MenC Conjugate Vaccine Research Articles

Antibody Persistence after Serogroup C Meningococcal Conjugate Immunization of United Kingdom Primary‐School Children in 1999–2000 and Response to a Booster: A Phase 4 Clinical Trial

After immunization with serogroup C meningococcal (MenC) conjugate vaccine, antibody responses and vaccine effectiveness are sustained in adolescents, in contrast to rapid waning in young children. We investigated the persistence of serum bactericidal antibody (SBA) titers in children 6 years after immunization with MenC vaccine (primed between 2 months and 6 years of age). The response to a Haemophilus influenzae type b-MenC conjugate (Hib-MenC) booster was also measured. A phase 4 clinical trial was conducted among 250 healthy 6-12-year-old children. SBA titers were measured before, 1 month after, and 1 year after Hib-MenC administration. The correlate of protection was an SBA titer of 8. An SBA titer of 8 was observed in 61 (25% [95% confidence interval {CI}, 20%-30%]) of 244 participants (mean age, 9.1 years; mean interval since MenC immunization, 6.75 years). The proportion with an SBA titer of 8 and the SBA geometric mean titer increased with age, from 12% (95% CI, 4%-23%) to 48% (95% CI, 29%-67%) and from 2.90 (95% CI, 2.11-3.99) to 17.20 (95% CI, 6.80-43.5), respectively, from a mean age of 7.0 to 12.1 years. One month after the Hib-MenC booster, all participants had an SBA titer of 8, which was sustained in 99.6% at 1 year. As a result of waning antibody, the majority of 6-12-year-old children in the United Kingdom have inadequate serological protection against MenC. The persistence of MenC immunity and the response to a Hib-MenC booster is dependent on age at priming. A booster was highly effective in this cohort and could sustain population immunity against MenC disease. Trial registration. Current Controlled Trials ( http://www.controlled-trials.com ) identifier: ISRCTN72858898 .

Serogroup C meningococci in Italy in the era of conjugate menC vaccination

BackgroundTo assess changes in the pattern of Invasive Meningococcal Disease (IMD) in Italy after the introduction of conjugate menC vaccine in the National Vaccine Plan 2005–2007 and to provide information for developing timely and appropriate public health interventions, analyses of microbiological features of isolates and clinical characteristics of patients have been carried out. In Italy, the number of serogroup C meningococci fell progressively following the introduction of the MenC conjugate vaccine, recommended by the Italian Ministry of Health but implemented according to different regional strategies.MethodsIMD cases from January 2005 through July 2008 reported to the National Meningococcal Surveillance System were considered for this study. Serogrouping and sero/subtyping were performed on 179 serogroup C strains received at the National Reference Laboratory of the Istituto Superiore di Sanità. Antibiotic susceptibility testing was possible for 157 isolates. MLST (Multilocus sequence typing), porA VRs (Variable Region) typing, PFGE (Pulsed Field Gel Electrophoresis), VNTR (Variable Number Tandem Repeats) analyses were performed on all C:2a and C:2b meningococci (n = 147), following standard procedures.ResultsIn 2005 and 2008, IMD showed an incidence of 0.5 and 0.3 per 100,000 inhabitants, respectively. While the incidence due to serogroup B remained stable, IMD incidence due to serogroup C has decreased since 2006. In particular, the decrease was significant among infants. C:2a and C:2b were the main serotypes, all C:2a strains belonged to ST-11 clonal complex and all C:2b to ST-8/A4. Clinical manifestations and outcome of infections underlined more severe disease caused by C:2a isolates. Two clusters due to C:2a/ST-11 meningococci were reported in the North of Italy in December 2007 and July 2008, respectively, with a high rate of septicaemia and fatal outcome.ConclusionPublic health surveillance of serogroup C invasive meningococcal disease and microbiological/molecular characterization of the isolates requires particular attention, since the hyper-invasive ST-11 predominantly affected adolescents and young adults for whom meningococcal vaccination was not recommended in the 2005–2007 National Vaccine Plan.

Immunogenicity of the 10-Valent Pneumococcal Non-typeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) When Coadministered With Different Neisseria meningitidis Serogroup C Conjugate Vaccines

Immunogenicity of the candidate 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed when coadministered with other routine pediatric vaccines including different Neisseria meningitidis serogroup C conjugate vaccines. One thousand five hundred forty-eight healthy infants received, according to a balanced (1:1:1:1) randomization, either PHiD-CV coadministered with (1) DTPa-HBV-IPV/Hib (Infanrix hexa) and MenC-CRM (Meningitec), (2) DTPa-HBV-IPV/Hib and MenC-TT (NeisVac-C), or (3) DTPa-HBV-IPV (Infanrix penta/Pediarix) and Hib-MenC-TT (Menitorix); or 7vCRM (Prevenar/Prevnar) coadministered with DTPa-HBV-IPV and Hib-MenC-TT at 2-4-6 months of age with a booster dose at 11-18 months. Serotype-specific pneumococcal responses were measured by 22F-inhibition ELISA and opsonophagocytic (OPA) assay. In all 3 coadministration groups, PHiD-CV was immunogenic for each of the 10 pneumococcal vaccine serotypes as assessed by post-primary and post-booster antibody ELISA and OPA responses. When coadministered with DTPa-HBV-IPV, Hib, and MenC antigens, PHiD-CV responses after the third primary dose were within the same range as 7vCRM responses in terms of the percentage of subjects achieving an ELISA antibody concentration >or=0.2 microg/mL for all common vaccine serotypes (over 92% of subjects) except for serotype 6B (at least 87% of subjects). ELISA and OPA immune responses were also evident after the second primary doses of PHiD-CV or 7vCRM vaccine, although antibody levels were below that achieved after 3 primary doses, particularly for serotypes 6B and 23F. The kinetics of the immune responses from after the second dose to after the booster dose were similar for most of the serotypes in both PHiD-CV and 7vCRM groups. PHiD-CV was immunogenic when coadministered with other routine pediatric vaccines including MenC conjugate vaccines.

A generic mechanism inNeisseria meningitidisfor enhanced resistance against bactericidal antibodies

The presence of serum bactericidal antibodies is a proven correlate of protection against systemic infection with the important human pathogen Neisseria meningitidis. We have identified three serogroup C N. meningitidis (MenC) isolates recovered from patients with invasive meningococcal disease that resist killing by bactericidal antibodies induced by the MenC conjugate vaccine. None of the patients had received the vaccine, which has been successfully introduced in countries in North America and Europe. The increased resistance was not caused by changes either in lipopolysaccharide sialylation or acetylation of the α2-9–linked polysialic acid capsule. Instead, the resistance of the isolates resulted from the presence of an insertion sequence, IS1301, in the intergenic region (IGR) between the sia and ctr operons, which are necessary for capsule biosynthesis and export, respectively. The insertion sequence led to an increase in the transcript levels of surrounding genes and the amount of capsule expressed by the strains. The increased amount of capsule was associated with down-regulation of the alternative pathway of complement activation, providing a generic mechanism by which the bacterium protects itself against bactericidal antibodies. The strains with IS1301 in the IGR avoided complement-mediated lysis in the presence of bactericidal antibodies directed at the outer membrane protein, PorA, or raised against whole cells.

Two versus three doses of a meningococcal C conjugate vaccine concomitantly administered with a hexavalent DTaP-IPV-HBV/Hib vaccine in healthy infants

The immunogenicity and reactogenicity of a meningococcal serogroup C (MenC) conjugate vaccine given concomitantly with DTaP-IPV-HBV/Hib vaccine according to a two- or three-dose schedule in healthy infants was evaluated. At 1 month post-vaccination, 98% (two doses) and 100% (three doses) of subjects had serum bactericidal antibody using human complement assay (hSBA) titres > or =1:8; at 12 months of age > or =89% of subjects in each group remained seroprotected. Induction of immunological memory, as evaluated by administration of a meningococcal serogroup A/C polysaccharide vaccine challenge dose, was similar for both regimens and no interference was observed in the immune response to MenC or hepatitis B virus antigens. Reactogenicity was similar in each group. MenC conjugate vaccine given concomitantly with DTaP-IPV-HBV/Hib to healthy infants in the first year of life using a two-dose schedule is as safe and immunogenic as a three-dose regimen.

The Magnitude of the Antibody and Memory B Cell Responses during Priming with a Protein-Polysaccharide Conjugate Vaccine in Human Infants Is Associated with the Persistence of Antibody and the Intensity of Booster Response

Rapid waning of anti-polysaccharide bactericidal Ab and vaccine effectiveness is observed following infant immunization with the serogroup C meningococcal (MenC) glycoconjugate vaccine. This is despite the demonstrable presence of immunological memory. Persistence of functional Ab, therefore, appears to be the key determinant of MenC conjugate vaccine effectiveness. Ab persistence is thought to depend in the short term on the survival of plasma cells generated during priming and in the longer term on the production of new Ab secreting cells from memory B cells. In this study, we found a strong association between the level of MenC-specific Ab and the frequency of memory B cells measured at 5 mo of age (1 mo after 3-dose primary immunization with MenC conjugate vaccine), and the persistence of functional Ab at one year of age. These findings suggest that these two parameters are good markers of B cell responses to priming and can be used as predictors of long term humoral immunity induced by glycoconjugate vaccines received in early infancy.

The development of a new heptavalent diphtheria–tetanus–whole cell pertussis–hepatitis B– Haemophilus influenzae type b– Neisseria meningitidis serogroups A and C vaccine: a randomized dose-ranging trial of the conjugate vaccine components

To assess immunogenicity, antibody persistence, immune memory, and reactogenicity of a novel heptavalent DTPw-HBV/Hib-MenAC (diphtheria, tetanus, whole cell pertussis-hepatitis B virus/Haemophilus influenzae type b-Neisseria meningitidis serogroups A and C) vaccine. This was an open, randomized study in the Philippines, with DTPw-HBV/Hib-MenAC administered at 6, 10, and 14 weeks of age. Three different polysaccharide contents of the conjugate vaccine components were assessed with conjugated PRP (polyribosylribitol phosphate), MenA, and MenC polysaccharides at the following doses: 2.5 microg of each, 5 microg of each, or 2.5 microg of PRP and 5 microg each of MenA and MenC. Controls received licensed DTPw-HBV and Hib or DTPw-HBV/Hib and MenC conjugate vaccines separately. Immune memory was evaluated via plain polysaccharide challenge administered to half of the subjects at 10 months of age. After primary vaccination, at least 97.7% of DTPw-HBV/Hib-MenAC recipients had serum bactericidal antibody (SBA)-MenA and SBA-MenC titers > or =1:8, and at least 99% had anti-PRP antibody concentrations > or =0.15 microg/ml. Immune responses to DTPw-HBV components were not impaired by the lowest dose of Hib-MenAC vaccine. Plain polysaccharide challenge induced marked increases in Hib, MenA, and MenC antibodies in primed subjects, indicative of immune memory. All of the experimental vaccines were well tolerated. The lowest dose of DTPw-HBV/Hib-MenAC polysaccharide conjugate vaccine was well tolerated, immunogenic, had good persistence of antibodies, and demonstrated immune memory, and consequently was selected for further development.

Safety and efficacy of meningococcal c vaccination in juvenile idiopathic arthritis

To determine whether vaccinations aggravate the course of autoimmune diseases such as juvenile idiopathic arthritis (JIA) and whether the immune response to vaccinations may be hampered by immunosuppressive therapy for the underlying disease. In this multicenter cohort study, 234 patients with JIA (ages 1-19 years) were vaccinated with meningococcal serogroup C (MenC) conjugate to protect against serogroup C disease (caused by Neisseria meningitidis). Patients were followed up for disease activity for 1 year, from 6 months before until 6 months after vaccination. IgG antibody titers against MenC polysaccharide and the tetanus carrier protein were determined by enzyme-linked immunosorbent assay and toxin binding inhibition assay, respectively. A serum bactericidal assay was performed to determine the function of the anti-MenC antibodies. No change in values for any of the 6 components of the core set criteria for juvenile arthritis disease activity was seen after MenC vaccination. Moreover, no increase in the frequency of disease relapse was detected. Mean anti-MenC IgG concentrations in JIA patients rose significantly within 6-12 weeks after vaccination. Of 157 patients tested, 153 were able to mount anti-MenC IgG serum levels >2 micro g/ml, including patients receiving highly immunosuppressive medication. The 4 patients with a lower anti-MenC antibody response displayed sufficient bactericidal activity despite receiving highly immunosuppressive medication. The MenC conjugate vaccine does not aggravate JIA disease activity or increase relapse frequency and results in adequate antibody levels, even in patients receiving highly immunosuppressive medication. Therefore, patients with JIA can be vaccinated safely and effectively with the MenC conjugate.

Antibody persistence and immunological memory at age 4 years after meningococcal group C conjugate vaccination in children in the United kingdom.

Antibody persistence and immunological priming for 2 formulations of a meningococcal group C (menC) conjugate (MCC) vaccine (containing 2 or 10 microg of menC polysaccharide) administered at 2, 3, and 4 months of age was investigated by boosting vaccine recipients at age 13-16 months or 4 years with 10 microg of unconjugated menC polysaccharide. At age 4 years, geometric mean titers (GMTs) and concentrations of menC-specific immunoglobulin G and serum bactericidal antibody (SBA) had decreased to prevaccination levels. Geometric mean avidity indices increased after the primary vaccination until age 13-16 months and then remained constant until age 4 years. One month after boosting at age 4 years, menC immunoglobulin G and SBA levels increased significantly. The postbooster SBA GMT for the 2-microg vaccination (2181.2; 95% confidence interval [CI], 975.9-4875.1) was 2-fold higher than that for the 10-microg vaccination (931.6; 95% CI, 338.0-2568.1). This is the first demonstration of immunological memory at 4 years of age in children receiving MCC vaccine on the United Kingdom's 2/3/4-month immunization schedule.

Chairman's summary

<h3>Objectives</h3> The kinetics of the antibody response induced by meningococcal serogroup C (MenC) conjugate vaccination was analysed in patients with juvenile idiopathic arthritis (JIA) to assess their long-term protection against MenC disease. <h3>Methods</h3> In The Netherlands, a nationwide catch-up campaign was performed in 2002 during which children aged 1–19 years, including JIA patients, received the MenC conjugate vaccination. From 127 JIA patients, IgG antibody concentrations against MenC-polysaccharide were determined by a fluorescent-bead-based immunoassay in 402 serum samples collected between 2002 and 2010. Using a hierarchical linear regression model, the 8 years course of MenC-specific antibodies was analysed in four age groups (13–19, 9–12.9, 5–8.9 and 1–4.9 years), and in patients starting with methotrexate or biologicals. In 65 randomly selected samples, the correlation of MenC-specific IgG concentrations with serum bactericidal assay (SBA) titres was assessed. MenC-specific IgG concentrations at 4.2 years after vaccination were compared with those of 1527 age-matched healthy controls. <h3>Results</h3> MenC-specific IgG concentrations postvaccination were highest in patients aged 13–19 years at time of vaccination. Antibodies gradually waned over time in patients, but their estimated concentrations at 4.2 years postvaccination were similar to those measured in controls. MenC-specific IgG concentrations correlated well with SBA titres (r=0.72, p&lt;0.001). By contrast with methotrexate, starting treatment with biologicals induced a trend towards accelerated decline of MenC-specific antibodies. <h3>Conclusions</h3> Persistence of MenC-specific IgG antibodies in JIA patients is similar to healthy controls, but treatment with biologicals may induce accelerated antibody waning, resulting in unprotected patients who may need revaccination.