MenC Conjugate Research Articles

Structured Benefit-Risk Assessment of a New Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) in Individuals Ages 12 Months and Older.

A favorable benefit-risk balance is required to support licensure of biologics, in keeping with regulatory agencies' evolving recommendations, including the United States Food and Drugs Administration. We present a structured semi-quantitative benefit-risk analysis of MenACYW-TT, a quadrivalent meningococcal conjugate vaccine against Neisseria meningitidis serogroups, A, C, W and Y versus licensed comparators in individuals aged ≥ 12 months. We used data from six MenACYW-TT clinical trials, stratified by age group, versus licensed vaccines: toddlers (12-23 months; Nimenrix® [MCV4-TT]), children (2-9 years; Menveo® [MCV4-CRM]), adolescents (10-17 years; MCV4-CRM or Menactra® [MCV4-DT]), adults (18-55 years; MCV4-DT) and older adults (≥ 56 years; Menomune®-A/C/Y/W-135 [MPSV4]). Eight benefit (seroresponse and seroprotection for A, C, W and Y) and five risk outcomes (any and grade 3 solicited injection site and systemic reactions, and serious adverse events) were measured at Day 30 after initial vaccination. Analyses were conducted by baseline vaccination status (meningococcal vaccine-naïve or vaccine-primed). MenACYW-TT showed favorable seroresponse and seroprotection among vaccine-naïve participants aged ≥ 2years, against all serogroups, compared with MCV4-CRM, MCV4-DT and MPSV4. In vaccine-naïve toddlers, there was a favorable effect for serogroup C, but no difference between MenACYW-TT and MCV4-TT for serogroups A, Y and W. A favorable effect for MenACYW-TT against serogroup C was observed in all vaccine-naïve and combined vaccine-naïve and MenC conjugate vaccine-primed groups. For all risk criteria, there were no differences between MenACYW-TT and MCV4s in toddlers, children, adolescents and adults. Results for solicited injection site and systemic reactions favored MPSV4 in older adults. The benefit-risk profile for MenACYW-TT showed favorable seroresponse and seroprotection in individuals aged ≥ 2 years and no difference in risk criteria between MenACYW-TT and MCV4s. MenACYW-TT may provide an alternative to the standard-of-care for meningococcal disease prevention in those aged ≥ 12 months.

Global Epidemiology of Vaccine-preventable Bacterial Meningitis.

Global Epidemiology of Vaccine-preventable Bacterial Meningitis.

Vaccine Impact and Effectiveness of Meningococcal Serogroup ACWY Conjugate Vaccine Implementation in the Netherlands: A Nationwide Surveillance Study.

BackgroundIn response to the recent serogroup W invasive meningococcal disease (IMD-W) epidemic in the Netherlands, meningococcal serogroup C (MenC) conjugate vaccination for children aged 14 months was replaced with a MenACWY conjugate vaccination, and a mass campaign targeting individuals aged 14–18 years was executed. We investigated the impact of MenACWY vaccination implementation in 2018–2020 on incidence rates and estimated vaccine effectiveness (VE).MethodsWe extracted IMD cases diagnosed between July 2014 and December 2020 from the national surveillance system. We calculated age group–specific incidence rate ratios by comparing incidence rates before (July 2017–March 2018) and after (July 2019–March 2020) MenACWY vaccination implementation. We estimated VE in vaccine-eligible cases using the screening method.ResultsOverall, the IMD-W incidence rate declined by 61% (95% confidence interval [CI], 40 to 74). It declined by 82% (95% CI, 18 to 96) in the vaccine-eligible age group (individuals aged 15–36 months and 14–18 years) and by 57% (95% CI, 34 to 72) in vaccine-noneligible age groups. VE was 92% (95% CI, –20 to 99.5) in vaccine-eligible toddlers (aged 15–36 months). No IMD-W cases were reported in vaccine-eligible teenagers after the campaign.ConclusionsThe MenACWY vaccination program was effective in preventing IMD-W in the target population. The IMD-W incidence reduction in vaccine-noneligible age groups may be caused by indirect effects of the vaccination program. However, disentangling natural fluctuation from vaccine effect was not possible. Our findings encourage the use of toddler and teenager MenACWY vaccination in national immunization programs.

Different Long-Term Duration of Seroprotection against Neisseria meningitidis in Adolescents and Middle-Aged Adults after a Single Meningococcal ACWY Conjugate Vaccination in The Netherlands.

Neisseria meningitidis is often asymptomatically carried in the nasopharynx but may cause invasive meningococcal disease, leading to morbidity and mortality. Meningococcal conjugate vaccinations induce functional protective antibodies against capsular antigens, but seroprotection wanes over time. We measured functional antibody titers five years after administration of a single dose of the meningococcal ACWY-polysaccharide-specific tetanus toxoid-conjugated (MenACWY-TT) vaccine in adolescents and middle-aged adults in the Netherlands, using the serum bactericidal antibody with baby rabbit complement (rSBA) assay. Protection was defined as rSBA titer ≥8. The meningococcal ACWY-specific serum IgG concentrations were measured with a multiplex immunoassay. Duration of protection was estimated by a bi-exponential decay model. Sufficient protection for MenC, MenW, and MenY was achieved in 94–96% of the adolescents five years postvaccination, but, in middle-aged adults, only in 32% for MenC, 65% for MenW and 71% for MenY. Median duration of protection for MenCWY was 4, 14, and 21 years, respectively, in middle-aged adults, while, in adolescents, it was 32, 98, and 33 years. Our findings suggest that adolescents, primed in early childhood with MenC conjugate vaccination, remain sufficiently protected after a single dose of MenACWY-TT vaccine. Middle-aged adults without priming vaccination show fast waning of antibodies, particularly MenC, for which protection is lost after four years.

Vaccines against Meningococcal Diseases.

Neisseria meningitidis is the main cause of meningitis and sepsis, potentially life-threatening conditions. Thanks to advancements in vaccine development, vaccines are now available for five out of six meningococcal disease-causing serogroups (A, B, C, W, and Y). Vaccination programs with monovalent meningococcal serogroup C (MenC) conjugate vaccines in Europe have successfully decreased MenC disease and carriage. The use of a monovalent MenA conjugate vaccine in the African meningitis belt has led to a near elimination of MenA disease. Due to the emergence of non-vaccine serogroups, recommendations have gradually shifted, in many countries, from monovalent conjugate vaccines to quadrivalent MenACWY conjugate vaccines to provide broader protection. Recent real-world effectiveness of broad-coverage, protein-based MenB vaccines has been reassuring. Vaccines are also used to control meningococcal outbreaks. Despite major improvements, meningococcal disease remains a global public health concern. Further research into changing epidemiology is needed. Ongoing efforts are being made to develop next-generation, pentavalent vaccines including a MenACWYX conjugate vaccine and a MenACWY conjugate vaccine combined with MenB, which are expected to contribute to the global control of meningitis.

Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine

An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 μg). All vaccines were well tolerated, apart from in the TLR7a 100 μg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56–81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 μg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.

Serogroup C Neisseria meningitidis disease epidemiology, seroprevalence, vaccine effectiveness and waning immunity, England, 1998/99 to 2015/16.

BackgroundIn 1999, the United Kingdom (UK) was the first country to introduce meningococcal group C (MenC) conjugate vaccination. This vaccination programme has evolved with further understanding, new vaccines and changing disease epidemiology.AimTo characterise MenC disease and population protection against MenC disease in England.MethodsBetween 1998/99–2015/16, surveillance data from England for laboratory-confirmed MenC cases were collated; using the screening method, we updated vaccine effectiveness (VE) estimates. Typing data and genomes were obtained from the Meningitis Research Foundation Meningococcus Genome Library and PubMLST Neisseria database. Phylogenetic network analysis of MenC cc11 isolates was undertaken. We compared bactericidal antibody assay results using anonymised sera from 2014 to similar data from 1996–1999, 2000–2004 and 2009.ResultsMenC cases fell from 883 in 1998/99 (1.81/100,000 population) to 42 cases (0.08/100,000 population) in 2015/16. Lower VE over time since vaccination was observed after infant immunisation (p = 0.009) and a single dose at 1–4 years (p = 0.03). After vaccination at 5–18 years, high VE was sustained for ≥ 8 years; 95.0% (95% CI: 76.0– 99.5%). Only 25% (75/299) children aged 1–14 years were seroprotected against MenC disease in 2014. Recent case isolates mostly represented two cc11 strains.ConclusionHigh quality surveillance has furthered understanding of MenC vaccines and improved schedules, maximising population benefit. The UK programme provides high direct and indirect protection despite low levels of seroprotection in some age groups. High-resolution characterisation supports ongoing surveillance of distinct MenC cc11 lineages.

Concomitant administration of a fully liquid ready-to-use DTaP-IPV-HB-PRP-T hexavalent vaccine with a meningococcal ACWY conjugate vaccine in toddlers

Invasive meningococcal disease caused by Neisseria meningitidis is a life-threatening disease. Several countries now include meningococcal serogroup C (MenC) conjugate and, more recently, a meningococcal serogroup ACWY conjugate (MenACWY) vaccination in their national immunization schedules. DTaP-IPV-HB-PRP-T is a hexavalent vaccine that provides protection against six diseases. The phase III, open-label, randomised, multicentre study enrolled healthy toddlers who received the DTaP-IPV-HB-PRP-T vaccine (at 2, 3 and 4 months) with or without a MenC vaccine (at 2 and 4 months) in the primary series study. At 12 months of age, 312 toddlers were randomised to receive DTaP-IPV-HB-PRP-T co-administered with MenACWY-TT vaccine (Group A; n = 104); DTaP-IPV-HB-PRP-T vaccine alone (Group B; n = 105); or MenACWY-TT vaccine alone (Group C; n = 103). At 12 months of age, there were no notable differences in terms of antibody persistence for any DTaP-IPV-HB-PRP-T vaccine antigen, whether MenC-TT conjugate vaccine was co-administered or not during the primary series. Following booster vaccination, immune responses to DTaP-IPV-HB-PRP-T and MenACWY-TT vaccines were not affected by co-administration. One month after vaccination, the immune responses elicited by both vaccines were high, whether administered concomitantly or separately. The administration of MenC vaccine during infancy did not preclude the use of a MenACWY-TT vaccine for booster vaccination. Even though the reactogenicity after co-administration was somewhat higher, the results of this study support the concomitant administration of the DTaP-IPV-HB-PRP-T vaccine with a MenACWY-TT conjugate vaccine when given from 12 months of age.The clinical trial registration numbers are: clinicaltrial.gov: NCT01839175; EudraCT: 2012-005547-24.

Baseline Circulating Activated TFH and Tissue-Like Exhausted B Cells Negatively Correlate With Meningococcal C Conjugate Vaccine Induced Antibodies in HIV-Infected Individuals.

Since 2006, meningococcal serogroup C (MenC) conjugate (MCC) vaccines have been supplied by the Brazilian government for HIV-infected children under 13 years old. For measuring protection against MenC, the serum bactericidal antibody (SBA) assay is the method of choice. The characterization of T follicular helper cells (TFH) cells has been an area of intensive study because of their significance in multiple human diseases and in vaccinology. The objective of this study was to characterize the phenotype of peripheral TFH cells and B cells and how they associated with each other and with SBA levels induced by vaccination as well as with serum cytokine levels of HIV-infected and non-infected children and adolescents. We found that CD27−IgD−CD21−CD38+ (exhausted B cells) as well as short-lived plasmablasts (CD27+IgD−CD21−CD38+) are increased in cART treated HIV patients and negatively associated with MCC vaccine induced SBA levels. Baseline frequency of activated peripheral TFH cells was a negative correlate for SBA response to MCC vaccine but positively correlated with circulating plasmablast frequency. Baseline IL4-levels positively associated with SBA response but showed a negative correlation with activated peripheral TFH cells frequency. The increased frequency of activated peripheral TFH cells found in non-responders to the vaccine implies that higher activation/differentiation of CD4 T cells within the lymph node is not necessarily associated with induction of vaccine responses.

Antibody persistence and booster response 68 months after vaccination at 2–10 years of age with one dose of MenACWY-TT conjugate vaccine

BackgroundWe evaluated antibody persistence up to 68 months (M) post-vaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) or a licensed monovalent MenC conjugate vaccine (MenC-CRM197) and subsequent booster responses to MenACWY-TT in healthy European children. MethodsIn the initial study (NCT00674583), healthy children, 2–10 years of age, were randomized to receive a single dose of either MenACWY-TT or MenC-CRM197. In the follow-up study, we present the persistence at 32, 44, 56, and 68 M post-vaccination, overall and stratified by age (2–5 and 6–10 years), and the immunogenicity and safety of MenACWY-TT administered to all study participants at M68 post-primary vaccination. ResultsAt M68, 33.3% (age group 2–5 years) and 47.1% (age group 6–10 years) of the children vaccinated with MenACWY-TT, and 50.0% (age group 2–5 years) and 75.9% (age group 6–10 years) vaccinated with MenC-CRM197 retained titers ≥1:8 for MenC, as assessed by a serum bactericidal assay using rabbit complement (rSBA). In the MenACWY-TT recipients, the percentages of children retaining rSBA titers ≥1:8 for MenA, MenW, and MenY were 81.7%, 47.3% and 66.7% in age group 2–5 years and 91.8%, 58,8% and 76.5% in age group 6–10 years, respectively. The booster dose induced robust responses (100% for all serogroups) and was well-tolerated. ConclusionsAntibody persistence (rSBA titers ≥ 1:8) for serogroups A, W and Y was observed in more than 50.0% of the children 68 M after receiving one dose of MenACWY-TT; for MenC, antibody persistence was observed in more than one third of MenACWY-TT and more than half of MenC-CRM197 recipients. Vaccination with a booster dose of MenACWY-TT induced robust immune responses for all serogroups.

Evidence for Rise in Meningococcal Serogroup C Bactericidal Antibody Titers in the Absence of Booster Vaccination in Previously Vaccinated Children.

The introduction of meningococcal serogroup C (MenC) conjugate vaccines in the United Kingdom and Australia led to an impressive decline in the incidence of invasive disease. This study examined bactericidal antibody titers over time in the UK and Australian children who received a MenC conjugate vaccine in early childhood to test the hypothesis that ongoing boosting of immunity in the absence of further doses of vaccine in some children may contribute to ongoing protection from disease. Serum bactericidal assay using rabbit complement (rSBA) titers at each follow-up visit were compared with all preceding visits to identify any ≥4-fold rise in titers. The proportion of children with a ≥4-fold rise in rSBA titers in paired sera at any visit-to-visit comparison was calculated. Of 392 children with at least one set of paired sera in the Australian cohort, 72 (18.4%) had a ≥4-fold increase in rSBA titers at least one year after vaccination, including six children (1.5%) who showed evidence of boosting twice. Of 234 children with at least one set of paired sera in the UK cohort, 39 (16.7%) had a ≥4-fold rise in rSBA titers at least one year after vaccination including 2 children (0.9%) with evidence of boosting twice. A substantial minority of children immunized with MenC conjugate vaccine in early childhood had a rise in bactericidal antibody titers in the years after immunization in the absence of booster vaccination. This occurs most commonly at around 6-7 years of age corresponding to school entry and greater social mixing and might indicate exposure to MenC carriage.

Meningococcal serogroup C immunogenicity, antibody persistence and memory B-cells induced by the monovalent meningococcal serogroup C versus quadrivalent meningococcal serogroup ACWY conjugate booster vaccine: A randomized controlled trial

Adolescents are considered the key transmitters of meningococci in the population. Meningococcal serogroup C (MenC) antibody levels wane rapidly after MenC conjugate vaccination in young children, leaving adolescents with low antibody levels. In this study, we compared MenC immune responses after booster vaccination in adolescence with either tetanus toxoid conjugated MenC (MenC-TT) or MenACWY (MenACWY-TT) vaccine, and aimed to establish an optimal age for this booster. Healthy 10-, 12-, and 15-year-olds, who received a single dose of MenC-TT vaccine in early childhood, were randomized to receive MenC-TT or MenACWY-TT vaccine. MenC serum bactericidal antibody (rSBA) titers, MenC polysaccharide (PS) specific IgG, IgG1 and IgG2 and MenC-specific IgG and IgA memory B-cells were determined before, one month and one year after the booster. Non-inferiority was tested by comparing geometric mean titers (GMTs) between vaccinees at one year. Of 501 participants, 464 (92.6%) were included in the 'according to protocol' cohort analysis. At one month, all participants developed high MenC rSBA titers (>24,000 in all groups) and MenC-PS-specific IgG levels. Non-inferiority was not demonstrated one year after the booster with higher MenC GMTs after the monovalent vaccine, but 462/464 (99.6%) participants maintained protective MenC rSBA titers. IgG levels mainly consisted of IgG1, but similar levels of increase were observed for IgG1 and IgG2. Both vaccines induced a clear increase in the number of circulating MenC-PS specific IgG and IgA memory B-cells. Between one month and one year, the highest antibody decay rate was observed in the 10-year-olds. Both MenC-TT and MenACWY-TT vaccines induced robust protective MenC immune responses after the booster vaccination, although non-inferiority could not be demonstrated for the MenACWY-TT vaccine after one year. Our results underline the importance of optimal timing of a meningococcal booster vaccination to protect against MenC disease in the long-term.

Quality, immunogenicity and stability of meningococcal serogroup ACWY-CRM197, DT and TT glycoconjugate vaccines

A physicochemical and immunological study of the stability of three different meningococcal (Men) ACWY conjugate vaccines was performed to evaluate any patterns of serogroup oligo- or polysaccharide-specific or carrier protein-specific stability that would affect immunogenicity. Critical quality and stability-indicating characteristics were measured, with the study supporting the suitability of both HPLC-SEC and HPAEC-PAD methods to detect changes following inappropriate vaccine storage. All three final products, ACWY-CRM197, -DT and -TT conjugate vaccines had expected quality indicator values and similar immunogenicity in a mouse model (anti-PS IgG and rSBA) when stored at +2–8°C. When stored at ≥+37°C, all conjugated carrier proteins and serogroup saccharides were affected. Direct correlations were observed between the depolymerization of the MenA saccharide as evidenced by a size-reduction in the MenA conjugates (CRM197, DT and TT) and their immunogenicity. MenA was the most labile serogroup, followed by MenC; then MenW and Y, which were similar. At high temperatures, the conjugated carrier proteins were prone to unfolding and/or aggregation. The anti-MenC IgG responses of the multivalent conjugate vaccines in mice were equivalent to those observed in monovalent MenC conjugate vaccines, and were independent of the carrier protein. For any newly developing MenACWY saccharide-protein conjugate vaccines, a key recommendation would be to consider the lyophilization of final product to prevent deleterious degradation that would affect immunogenicity.

Kinetics of Meningococcal Serogroup C-Specific Functional Antibody Levels Up to 15 Years after a Single Immunization with a Meningococcal Serogroup C Conjugate Vaccine during Adolescence.

Adolescent vaccination is now considered the key factor for offering direct protection against meningococcal disease but also for reducing carriage and transmission and, in this way, establishing herd protection. This study estimated age-dependent patterns in functional meningococcal serogroup C (MenC) antibody kinetics after primary MenC conjugate (MenCC) vaccination in adolescents. Serum samples (n = 1,676) were drawn from 2006 to 2011 from individuals aged 9 to 18 years at the time of primary MenCC vaccination in 2002. Functional antibody levels were measured with a serum bactericidal antibody assay (SBA) using rabbit complement. SBA titers gradually declined with time. Up to 9 years after primary vaccination, SBA titers were estimated to be higher in individuals who were aged 13 to 18 years at priming than in those who were aged 9 to 10 years at priming. Based on a linear mixed model, the higher functional antibody levels with age seem to be due to the achievement of higher peak levels upon vaccination rather than to lower rates of decline. It is estimated that 35 to 50% of individuals who received a single primary MenCC vaccination at an age of 9 to 18 years in 2002 will still have sufficient protective antibody levels 15 years later. Using a linear mixed model based on cohort data for a single dated serum sample per person, we were able to estimate the level of protection against MenC up to 15 years after a single vaccination. The current study shows that analysis of antibody kinetics can be done using cross-sectional serology data and is therefore relevant for future serosurveillance studies.

Association of serum bactericidal antibody and opsonic antibody levels after Neisseria meningitidis serogroup C conjugate vaccine in Brazilian children and adolescents infected or not infected with HIV

Neisseria meningitidis serogroup C (MenC) is the main causative agent of meningitis in Brazil. HIV infection affects the quality of the immune system. HIV+ children have an increased risk of infection to encapsulated bacteria such as N. meningitidis. We evaluated the opsonic antibody (OPA) levels and its correlation with serum bactericidal antibody (SBA) levels induced by one and two doses of a MenC conjugate vaccine in children and adolescents HIV+ and HIV-exposed but uninfected children (HEU) group. Overall the data show the importance of two doses of vaccine for HIV+ individuals. About 79% and 58% of HIV+ patients showed SBA and OPA positive response after two doses of vaccine, respectively. For HEU group, 62% and 41% of patients showed SBA and OPA positive response after one dose of vaccine, respectively. A positive and significant association between SBA and OPA levels was seen after two doses of vaccine in HIV+ patients.

Antibody Persistence in Young Children 5 Years after Vaccination with a Combined Haemophilus influenzae Type b-Neisseria meningitidis Serogroup C Conjugate Vaccine Coadministered with Diphtheria-Tetanus-Acellular Pertussis-Based and Pneumococcal Conjugate Vaccines.

We evaluated antibody persistence in children up to 5 years after administration of a combined Haemophilus influenzae type b (Hib)-Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine coadministered with a pneumococcal conjugate vaccine. This is the follow-up study of a randomized trial (ClinicalTrials.gov registration no. NCT00334334/00463437) in which healthy children were vaccinated (primary vaccinations at 2, 4, and 6 months of age and booster vaccination at 11 to 18 months of age) with Hib-MenC-TT or a control MenC conjugate vaccine, coadministered with diphtheria-tetanus-acellular pertussis (DTPa)-based combination vaccines (DTPa/Hib for control groups) and a pneumococcal conjugate vaccine (10-valent pneumococcal nontypeable H. influenzae protein D conjugate vaccine [PHiD-CV] or 7-valent cross-reacting material 197 [CRM197] conjugate vaccine [7vCRM]). MenC antibody titers were measured with a serum bactericidal antibody (SBA) assay using rabbit complement (i.e., rabbit SBA [rSBA]), and antibodies against Hib polyribosylribitol phosphate (PRP) were measured with an enzyme-linked immunosorbent assay. Antibody persistence up to 5 years after booster vaccination is reported for 530 children ∼6 years of age. The percentages of children with seroprotective rSBA-MenC titers were between 24.2% and 40.1% in all groups approximately 5 years after booster vaccination. More than 98.5% of children in each group retained seroprotective anti-PRP concentrations. No vaccine-related serious adverse events and no events related to a lack of vaccine efficacy were reported. Approximately 5 years after booster vaccination, the majority of children retained seroprotective anti-PRP antibody concentrations. The percentage of children retaining seroprotective rSBA-MenC titers was low (≤40%), suggesting that a significant proportion of children may be unprotected against MenC disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT00891176.)

Can we control all-cause meningococcal disease in Europe?

Invasive disease caused by Neisseria meningitidis is potentially devastating, with a case fatality rate of 5–15% and high rates of significant sequelae among survivors after septicaemia or meningitis. Capsular group C (MenC) conjugate vaccines have been highly successful in achieving control of MenC disease across Europe, and some countries have also introduced quadrivalent MenACWY conjugate vaccines to reduce disease caused by groups A, W and Y in addition to C. These vaccines putatively elicit protective levels of bactericidal antibodies in all age groups, induce immunologic memory and reduce nasopharyngeal carriage, thereby leading to herd protection. Protein-based meningococcal vaccines based on subcapsular components, and designed primarily to target capsular group B (MenB) disease, have recently been licensed. These vaccines are highly immunogenic in infants and adolescents, inducing bactericidal antibodies against strains expressing high levels of vaccine antigens which are identical to the variants present in the vaccines. Effectiveness of these vaccines at a population level will be determined by whether vaccine-induced antibodies provide cross-protection against variants of the vaccine antigens present on the surface of the diverse collection of circulating invasive strains. The level of serum bactericidal activity induced against strains also seems to depend on the level of expression of the vaccine antigens. The duration of protection and the impact on carriage of meningococci will have a major bearing on the overall effectiveness of the programme. In September 2015 the UK became the first country to introduce the multicomponent meningococcal serogroup B vaccine (4CMenB) into a national routine immunization schedule, and data on the effectiveness of this programme are anticipated in the next few years.

Update on the use of meningococcal serogroup C CRM197-conjugate vaccine (Meningitec) against meningitis

Meningitec is a CRM197-conjugated meningococcal serogroup C (MenC) vaccine, first licensed in 1999. It has been used as a primary and booster vaccine in infants, toddlers, older children and adults, and has been shown to be immunogenic and well-tolerated in all age groups, including premature infants. Vaccine effectiveness has been demonstrated using combined data on all three licensed MenC conjugate vaccines. Evidence from clinical trials, however, suggests that the different MenC conjugate vaccines behave differently with respect to the induction and persistence of bactericidal antibody and generation of immune memory. It appears that Meningitec has a less favorable immunologic profile compared particularly to tetanus toxoid (TT) MenC conjugate vaccines. Data from comparative trials have raised interesting questions on priming of the immune system by conjugate vaccines, particularly in infants. The results from these and other studies are reviewed here with specific focus on Meningitec.

Antibody persistence up to 5 years after vaccination of toddlers and children between 12 months and 10 years of age with a quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine

We studied the persistence of serum bactericidal antibody using rabbit and human complement (rSBA/hSBA, cut-offs 1:8) 5 y after a single dose of meningococcal serogroups A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT) compared with age-appropriate control vaccines in toddlers and children (NCT00427908). Children were previously randomized (3:1) to receive either MenACWY-TT or control vaccine (MenC-CRM197 in 1-<2 y olds; MenACWY-polysaccharide vaccine [Men-PS] in 2-<11 y olds). Subjects with rSBA-MenC titers <1:8 at any time point were revaccinated with MenC conjugate vaccine and discontinued from the study. A repeated measurement statistical model assessed potential selection effects due to drop-outs. At year 5 in MenACWY-TT-vaccinated-toddlers for serogroups A, C, W, and Y respectively, percentages with rSBA titers ≥1:8 were 73.5%, 77.6%, 34.7%, and 42.9%, hSBA ≥1:8 were 35.6%, 91.7%, 82.6% and 80.0%. For MenC-CRM197 recipients, 63.6% had persisting rSBA-MenC titers ≥1:8 and 90.9% had hSBA-MenC ≥1:8 (not significantly different versus MenACWY-TT for either assay: exploratory analyses). In 2-<11 y olds rSBA titers ≥1:8 in MenACWY-TT-vaccinees were 90.8%, 90.8%, 78.6%, and 78.6% and 15.4%, 100%, 0.0%, 7.7% in Men-PS-vaccinees (significantly different for serogroups A, W and Y, exploratory analyses). Serogroups A, W and Y rSBA GMTs were ≥ 26-fold higher in MenACWY-TT-vaccinees. As expected, GMTs modeled at year 5 to assess the impact of subject drop out (mainly for revaccination), appeared lower for serogroup C. No vaccine-related SAEs were reported. Antibody persistence was observed for all serogroups up to 5 y after MenACWY-TT vaccination.

Salivary antibody levels in adolescents in response to a meningococcal serogroup C conjugate booster vaccination nine years after priming: systemically induced local immunity and saliva as potential surveillance tool

BackgroundIn several countries large-scale immunization of children and young adults with Meningococcal serogroup C (MenC) conjugate vaccines has induced long-standing herd protection. Salivary antibodies may play an important role in mucosal protection against meningococcal acquisition and carriage. AimTo investigate antibody levels in (pre)adolescents primed 9 years earlier with a single dose of MenC-polysaccharide tetanus toxoid conjugated (MenC-TT) vaccine and the response to a booster vaccination, with special focus on age-related differences and the relation between salivary and serum antibody levels. MethodsNine years after priming, healthy 10- (n=91), 12- (n=91) and 15-year-olds (n=86) received a MenC-TT booster vaccination. Saliva and serum samples were collected prior to and 1 month and 1 year after vaccination. MenC-polysaccharide(MenC-PS)-specific antibody levels were measured using a fluorescent-bead-based multiplex immunoassay. ResultsBefore the booster, MenC-PS-specific IgG and IgA levels in saliva and serum were low and correlated with age at priming. The booster induced a marked increase in salivary MenC-PS-specific IgG (>200-fold), but also in IgA (∼10-fold). One year after the booster, salivary IgG and IgA had remained above pre-booster levels in all age groups (∼20-fold and ∼3-fold, respectively), with persistence of highest levels in the 15-year-olds. MenC-PS-specific IgG and IgA levels in saliva strongly correlated with the levels in serum. ConclusionParenteral MenC-TT booster vaccination induces a clear increase in salivary MenC-PS-specific IgG and IgA levels and persistence of highest levels correlates with age. The strong correlation between serum and salivary antibody levels indicate that saliva may offer an easy and reliable tool for future antibody surveillance.