs remained higher at year 3 than before vaccination at age 12–18 months (Table 1). A post hoc statistical analysis was conducted to calculate the number of children with a 4-fold or greater increase in rSBA–MenC GMT or anti–PRP GMC between each time point as an indicator of natural boosting resulting from possible bacterial colonization. The results showed a minority of children had ≥4-fold increase in rSBA–MenC GMT (42 children overall showed ≥4-fold increase at year 2 or year 3 compared with a previous year) or anti–PRP GMC (28 children overall; Table 4).

Table 4
Table 4
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The results of the analyses on the total enrolled cohorts at years 2 and 3 were consistent with those for the corresponding ATP cohorts for persistence. An additional statistically significant difference was detected in the exploratory analysis between the 2 study groups in the total enrolled cohort at year 3; the percentage of children with rSBA-MenC titers ≥1:8 was statistically significantly higher in the Hib-MenC group than in the Hib plus MCC group for Hib-OMP–primed children (95% CI for group difference: 1.14–45.50%).

No vaccination–related serious adverse events were reported in the persistence phase of the study.

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DISCUSSION

The immunogenicity of a single dose of Hib-MenC-TT administered at age 12–18 months was not inferior to separately administered Hib-TT and MenC-CRM197 vaccines in terms of immune responses to both components and was well-tolerated in Hib-primed but MenC-naïve toddlers.4 Three years after vaccination with Hib-MenC-TT, 64.2% (95% CI: 57.5–70.4%) of children had rSBA-MenC titers ≥1:8 and 99.1% (95% CI: 96.9–99.9%) had anti-PRP ≥0.15 μg/mL.

Persistence of rSBA-MenC titers ≥1:8 after immunization is regarded as the key protective mechanism against invasive MenC infection,2 which is supported by observations suggesting circulating antibodies are more important than immune memory for long-term protection.3 At 1 year after vaccination, a statistically significantly higher percentage of children had seroprotective rSBA-MenC titers in the Hib-MenC group than in the control group in the exploratory analysis,4 which was in line with reports suggesting TT is a more immunogenic carrier protein for primary immunization against the MenC antigen than CRM197.7,8 At 2 and 3 years after vaccination, however, there were no significant differences between groups.

We are not aware of any other published 3-year antibody persistence data after a single MenC conjugate vaccine dose in MenC-naïve toddlers that can be compared against the results of this study. A recently reported assessment of quadrivalent meningococcal serogroups A, C, W-135 and Y conjugate vaccines included a control group that received MenC conjugate vaccine at 12 months of age only, but long-term antibody persistence results from this group were combined with those from a group that received MenC at 2 and 12 months of age.9 In this combined group, 53% of children 5 years of age had seroprotective SBA-MenC titers (≥1:8) measured with human complement. In a previous study conducted in the United States, where children aged 12–15 months received a single dose of Hib-N. meningitidis serogroup C and serogroup Y TT conjugate vaccine (HibMenCY-TT), after 3 years 57% had seroprotective SBA-MenC titers measured with human complement.10 In a Spanish trial in which children were primed with Hib-MenC-TT or MenC-TT (NeisVac-C) on a 2-month, 4-month and 6-month schedule, a higher proportion of children with persistent seroprotective MenC titers (83–94%) was reported >5 years after Hib-MenC-TT booster vaccination.11 However, our observed rates were comparable with the rate (67%) reported in a study conducted in Poland and the United Kingdom 2 years after Hib-MenC-TT booster vaccination after Hib-MenC-TT priming on a 2-month, 3-month, 4-month schedule.12 In contrast, the proportions of children with seroprotective MenC titers were higher in our study than in a United Kingdom study of antibody persistence 2 years after priming in infancy with a MenC-CRM197 or MenC-TT vaccine and boosting with Hib-MenC-TT at 12 to 14 months of age.7 Differences between the results of our study and those of studies that incorporated MenC priming in infancy are, however, difficult to interpret not only because of the vaccination schedule used but also because of other differences, such as study population, vaccine antigen content and laboratory assay methodologies. Another factor that might have contributed to this variation is the epidemiology of N. meningitidis carriage in the countries in which the studies were performed, which may lead to differences between populations in terms of natural boosting of immune responses.13,14 In our study, an increase in antibodies that possibly could be attributed to bacterial colonization (although carriage was not assessed in our study) was observed in a minority of the children. This will be reanalyzed at future time points to help determine whether an additional booster dose in children may be required.

In this Australian study, all children had been primed in infancy with either Hib-OMP or a DTPa/Hib-TT combination vaccine and, at study enrollment, >70% of children in each priming vaccine subgroup had anti-PRP concentrations ≥0.15 µg/mL.4 This suggests that both vaccines are effective for priming in infancy, and either can be followed by Hib-MenC-TT as a Hib booster. In both the Hib-MenC and the Hib plus MCC groups, Hib-OMP–primed children tended to have higher anti-PRP GMCs 2 and 3 years after vaccination. This also was observed at 1 month and 1 year after vaccination.4

In conclusion, 3 years after vaccination with a single dose of the combined Hib-MenC-TT conjugate vaccine, antibody levels likely to be protective against Hib and MenC are maintained in the majority of Hib-primed but MenC-naïve children. The rSBA-MenC GMTs and anti-PRP GMCs remain above levels observed before Hib-MenC-TT immunization.

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ACKNOWLEDGMENTS

The authors thank all the children and their parents, as well as the staff members and nurses, who were involved in this study. The authors thank the following people from Sydney: Annemarie Egan, Rosemary Joyce, Kylee Gibbins, Lyn Barnes, Laura Rost, Pamela Cheung, Jennifer Murphy, Camille Lang, Elizabeth Deegan, Elizabeth Clarke, Carol Shineberg, Edwina Jacobs, Stephen George, Katherine Hale, Mary Iskander, Nicholas Wood, Monica Lahra, Joseph Khouri, Gulam Khandaker, Tony Yee, Briget Evans, Susan Smith and Vanessa Bonett; from Perth: Jennifer Kent and Larissa Rhind (site coordinators), Jan Adams, Dr. Gabriela Dixon, Lisa Montgomery and Dr. Karen Prosser; from Melbourne: Marita Kefford (study manager), Dr. Karyn Alexander, Michelle Boglis, Janet Briggs, Clare Brophy, Elizabeth Christie, Dr. Jenny Davey, Jane Gibson, Erin Hill, Alice Holloway, Dr. Lana Horng, Ruth Lawrence, Stephanie Lenko, Betty Lim, Sarah Macnee, AnnMarie McEvoy, Liz McGrath, Elanna Nolan, Jacinta O’Keefe, Mairead Phelan, Dr. Nicole Rose, Jane Ryrie, Charan Sandhu, Deb Saunders, Jacinta Sonego, Judith Spotswood, Dr. Loretta Thorn and Marie West; from Brisbane: Aaron Buckner (site coordinator), Dr. Raymond Chuk, Lisa Mulhearn, Kylie Berglund, Ria Halstead and Jane Yunus; from Canberra Hospital: Dr. Sandra Gillet; from Adelaide: Diana Weber, Louise DeGaris, Chris Heath, Michelle Clarke, Jane Tidswell, Dr. Jan Walker and Dr. Susan Evans. The authors also thank Pascale Lestrate and Koen Maleux for serology analysis, Sheila Woods for report writing, Dr. Wouter Houthoofd (XPE Pharma and Science) for publication management and Dr. Joanne Knowles (independent medical writer) for initial drafting of the manuscript and incorporation of comments received from the authors.

Sponsored by GlaxoSmithKline Biologicals, Rixensart, Belgium (institutional funding to RB, PR, TN, JM, HM, MN, GR, JBZ, TS, LH and SL). Occasionally funded by organizations such as Commonwealth Serum Laboratory (CSL), Roche, Sanofi, GlaxoSmithKline and Pfizer (Wyeth) to attend and present at scientific meetings (to RB). Any funding received is directed to a research account at The Children’s Hospital at Westmead and is not personally accepted by RB. Supported by institutional funding from GlaxoSmithKline for investigator-led epidemiologic studies and received travel support from GlaxoSmithKline and other vaccine companies to present scientific data and chair workshops (to PR). Travel support was received from GlaxoSmithKline, CSL, Novartis, Sanofi-Pasteur and Wyeth for participation in investigator meetings or for the presentation of scientific data at research meetings and honoraria was received for participation in a GlaxoSmithKline independent data monitoring and safety board for an unrelated vaccine (to TN). Sponsored by a range of vaccine manufacturers, travel grants were received from vaccine companies to attend and chair scientific meetings and honoraria for membership of scientific advisory boards for Novartis Vaccines was paid into an institutional educational fund (to JM, investigator on vaccine studies). Supported by travel grants from GlaxoSmithKline and other companies to attend scientific meetings to present independent scientific data and by industry funding for investigator-led studies (to HM, investigator on vaccine studies and a member of vaccine advisory boards for GlaxoSmithKline and other companies). Support was received from GlaxoSmithKline and Pfizer (Wyeth) for participation in investigator meetings or for the presentation of scientific data at research meetings (to MN and GR). Support was received from Wyeth, Nutricia and Octapharma for participation in investigator meetings or to attend, chair and present at scientific meetings (to JBZ, investigator in industry-sponsored vaccine and other clinical trials). Honoraria was received from GlaxoSmithKline for study committee membership and travel support from Baxter, CSL and GlaxoSmithKline for participation in investigator meetings or the presentation of scientific data at research meetings (to TS). Sponsored by GlaxoSmithKline and other companies. Support was received for conference attendance from GlaxoSmithKline and Sanofi Pasteur (to LH, member of a vaccine advisory board for Novartis). The money is directed to a research account at the Children’s Hospital at Westmead. Supported by travel grants from GlaxoSmithKline and other companies for participation in investigator meetings or for the presentation of scientific data at research meetings, and honoraria was received for being a member of vaccine advisory boards for GlaxoSmithKline and other companies (to SL). PR, JM, HM, MN, GR, JBZ, LH and SL have no shares, paid employment or consultancies with GlaxoSmithKline or other pharmaceutical companies. NM, KP and JMM are employees of GlaxoSmithKline Biologicals. NM and JMM own GlaxoSmithKline stock shares and stock options. HM received support from the National Health and Medical Research Council of Australia (Career Development Fellowship 1016272). GlaxoSmithKline Biologicals was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals also underwrote all costs associated with the development and publishing of the present manuscript. All authors contributed to the study and writing of the manuscript and the corresponding author had full access to the data and final responsibility for submission of the publication. GlaxoSmithKline Biologicals (Rixensart, Belgium) was the funding source of this study. GlaxoSmithKline Biologicals also funded all costs associated with the development and the publishing of the present manuscript. Menitorix, Priorix and Hiberix are trademarks of the GlaxoSmithKline group of companies. Meningitec is a trademark of Pfizer Inc. The authors have no other funding or conflicts of interest to disclose.

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REFERENCES

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5. Käyhty H, Peltola H, Karanko V, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1983;147:1100

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8. Díez-Domingo J, Cantarino MV, Torrentí JM, et al.MenC Study Group. A randomized, multicenter, open-label clinical trial to assess the immunogenicity of a meningococcal C vaccine booster dose administered to children aged 14 to 18 months. Pediatr Infect Dis J. 2010;29:148–152

9. Khatami A, Snape MD, Davis E, et al. Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations. Vaccine. 2012;30:2831–2838

10. Marshall GS, Mesaros N, Aris E, et al. Persistence of immunity three years after an investigational Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y tetanus toxoid (HibMenCY-TT) conjugate vaccine. 2011 Paper presented at: 45th National Immunization Conference March 28–31. Washington, DC; Abstract 25219

11. Tejedor JC, Merino JM, Moro M, et al. Five-year Antibody Persistence and Safety Following a Booster Dose of Combined Haemophilus influenzae Type b-Neisseria meningitidis Serogroup C-Tetanus Toxoid Conjugate Vaccine. Pediatr Infect Dis J. 2012;31:1074–1077

12. Khatami A, Snape MD, John T, et al. Persistence of immunity following a booster dose of Haemophilus influenzae type B-Meningococcal serogroup C glycoconjugate vaccine: follow-up of a randomized controlled trial. Pediatr Infect Dis J. 2011;30:197–202

13. Trotter CL, Borrow R, Findlow J, et al. Seroprevalence of antibodies against serogroup C meningococci in England in the postvaccination era. Clin Vaccine Immunol. 2008;15:1694–1698

14. de Voer RM, Mollema L, Schepp RM, et al. Immunity against Neisseria meningitidis serogroup C in the Dutch population before and after introduction of the meningococcal c conjugate vaccine. PLoS ONE. 2010;5:e12144

Haemophilus influenzae type b; Neisseria meningitidis serogroup C; antibody persistence; toddlers

© 2013 Lippincott Williams & Wilkins, Inc.

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