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.     

Effectiveness of meningococcal serogroup C vaccine programmes

Since the introduction of monovalent meningococcal serogroup C (MenC) glycoconjugate (MCC) vaccines and the implementation of national vaccination programmes, the incidence of MenC disease has declined markedly as a result of effective short-term vaccination and reduction in acquisition of MenC carriage leading to herd protection. Monovalent and quadrivalent conjugate vaccines are commonly used vaccines to provide protection against MenC disease worldwide. Studies have demonstrated that MCC vaccination confers protection in infancy (0–12 months) from the first dose but this is only short-term. NeisVac-C^® has the greatest longevity of the currently licensed MCC vaccines in terms of antibody persistence, however antibody levels have been found to fall rapidly after early infant vaccination with two doses of all MCC vaccines – necessitating a booster at ∼12 months. In toddlers, only one dose of the MCC vaccine is required for routine immunization. If herd protection wanes following catch-up campaigns, many children may become vulnerable to infection. This has led many to question whether an adolescent booster is also required.     

Baseline polysaccharide-specific antibodies may not consistently inhibit booster antibody responses in infants to a serogroup C meningococcal protein-polysaccharide conjugate vaccine

Negative correlations between baseline antibody concentrations and increases in antibody concentrations (after booster doses of vaccines) have been reported previously. Such correlation coefficients are widely reported by statisticians to be subject to mathematical coupling. Negative correlations may be attributable partly or wholly to the combination of mathematical coupling and measurement error (or other short term fluctuations in measurements) and therefore not clinically interpretable. In this study we re-analysed the serum antibody responses from five clinical trials of serogroup C meningococcal conjugate vaccine (MenCV) given to infants for priming followed by boosting with MenCV or a meningococcal A/C polysaccharide vaccine (MenA/C) at 12 months of age. Using Pearson's correlation method to assess the effect of pre-booster MenC-IgG concentration on the relative increase in MenC-IgG concentration post-booster, a significant negative correlation was observed for all the groups, indicating that high pre-booster antibody was associated with a smaller rise in antibody post-booster. We tested two additional statistical methods that account for mathematical coupling. Using Blomqvist method of adjustment to assess the plausible extent of bias, correlation coefficients were still negative providing error variance was low. The other method, a multilevel modelling specification of Oldham's method appeared not to be appropriate. In contrast, using Pearson's correlation method a consistent negative correlation between carrier protein-specific baseline antibody concentration and the increase in MenC-specific antibody concentration was only observed following booster immunisation with the protein-polysaccharide conjugate vaccine but not following the MenA/C plain polysaccharide vaccine. These findings suggest that analysis of the inhibitory effect of baseline antibody on the response to booster immunisation is challenging and should account for the possibility of mathematical coupling and measurement error. That an inhibitory effect of baseline antibody cannot be assumed a priori is supported by observations in animal models, which show that baseline antibody can both suppress or enhance the antibody response to a specific antigen.     

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

BackgroundAdolescents 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.MethodsHealthy 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.ResultsOf 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.ConclusionBoth 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.     

Seroprevalence of antibodies against serogroup C meningococci in the region of Valencia,Spain: Impact of meningococcal C conjugate vaccination

Background and aimsMeningococcal C conjugate (MCC) vaccination programs provide direct and indirect protection against meningococcal disease. However, a decrease in the antibodies could affect herd immunity. We conducted a seroprevalence study to assess the immunity in subjects 8–12 years after different MCCV vaccination programs were launched and evaluated the impact of vaccination on seroprotection.MethodsSeroepidemiological study conducted from October 2010 to April 2012 in the region of Valencia, Spain. Sample size was not proportional to the population but to the expected seroprotection by age group. Sera from subjects that were ≥ 3 years old were tested using a standardized complement-mediated serum bactericidal antibodies (SBA) assay. Age-stratified proportions of subjects with SBA titers ≥ 8 were considered seroprotected and evaluated. A multivariate logistic regression model was performed to evaluate the impact of vaccination on the seroprotection.ResultsSerum samples from 1880 subjects were collected. In total, 523 (27.8%) of the 1880 subjects and 446 (31.2%) of the 1430 subjects < 30 years (targeted to any vaccination campaign) showed protective SBA titers. The highest percentage of seroprotected subjects (67.8%, 95%CI 56.9–77.4) was observed in those that were vaccinated in a catch-up campaign at 10–13 years of age (20–21 years old at the time of blood sampling). Those scheduled for immunization in infancy at 2, 4 and 6 months of age (7–8 years at blood sample) represented the lowest (7.1%, 95% CI 3.3–13.1) number of seroprotected subjects. Having received one vaccine dose after 12 months of age was associated with increased seroprotection. The present study revealed a positive correlation between the increasing age at vaccination and longer duration of seroprotection.ConclusionOnly one in three subjects who were vaccinated with MCC vaccine was seroprotected after 8–12 years. These findings emphasize that seroprevalence studies are essential to identify susceptible cohorts and to inform vaccine policy.     

Immunogenicity of a meningococcal serogroup C conjugate vaccine in HIV-infected children, adolescents, and young adults

Children and adolescents infected with HIV typically have a lower response to immunization than do those in the general population. In most developed countries, meningococcal serogroup C conjugate vaccine is one of the recommended vaccines for such individuals. However, there have been no studies evaluating the antibody response to this vaccine in HIV-infected children, adolescents or young adults. In this study, we evaluated that response using serum bactericidal antibody (SBA) and enzyme-linked immunosorbent assay, comparing HIV-infected with non-HIV-infected patients, as well as analysing the occurrence of side effects. In non-responders, we assessed the antibody response to revaccination. This clinical trial involved 92 patients between 10 and 20 years of age: 43 HIV-infected patients (HIV+ group) and 49 non-HIV-infected patients (HIV- group). After one dose of the vaccine, 72.1% of the HIV+ group patients and 100% of the HIV- group patients were considered protected. Of the HIV+ group patients who received a second dose of the vaccine, only 40% acquired protection. Overall, 81.4% of the HIV+ group patients acquired protection (after one or two doses of the vaccine). Side effects occurred in 16.3% and 44% of the HIV+ group and HIV- group patients, respectively. Therefore, the meningococcal serogroup C conjugate vaccine proved to be safe and effective for use in HIV-infected children, adolescents, and young adults, although their antibody response was weaker than that shown by non-HIV-infected patients. This indicates the need to discuss changes to the immunization schedule for children, adolescents, and young adults infected with HIV, in order to ensure more effective protection against meningococcal disease.     

Evaluation of meningococcal serogroup C conjugate vaccine programs in Canadian children: interim analysis

Background

To assess antibody titers afforded by meningococcal C- (MenC) tetanus toxoid conjugate vaccine at 12 months of age in three different immunization schedules.

Methods

This prospective study included three similar cohorts of healthy infants from 1-dose, 2-dose and 3-dose MenC infant immunization programs. Infants were enrolled at 12 months of age and given the final scheduled dose of MenC-tetanus toxoid conjugate vaccine with sera collected prior to and 1 month after the vaccination. Serum bactericidal activity (SBA) titers ≥ 1:8 were considered protective.

Results

Before the 12 month dose, participants had significantly different protective titers according to the number of prior doses received: 100% (95% CI 97.6–100%) of infants who had 2 prior doses (at 2 and 4 months) were protected compared to 84.0% (76.7–89.3%) of participants with one dose (at 2 months) and 27.6% (21.0–35.4%) of unvaccinated infants. All subjects were protected after the 12 month MenC dose, but titers were higher with prior priming.

Conclusions

Two MenC doses given in infancy afford optimal protection during the first year of life; however, substantial protection was seen after one dose at 2 months.     

Meningococcal C conjugate vaccine effectiveness before and during an outbreak of invasive meningococcal disease due to Neisseria meningitidis serogroup C/cc11, Tuscany,Italy

IntroductionIn Tuscany, Italy, where a universal immunization program with monovalent meningococcal C conjugate vaccine (MCC) was introduced in 2005, an outbreak of invasive meningococcal disease (IMD) due to the hypervirulent strain of Neisseria meningitidis C/cc11 occurred in 2015–2016, leading to an immunization reactive campaign using either the tetravalent (ACWY) meningococcal conjugate or the MCC vaccine. During the outbreak, IMD serogroup C (MenC) cases were also reported among vaccinated individuals. This study aimed to characterize meningococcal C conjugate vaccines (MenC-vaccines) failures and to estimate their effectiveness since the introduction (2005–2016) and during the outbreak (2015–2016).MethodsMenC cases and related vaccine-failures were drawn from the National Surveillance System of Invasive Bacterial Disease (IBD) for the period 2006–2016. A retrospective cohort-study, including the Tuscany' population of the birth-cohorts 1994–2014, was carried out. Based on annual reports of vaccination, person-years of MenC-vaccines exposed and unexposed individuals were calculated by calendar-year, birth-cohort, and local health unit. Adjusted (by birth-cohort, local health unit, and calendar-year) risk-ratios (ARR) of MenC invasive disease for vaccinated vs unvaccinated were estimated by the Poisson model. Vaccine-effectiveness (VE) was estimated as: VE = 1-ARR.ResultsIn the period 2006–2016, 85 MenC-invasive disease cases were reported; 61 (71.8%) from 2015 to 2016. Twelve vaccine failures occurred, all of them during the outbreak. The time-interval from immunization to IMD onset was 20 days in one case, from 9 months to 3 years in six cases, and ≥7 years in five cases. VE was, 100% (95%CI not estimable, p = 0.03) before the outbreak (2006–2014) and 77% (95%CI 36–92, p < 0.01) during the outbreak; VE was 80% (95%CI 54–92, p < 0.01) during the overall period.ConclusionsIn Tuscany, MenC-vaccine failures occurred exclusively during the 2015–2016 outbreak. Most of them occurred several years after vaccination. VE during the outbreak-period was rather high supporting an effective protection induced by MenC-vaccines.     

Impact of vaccination during an epidemic of serogroup C meningococcal disease in Salvador, Brazil

To combat rising incidence of serogroup C meningococcal disease in the city of Salvador, Brazil, the Bahia state immunization program initiated routine childhood immunization with meningococcal C conjugate vaccine (MenC) in February 2010, followed by mass MenC vaccination of city residents 10-24 years of age from May through August 2010. We analyzed trends in incidence of reported cases of meningococcal disease and serogroup distribution among meningococcal isolates identified in hospital-based surveillance in Salvador from January 2000 to December 2011 and estimated vaccine effectiveness using the screening method. Annual incidence of serogroup C meningococcal disease increased from 0.1 cases per 100,000 population during 2000-2006 to 2.3 in 2009 and 4.1 in 2010, before falling to 2.0 per 100,000 in 2011. Estimated coverage of mass vaccination reached 80%, 67% and 41% among 10-14, 15-19 and 20-24 year olds, respectively. Incidence in 2011 was significantly lower than average rates in 2008-2009 among children <5 years, but reductions among 10-24 year olds were not significant. Among 10-24 year olds, a single dose of MenC vaccine was 100% effective (95% confidence interval, 79-100%) against serogroup C meningococcal disease. Low coverage in the population targeted for mass vaccination may have limited impact on ongoing transmission of serogroup C meningococcal disease despite high vaccine effectiveness.     

Immunogenicity of meningococcal polysaccharide conjugate vaccine as a replacement for meningococcal polysaccharide vaccine in children in Guangzhou,China

To assess the durability of antibody persistence after substitution of the MPCV vaccine for the MPSV-A vaccine in children, an observational study was conducted in children who voluntarily received two doses of MPCV-AC instead of MPSV-A between March 2017 and March 2018 in Guangzhou, China. In total, 131 and 47 participants were enrolled in the 3-year-old and 6-year-old groups, respectively. In the 3-year-old group, the seroprotection rate and GMT values for Men A and Men C were raised significantly after 1-month post- dose 1 MPSV booster vaccination. All immune indicators were significantly lower in pre- dose 1 MPSV booster vaccination in the 3-year-old group than after pre- dose 2 MPSV booster vaccination in the 6-year-old group. While no significant differences were found in most immune indicators between the 1-month post- dose 1 MPSV booster vaccination in the 3-year-old group and pre- dose 2 MPSV booster vaccination in 6-year-old group. The substitute meningococcal immunization schedule showed a good immunogenicity in young children, and good sequential immunogenicity with MPSV booster immunization.     

Meningococcal serogroup C serum and salivary antibody responses to meningococcal quadrivalent conjugate vaccine in Saudi Arabian adolescents previously vaccinated with bivalent and quadrivalent meningococcal polysaccharide vaccine

Following repeated polysaccharide vaccination, reduced immune responses have been reported, but there are limited data on the mucosal response of meningococcal polysaccharide vaccine (PSV) or meningococcal conjugate vaccination. Saudi Arabian adolescents (aged 16–19 years) who had previously been vaccinated with ≥1 dose of bivalent meningococcal polysaccharide vaccine and 1 dose of quadrivalent meningococcal polysaccharide (MPSV4) were enrolled in a controlled, randomised, and modified observer-blind study (collectively termed the PSV-exposed group). The PSV-exposed group was randomised to receive either quadrivalent meningococcal conjugate vaccine (MCV4) (PSV-exposed/MCV4 group) or MPSV4 (PSV-exposed/MPSV4 group), and a PSV-naïve group received MCV4. Serum and saliva samples were collected pre-vaccination and 28 days post-vaccination. Serum serogroup-specific A, C, W and Y IgG were quantified as were salivary serogroup-specific C IgG and IgA together with total salivary IgG and IgA. For each serogroup, the post-vaccination serum geometric mean concentrations (GMCs) were significantly higher in the PSV-naïve and the PSV-exposed/MCV4 group than in the PSV-exposed/PSV4 group. For serogroup C, serum serogroup-specific IgG for the PSV-naïve group was significantly higher than both the PSV exposed groups. Higher levels of salivary serogroup C-specific IgG were found in the PSV-naïve group than those who had received two doses of polysaccharide but no significant differences were noted with regards to serogroup-specific IgA.     

Adolescent meningococcal serogroup A,W and Y immune responses following immunization with quadrivalent meningococcal A,C, W and Y conjugate vaccine: Optimal age for vaccination

BackgroundRecently the incidence of meningococcal serogroup Y (MenY) and in particular serogroup W (MenW) invasive disease has risen in several European countries, including the Netherlands. Adolescents are a target group for primary prevention through vaccination to protect against disease and reduce carriage and induce herd protection in the population. The present study assessed MenA, MenW and MenY antibody levels in adolescents up to one year following primary vaccination with quadrivalent MenACWY-PS conjugated to tetanus toxoid (MenACWY-TT).MethodsIn this phase IV, open-label study, healthy 10-, 12- and 15-year-olds received the MenACWY-TT vaccine. Blood samples were collected before, 1 month and 1 year after the vaccination. Functional antibody levels against MenA, MenW and MenY were measured with serum bactericidal assay using baby rabbit complement (rSBA). MenA-, MenW-, and MenY-PS specific IgG, IgG1 and IgG2 levels were measured using fluorescent-bead-based multiplex immunoassay.ResultsThe quadrivalent MenACWY-TT vaccine elicited robust antibody responses against MenA, MenW and MenY, and the majority (94%) of the participants maintained rSBA titers ≥128 one year after the vaccination against all three serogroups. After one year, higher MenW rSBA GMTs were observed in the 12- and 15-year-olds compared to the 10-year-olds, while rSBA GMTs against MenA and MenY were similar between age groups. Furthermore, those participant who showed SBA titer ≥8 at baseline, also had higher antibody levels one year after vaccination as compared to participants with rSBA titer <8 at baseline.ConclusionThe MenACWY-TT vaccine induces robust protective primary immune responses up to one year after vaccination. Our results suggest that persistence of individual protection increases with the age at which a primary quadrivalent MenACWY-TT vaccination is administered. Our results indicate that 12 or 15 years seems a more optimal age for a primary quadrivalent MenACWY-TT vaccination to protect against the rapid increase of MenW disease.     

Antibody persistence after serogroup C meningococcal conjugate vaccine in children with sickle cell disease

BackgroundA decline of protective antibody titers after MCC vaccine has been demonstrated in healthy children, this may be an issue of concern for risk groups. The aim of this study was to evaluate the persistence of bactericidal antibodies after MCC vaccine in sickle cell disease (SCD) patients. The type of vaccine used and booster response were also analyzed.MethodsSCD patients (n = 141) previously immunized with MCC vaccines had blood drawn 2–8 years after the last priming dose. They were distributed according to age at primary immunization into groups: <2 years and 2–13 years and evaluated by years since vaccination (2–3, 4–5 and 6–8). Serum bactericidal antibodies with baby rabbit complement (rSBA) and serogroup C-specific IgG concentrations were measured. The correlate of protection was rSBA titer ⩾8. Subjects with rSBA <8 received a booster dose and antibody levels re-evaluated after 4–6 weeks.ResultsFor children primed under 2 years of age rSBA titer ⩾8 was demonstrated in 53.3%, 21.7% and 35.0%, 2–3, 4–5, 6–8 years, respectively, after vaccination, compared with 70.0%, 45.0% and 53.5%, respectively, for individuals primed at ages 2–13 years. rSBA median titers and IgG median levels were higher in the older group. Six to eight years after vaccination the percentage of patients with rSBA titers ⩾8 was significantly higher in the group primed with MCC-TT (78.5%) compared with those primed with MCC-CRM₁₉₇ [Menjugate® (33.3%) or Meningitec® (35.7%)] (p = 0.033). After a booster, 98% achieved rSBA titer ⩾8.ConclusionImmunity to meningococcal serogroup C in SCD children declines rapidly after vaccination and is dependent on the age at priming. Booster doses are needed to maintain protection in SCD patients. Persistence of antibodies seems to be longer in individuals primed with MCC-TT vaccine comparing to those immunized with MCC-CRM₁₉₇.     

ACYW135群脑膜炎球菌多糖结合破伤风毒素疫苗免疫学效果的Meta分析

目的 评价ACYW135群脑膜炎球菌多糖结合破伤风毒素疫苗(MPCV-ACYW135-TT)的免疫学效果.方法 检索National Center for Biotechnology Information (NCBI)、Cochrane协作网图书馆、中国生物医学文献数据库、中国期刊全文数据库和万方全文数据库,将有关评价MPCV-ACYW135免疫学效果的随机对照试验(RCT)的研究纳入分析.以接种疫苗1个月后产生的血清杀菌活性(SBA)抗体阳转率(PRR)和几何平均滴度(GMT)作为结局指标,合并不同研究中试验组与对照组间的PRR和GMT的率差(RD)或标准化均数差(SMD).使用RevMan5.1软件进行Meta分析.结果 共纳入13篇文献:有9篇比较了MPCV-ACYW135-TT和ACYW135群脑膜炎球菌多糖疫苗(MPV-ACYW135)之间免疫学效果差异,4篇比较了MPCV-ACYW135-TT和C群脑膜炎球菌多糖结合白喉毒素变异体197疫苗(MPCV-C-CMR197)之间免疫学效果差异.相比于MPV-A-CYW135;受试者在接种MPCV-ACYW135-TT后产生的针对A、C、Y和W135这4个血清型抗体PRR的RD在0.03～0.15之间;产生的针对A、Y和W135这3个血清型抗体GMT的SMD在0.33～1.22之间.1～2岁组幼儿在接种MPCV-ACYW135-TT后产生的针对C群抗体GMT与接种MPCV-C-CMR197差异无统计学意义(H＞0.05).结论 MPCV-ACYW135-TT与其他已上市应用的脑膜炎球菌疫苗有相似的免疫效果.     

Kinetics of antibody responses after primary immunization with meningococcal serogroup C conjugate vaccine or secondary immunization with either conjugate or polysaccharide vaccine in adults

In the Netherlands the meningococcal serogroup C conjugate (MenCC) vaccine is administered as a single dose at 14 months. We evaluated the kinetics of isotype-specific antibodies in adults (n = 21) after primary immunization with MenCC or secondary immunization with MenCC or plain MenC polysaccharide vaccine. Blood samples were collected prior to immunization and at 6 additional time points, from 3 to 25 days post-immunization. Secondary immunization resulted in 5–10-fold higher IgG titers compared to the primary immunization group, 25 days post-immunization. Prior to the secondary immunization, but 5 years after the first immunization, protective bactericidal antibodies and levels of MenC-specific IgG and IgM were still present. Furthermore, IgG antibodies present before secondary immunization were of higher avidity compared to antibodies produced one month after primary immunization. In addition, secondary immunization with nonconjugated MenC polysaccharide seemed to induce a higher IgG2 response compared to MenCC immunization. The kinetics of the observed secondary immune responses were not really faster than the observed primary responses. However, the rate of increase in antibodies seemed faster than the primary responses, representing a booster response. As the course of infection by Neisseria meningitidis can be very rapid, these data support the idea that sustainment of high antibody levels induced by MenCC are important for immediate protection.     

Multicomponent meningococcal serogroup B vaccination elicits cross-reactive immunity in infants against genetically diverse serogroup C,W and Y invasive disease isolates

BackgroundThe multicomponent meningococcal serogroup B vaccine (4CMenB) is currently indicated for active immunization against invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB). However, genes encoding the 4CMenB antigens are also variably present and expressed in strains belonging to other meningococcal serogroups. In this study, we evaluated the ability of antibodies raised by 4CMenB immunisation to induce complement-mediated bactericidal killing of non-MenB strains.MethodsA total of 227 invasive non-MenB disease isolates were collected between 1 July 2007 and 30 June 2008 from England and Wales, France, and Germany; 41 isolates were collected during 2012 from Brazil. The isolates were subjected to genotypic analyses. A subset of 147 isolates (MenC, MenW and MenY) representative of the meningococcal genetic diversity of the total sample were tested in the human complement serum bactericidal antibody assay (hSBA) using sera from infants immunised with 4CMenB.ResultsSerogroup and clonal complex repertoires of non-MenB isolates were different for each country. For the European panel, MenC, MenW and MenY isolates belonged mainly to ST-11, ST-22 and ST-23 complexes, respectively. For the Brazilian panel, most MenC and MenW isolates belonged to the ST-103 and ST-11 complexes, respectively, and most MenY isolates were not assigned to clonal complexes. Of the 147 non-MenB isolates, 109 were killed in hSBA, resulting in an overall coverage of 74%.ConclusionThis is the first study in which 147 non-MenB serogroup isolates have been analysed in hSBA to evaluate the potential of a MenB vaccine to cover strains belonging to other serogroups. These data demonstrate that antibodies raised by 4CMenB are able to induce bactericidal killing of 109 non-MenB isolates, representative of non-MenB genetic and geographic diversity. These findings support previous evidence that 4CMenB immunisation can provide cross-protection against non-MenB strains in infants, which represents an added benefit of 4CMenB vaccination.     

Persistence of serogroup C antibody responses following quadrivalent meningococcal conjugate vaccination in United States military personnel

Serogroup C meningococcal (MenC) disease accounts for one-third of all meningococcal cases and causes meningococcal outbreaks in the U.S. Quadrivalent meningococcal vaccine conjugated to diphtheria toxoid (MenACYW_D) was recommended in 2005 for adolescents and high risk groups such as military recruits. We evaluated anti-MenC antibody persistence in U.S. military personnel vaccinated with either MenACYW_D or meningococcal polysaccharide vaccine (MPSV4). Twelve hundred subjects vaccinated with MenACYW_D from 2006 to 2008 or MPSV4 from 2002 to 2004 were randomly selected from the Defense Medical Surveillance System. Baseline serologic responses to MenC were assessed in all subjects; 100 subjects per vaccine group were tested during one of the following six post-vaccination time-points: 5–7, 11–13, 17–19, 23–25, 29–31, or 35–37 months. Anti-MenC geometric mean titers (GMT) were measured by rabbit complement serum bactericidal assay (rSBA) and geometric mean concentrations (GMC) by enzyme-linked immunosorbent assay (ELISA). Continuous variables were compared using the Wilcoxon rank sum test and the proportion of subjects with an rSBA titer ≥8 by chi-square. Pre-vaccination rSBA GMT was <8 for the MenACWY_D group. rSBA GMT increased to 703 at 5–7 months post-vaccination and decreased by 94% to 43 at 3 years post-vaccination. GMT was significantly lower in the MenACWY_D group at 5–7 months post-vaccination compared to the MPSV4 group. The percentage of MenACWY_D recipients achieving an rSBA titer of ≥8 decreased from 87% at 5–7 months to 54% at 3 years. There were no significant differences between vaccine groups in the proportion of subjects with a titer of ≥8 at any time-point. GMC for the MenACWY_D group was 0.14 μg/mL at baseline, 1.07 μg/mL at 5–7 months, and 0.66 μg/mL at 3 years, and significantly lower than the MPSV4 group at all time-points. Anti-MenC responses wane following vaccination with MenACYW_D; a booster dose is needed to maintain protective levels of circulating antibody.     

Introducing vaccination against serogroup B meningococcal disease: An economic and mathematical modelling study of potential impact

Background

Meningococcal disease remains an important cause of morbidity and mortality worldwide. The first broadly effective vaccine against group B disease (which causes considerable meningococcal disease in Europe, the Americas and Australasia) was licensed in the EU in January 2013; our objective was to estimate the potential impact of introducing such a vaccine in England.

Methods

We developed two models to estimate the impact of introducing a new ‘MenB’ vaccine. The cohort model assumes the vaccine protects against disease only; the transmission dynamic model also allows the vaccine to protect against carriage (accounting for herd effects). We used these, and economic models, to estimate the case reduction and cost-effectiveness of a number of different vaccine strategies.

Results

We estimate 27% of meningococcal disease cases could be prevented over the lifetime of an English birth cohort by vaccinating infants at 2,3,4 and 12 months of age with a vaccine that prevents disease only; this strategy could be cost-effective at £9 per vaccine dose. Substantial reductions in disease (71%) can be produced after 10 years by routinely vaccinating infants in combination with a large-scale catch-up campaign, using a vaccine which protects against carriage as well as disease; this could be cost-effective at £17 per vaccine dose.

Conclusions

New ‘MenB’ vaccines could substantially reduce disease in England and be cost-effective if competitively priced, particularly if the vaccines can prevent carriage as well as disease. These results are relevant to other countries, with a similar epidemiology to England, considering the introduction of a new ‘MenB’ vaccine.     

Long-term antibody persistence after a booster dose of quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in healthy 5-year-old children

BackgroundTo provide continuing protection, available meningococcal vaccines must provide long-term persistence of circulating functional antibodies against prevalent serogroups causing invasive meningococcal disease (IMD). This study assessed antibody persistence and safety of the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) and the meningococcal serogroup C vaccine conjugated to Corynebacterium diphtheriae CRM₁₉₇ protein (MenC-CRM) for up to 6 years after booster dosing in children.MethodsIn the primary vaccination study, children were vaccinated at age 12 to 23 months. In the first extension study, children who completed the primary study received a booster dose 4 years later with the same primary vaccine. The current study assessed antibody persistence at 2 to 6 years postbooster against each of the 4 meningococcal serogroups using serum bactericidal assays using rabbit (rSBA) or human (hSBA) complement with antibody titer thresholds of ≥1:8 or ≥1:4, respectively, and geometric mean titers (GMTs). Safety evaluations during this period included serious adverse events (SAEs) related to vaccination and any event related to lack of vaccine efficacy.ResultsA total of 184 subjects were enrolled (MenACWY-TT = 159; MenC-CRM = 25). For MenACWY-TT, the percentages of subjects with rSBA titers ≥1:8 ranged from 96.7% to 100% across serogroups at 2 years postbooster and 71.6% to 94.0% at 6 years postbooster; rSBA GMTs decreased from Year 2 to 4 and generally remained stable thereafter. The percentages of subjects in the MenACWY-TT group with hSBA titers ≥1:4 were 70.0% to 100% across serogroups at 2 years postbooster and 58.5% to 98.5% at 6 years postbooster. No lack of efficacy, SAEs, or vaccine-related adverse events were reported.ConclusionsThe persistence of rSBA and hSBA antibodies was shown up to 6 years postbooster (10 years postprimary vaccination) with either MenACWY-TT or MenC-CRM, suggesting that this schedule may provide long-term protection against IMD. Clinicaltrials.gov: NCT01900899.