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Objectives: To estimate vaccine effectiveness (VE) and duration of protection of single primary and booster immunisation with meningococcal C (MenC) and ACWY (MenACWY) conjugate vaccines in preventing MenC invasive meningococcal disease (IMD)., Methods: We performed a systematic review on studies of VE and immunogenicity (rSBA/hSBA titers) of participants aged 12-23 months for primary and 6-18 years for booster immunisation (last search: 18 August 2023). Risk of bias and certainty of evidence were evaluated (PROSPERO: CRD42020178773)., Results: We identified 10 studies. Two studies reported VE of primary immunisation with MenC vaccines ranging between 90% (74.9 - 96.1) and 84.1% (41.5 - 95.7) for periods of 2 and 7 years, respectively. Eight studies reported immunogenicity of primary immunisation with MenC and/or MenACWY vaccines, of which two reported -in addition- on booster immunisation. The percentage of participants with protective rSBA titers was high after primary immunisation but waned over the following 6 years. A single booster at the age of 7 years or older seems to prolong protection for several years., Conclusions: A single dose of MenC or MenACWY vaccine at 12-23 months of age provides robust protection against MenC IMD. Data on booster immunisation are sparse, but indicate prolonged protection for three years at least., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The incidence of invasive meningococcal disease due to serogroup C (MenC) decreased in Portugal since the introduction of the conjugate vaccine (MCC) in the free market in 2001 and in the National Immunisation Plan in 2006. Considering the potential waning of the antibody response reported in the literature, the different vaccination schemes that were used in our country over the past decade, and that Neisseria meningitidis serogroup C continues to circulate, the Portuguese population may currently be at increased risk of infection. In the absence of national data, we evaluated the seroprotection level of the Portuguese population against MenC, in order to identify the protected fraction of the population and ponder on the necessity of a booster dose of the MCC vaccine., Methods: We measured serum bactericidal antibody levels against MenC in a representative sample of the population (n = 1500) aged 2-64 years who participated in the 2015/2016 National Serological Survey., Results: A total of 31.1% (466/1500, 95%CI: 29-33%) of the individuals studied were protected against MenC. The geometric mean titre was 6.5. The proportion of seroprotected was particularly low in children aged 2-4 years (<16%) who received a single dose of the vaccine at 12 months of age (vaccination strategy since 2012). The proportion of seroprotected was higher (44.7% to 53.5%) in adolescent and young adults (15-24 years of age), resulting from vaccination during the catch-up campaign at 5-15 years of age. The highest protection rates were observed when the vaccine was administered during adolescence., Conclusion: The small fraction of population seroprotected, combined with the already known waning effect of the antibody response over time, may indicate that the Portuguese population will become progressively more exposed to the risk of infection. Taking in consideration our results, we recommend to change the current vaccination strategy and introduce a booster dose of the MCC vaccine during adolescence., Competing Interests: The authors have declared that no competing interests exist.

Neisseria meningitidis bacterial infection can cause severe life-threatening meningitis. Individuals who survive may be left with profound sequelae. In epidemic regions such as the meningitis belt of Africa, the case rate is drastically higher than in nonepidemic regions and is due to distinct outbreak serogroups. Two highly effective conjugate meningococcal vaccine against serogroups A, C, W and Y are licensed and indicated for prevention in childhood vaccination schedules and for travelers to outbreak regions. In the US, meningococcus serogroup B is the main cause of outbreaks, in areas with crowding such as college dorms. It has taken over 40 years to develop a meningitis type B vaccine and now there are 2 brands available for children and teens. All college-bound individuals should complete schedules of both conjugate ACWY serotypes and meningitis B vaccine series. This paper reviews details on who to vaccinate and how to use the currently available meningococcal meningitis vaccines.

To examine the link between meningococcal C (MenC) vaccine size and immunogenic response, a panel of MenC glycoconjugate vaccines were prepared differing in chain length, molar mass and hydrodynamic volume. The preparations consisted of different lengths of MenC polysaccharide (PS) covalently linked to monomeric purified tetanus toxoid (TT) carrier protein using the coupling reagent ethylcarbodiimide hydrochloride (EDC). Size exclusion chromatography with multi-angle light scattering (SEC-MALS) and viscometry analysis confirmed that the panel of MenC-TT conjugates spanned masses of 191,500 to 2,348,000 g/mol, and hydrodynamic radii ranging from 12.1 to 47.9 nm. The two largest conjugates were elliptical in shape, whereas the two smallest conjugates were more spherical. The larger conjugates appeared to fit a model described by multiple TTs with cross-linked PS, typical of lattice-like networks described previously for TT conjugates, while the smaller conjugates were found to fit a monomeric or dimeric TT configuration. The effect of vaccine conjugate size on immune responses was determined using a two-dose murine immunization. The two larger panel vaccine conjugates produced higher anti-MenC IgG1 and IgG2b titres after the second dose. Larger vaccine conjugate size also stimulated greater T-cell proliferative responses in an in vitro recall assay, although cytokines indicative of a T-helper response were not measurable. In conclusion, larger MenC-TT conjugates up to 2,348,000 g/mol produced by EDC chemistry correlate with greater humoral and cellular murine immune responses. These observations suggest that conjugate size can be an important modulator of immune response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Meningococcal disease is a devastating infection caused by Neisseria meningitidis (meningococcus), and it is classified into serogroups according to its polysaccharide capsule composition. In Brazil, serogroup C is the most frequently responsible for the majority of cases, representing a serious public health challenge. In 2010, the meningococcal serogroup C conjugate vaccine was included in the calendar of the National Immunization Program. We have evaluated 163 meningococcal isolates collected during the pre (2006-2010) and post (2011-2016) vaccination periods. Epidemiological data were determined through Multilocus Sequence Typing (MLST) analysis, vaccine antigens and Bexsero Antigen Sequence Typing (BAST) variant. Clonal complex 103 remains the most prevalent in the country with a high number of serogroup C strains to which CC103 is directly associated. A total of 42 different ST were found. The two most prevalent ST were ST-3780 (CC103) with 38 strains and ST-10781, which was not associated with a CC with nine strains. Allele abcZ-276 was reported among 98% of the strains analyzed and it was not found among other CC103 strains worldwide, makes this allele an important genetic marker for a specific new clone only assigned to Brazilian serogroup C strains, ST-3780. FHbp-25 and NHBA-42 peptides were the most prevalent among isolates in both periods studied. BAST-824 and BAST-3073 have been expressed only in CC103 over the studied years, however, it was not possible to associate a BAST variant to a specific CC. Serogroup C phenotype [P1.22,14-6,36-2: F3-9: ST-3780 (CC103)] was the most prevalent according to the antigenic profiles of circulating strains in Brazil (2007-2016). Our study suggests that CC103 is still a major hypervirulent CC circulating in Brazil and ST-3780 is currently spreading all over the country even after the introduction of MenC in 2010., Competing Interests: Declaration of Competing Interest No conflict of interest related to this article for all authors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: After the re-emergence of serogroup C meningococcal meningitis (MM) in Nigeria and Niger, we aimed to re-evaluate the vaccination policy used to respond to outbreaks of MM in the African meningitis belt by investigating alternative strategies using a lower incidence threshold and information about neighboring districts., Methods: We used data on suspected and laboratory-confirmed cases in Niger and Nigeria from 2013 to 2017. We calculated global and local Moran's I-statistics to identify spatial clustering of districts with high MM incidence. We used a Pinner model to estimate the impact of vaccination campaigns occurring between 2015 and 2017 and to evaluate the impact of 3 alternative district-level vaccination strategies, compared with that currently used., Results: We found significant clustering of high incidence districts in every year, with local clusters around Tambuwal, Nigeria in 2013 and 2014, Niamey, Niger in 2016, and in Sokoto and Zamfara States in Nigeria in 2017.We estimate that the vaccination campaigns implemented in 2015, 2016, and 2017 prevented 6% of MM cases. Using the current strategy but with high coverage (85%) and timely distribution (4 weeks), these campaigns could have prevented 10% of cases. This strategy required the fewest doses of vaccine to prevent a case. None of the alternative strategies we evaluated were more efficient, but they would have prevented the occurrence of more cases overall., Conclusions: Although we observed significant spatial clustering in MM in Nigeria and Niger between 2013 and 2017, there is no strong evidence to support a change in methods for epidemic response in terms of lowering the intervention threshold or targeting neighboring districts for reactive vaccination., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Significant improvement has been made in the development of vaccines against Neisseria meningitidis infections since the introduction of polysaccharide-protein conjugate vaccines. Conventional bacterial capsular polysaccharide (PS) based conjugate vaccines require unique and expensive manufacturing facilities, complex production processes and extensive quality testing. Synthetic oligosaccharide (OS) based approach is one of the novel technologies that is being developed to simplify production of conjugate vaccines. OSs can be chemically synthesized to a desired length long enough to represent the antigenic epitopes which often present as a homogenous mixture. We prepared OSs corresponding to tetramer and octamer of N. meningitidis serogroup C (MenC) PS by organic synthesis. The MenC tetramer and octamer were further conjugated with tetanus toxoid to produce respective monovalent conjugates having the desired physico-chemical characteristics. The conjugates were evaluated in a mouse model for immunogenicity and compared with a licensed PS conjugate vaccine. Synthetic conjugates could induce anti-MenC PS IgG as well as serum bactericidal titers at levels comparable to those elicited by the licensed vaccine. The increase in length of synthetic oligomers from tetramer to octamer did not appear to increase immunogenicity. The results establish the pre-clinical proof of concept for a synthetic MenC oligosaccharide conjugate vaccine candidate., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: We assessed immunogenicity, antibody persistence and safety of the meningococcal serogroups A, C, W and Y-tetanus toxoid (TT) conjugate vaccine (MenACWY-TT) in children primed as toddlers with MenC vaccine., Methods: This open, multicenter extension study enrolled children 84-95 months of age who had received one dose of the combined Haemophilus influenzae type b (Hib)-MenC-TT conjugate vaccine (HibMenC group) or Hib-TT and monovalent MenC (MCC)-CRM197 vaccines (Hib+MCC group) at 12-18 months of age, in the primary study. All participants received one dose of MenACWY-TT. We assessed immunogenicity against MenA, MenC, MenW and MenY at 1 month and 2 years postvaccination by serum bactericidal assay using baby rabbit complement (rSBA). Safety and reactogenicity were evaluated., Results: Six years post-MenC vaccination, <20% of children retained rSBA-MenC titers ≥1:8. At 1 month post-MenACWY-TT vaccination, vaccine response rates against all serogroups were high for both groups with ≥97.1% of children having rSBA ≥1:8. Two years postvaccination, ≥63.6% of children retained rSBA-MenA ≥1:8, and ≥87.9% for other serogroups. Geometric mean titers for all serogroups declined at 2 years post-MenACWY-TT vaccination, but remained ≥13 times higher than prevaccination levels. For both groups, pain (≤58.5%), redness (≤51.4%) and fatigue (≤27.0%) were the most frequently reported adverse events. No serious adverse events were reported., Conclusions: One dose of MenACWY-TT boosts protection against MenC in primed children, is safe and extends protection against MenA, MenW and MenY. Immunogenicity and safety were comparable in infants vaccinated with conjugated vaccine (HibMenC-TT) or the separate vaccines (Hib-TT and MCC-CRM197).

Neisseria meningitidis caused meningitis is life-threatening acute infection with high fatality and high frequency of severe sequelae. Meningococcal capsular polysaccharides can be used to prevent meningococcal disease; while conjugating the polysaccharides to carrier protein was found necessary to improve the immunogenicity and induce memory responses in infants and young children. Nevertheless, repeated administration of glycoconjugate vaccines might lead to carrier-induced epitope suppression due to limited number of carrier proteins. Here in this study, full-length hepatitis B core antigen virus-like particles (HBc VLPs) was used as a novel potential carrier protein for conjugation of meningococcal group C polysaccharides (CPS) with heterobifunctional polyethylene glycol (PEG) of different length (2, 5 and 10 kDa) as linkers. The physiochemical properties of the CPS-PEG-HBc conjugate vaccines were fully characterized. The TEM, DLS, native agarose gel electrophoresis, and HPLC analyses all confirmed the successful conjugation. As compared to plain CPS and the physical mixture of CPS and HBc, the immunization with the conjugate vaccines can generate about 10 times increase in CPS specific IgG titers with a significant boosting effect. HBc conjugation induced a shift to a Th1 cellular immune type response, as assessed by the increased IgG2a subclass production. In addition, vaccination of the conjugate vaccines elicited much enhanced avidity functional antibody and long-lasting immunological memory. IgG titers elicited by CPS-P2k-HBc, CPS-P5k-HBc and CPS-P10k-HBc at week 18 maintained 38.1%, 17.9% and 33.3% of their peak values. All these results demonstrated that HBc VLPs can be used as potential carrier protein to develop polysaccharide conjugate vaccines effective in eliciting long-lasting and strong cellular immune response., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Mucosal antibodies against capsular polysaccharides offer protection against acquisition and carriage of encapsulated bacteria like Neisseria meningitidis serogroup C. Measurements of salivary antibodies as replacement for blood testing has important (cost-effective) advantages, particular in studies that assess the impact of large-scale vaccination or in populations in which blood sampling is difficult. This study aimed to estimate a threshold for meningococcal IgG salivary antibody levels to discriminate between unprotected and protected vaccinated individuals., Methods: MenA-, MenC-, MenW- and MenY-polysaccharide (PS) specific IgG levels in serum and saliva from participants in a meningococcal vaccination study were measured using the fluorescent-bead-based multiplex immunoassay. Functional antibody titers in serum against the four serogroups were measured with serum bactericidal assay using rabbit complement (rSBA). A threshold for salivary IgG was determined by analysis of ROC curves using a serum rSBA titer ≥128 as correlate of protection. The area under the curve (AUC) was calculated to quantify the accuracy of the salivary test and was considered adequate when ≥0.80. The optimal cut-off was considered adequate when salivary IgG cut-off levels provided specificity of ≥90%. True positive rate (sensitivity), positive predictive value, and negative predictive value were calculated to explore the possible use of salivary antibody levels as a surrogate of protection., Results: The best ROC curve (AUC of 0.95) was obtained for MenC, with an estimated minimum threshold of MenC-PS specific salivary IgG ≥3.54 ng/mL as surrogate of protection. An adequate AUC (> 0.80) was also observed for MenW and MenY with an estimated minimal threshold of 2.00 and 1.82 ng/mL, respectively. When applying these thresholds, all (100%) samples collected 1 month and 1 year after the (booster) meningococcal vaccination, that were defined as protective in the saliva test for MenC, MenW and MenY, corresponded with concomitant serum rSBA titer ≥128 for the respective meningococcal serogroups., Conclusion: The saliva test offers an alternative screening tool to monitor protective vaccine responses up to one year after meningococcal vaccination against MenC, MenW and MenY. Future (large) longitudinal vaccination studies evaluating also clinical protection against IMD or carriage acquisition are required to validate the currently proposed threshold in saliva.

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.

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., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent serogroup C meningococcal disease outbreaks led to meningococcal vaccine recommendations for Southern California men who have sex with men (MSM). Assessment of vaccine confidence is critical to improving vaccine coverage in the context of disease outbreaks wherein immunization(s) are recommended., Methods: We surveyed MSM using venue-based sampling and began development of the vaccine confidence index (VCI) with 30 survey items corresponding to trust- and safety-related perceptions. We performed exploratory factor analyses and computed the Cronbach's alpha coefficient to assess internal consistency of the VCI. We created a categorical confidence variable (low, medium, and high confidence) and conducted bivariate and multivariate analyses to evaluate associations with reported confidence and immunization uptake., Results: Ten survey items were included in the final VCI and formed the confidence measure. Participants with low confidence had the lowest levels of reported uptake for both meningococcal vaccines. Confidence differed significantly (p ≤ 0.05) between MSM who indicated they received vaccines recommended within the context of the outbreak and those who did not., Conclusions: Our VCI is sensitive to a number of issues that may influence vaccine confidence. It is useful for assessing MSM trust and acceptance of recommended immunizations and may be used to inform intervention development.

After the successful roll out of MenAfriVac, Nigeria has experienced sequential meningitis outbreaks attributed to meningococcus serogroup C (NmC). Zamfara State in North-western Nigeria recently was at the epicentre of the largest NmC outbreak in the 21 st Century with 7,140 suspected meningitis cases and 553 deaths reported between December 2016 and May 2017. The overall attack rate was 155 per 100,000 population and children 5-14 years accounted for 47% (3,369/7,140) of suspected cases. The case fatality rate (CFR) among children 5-9 years was 10%, double that reported among adults ≥ 30 years (5%). NmC and pneumococcus accounted for 94% (172/184) and 5% (9/184) of the laboratory-confirmed cases, respectively. The sequenced NmC belonged to the ST-10217 clonal complex (CC). All serotyped pneumococci were PCV10 serotypes. The emergence of NmC ST-10217 CC outbreaks threatens the public health gains made by MenAfriVac, which calls for an urgent strategic action against meningitis outbreaks.

In 2015 an increased incidence of invasive meningococcal disease due to serogroup-C (MenC) occurred in Tuscany, Italy. This led the Regional Health Authority of Tuscany to implement a reactive immunisation campaign and to launch an epidemiological field investigation aiming to address targeted immunisation interventions. In 2011-14, 10 MenC cases had been reported compared with 62 cases in 2015-16. The case fatality rate was 21% (n = 13) and 51 cases (82.3%) were confirmed as C:P1.5-1,10-8:F3-6:ST-11(cc11). Overall, 17 clusters were recognised. Six discos and four gay-venues were found to have a role as transmission-hotspots, having been attended by 20 and 14 cases in the 10 days before symptoms onset. Ten and three cases occurred, respectively, among men who have sex with men (MSM) and bisexual individuals, who were involved in 11 clusters. In addition, heterosexual cases (n = 5) attending gay-venues were also found. Secondary cases were not identified. Molecular typing indicated close relationship with MenC clusters recently described among gay, bisexual and other MSM in Europe and the United States, suggesting a possible international spread of the serogroup-C-variant P1.5-1,10-8:F3-6:ST-11(cc11) in this population-group; however, epidemiological links were not identified. In December 2016, a targeted vaccination campaign involving discos and lesbian, gay, bisexual, and transgender (LGBT) associations was implemented. During 2017, 10 cases of MenC occurred, compared with 32 and 30 cases reported in 2015 and 2016 respectively, suggesting the effectiveness of the reactive and targeted immunisation programmes.

Introduction: In 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)., Methods: MenC 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., Results: In 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., Conclusions: In 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., (Copyright © 2018. Published by Elsevier Ltd.)

INTRODUCTION Serogroup B meningococcal outer membrane vesicle vaccines have been effective against vaccine-type strains, but their effectiveness against heterologous strains has been controversial. The Cuban VA-MENGOC-BC vaccine is of this type, but also includes meningococcus C capsular polysaccharide. OBJECTIVES Assess the effectiveness of VA-MENGOC-BC in reducing meningococcal disease caused by homologous or heterologous serogroup B strains and its serological effectiveness against meningococcus C. METHODS A review of studies of VA-MENGOC-BC's application in Cuba, Brazil, Uruguay and Colombia was carried out to examine the vaccine's effectiveness in reducing meningococcal disease during serogroup B outbreaks. Serological effectiveness against serogroup C determined in these studies (indicated by bactericidal antibody titers before and after vaccination) was also analyzed. RESULTS VA-MENGOC-BC's effectiveness against homologous serogroup B strains has consistently been greater than 80% in all age groups. Effectiveness in heterologous contexts was also above 80% in individuals aged >4 years. Lower effectiveness in heterologous contexts was found in Brazilian children aged <2 years, although still >50%. Effectiveness increased when assessed based on mortality rates, as well as in cases of clinically severe meningococcal disease. The carrier-state pattern was modified after vaccination with reduction of hypervirulent lineages. Some 60% of infants (aged <1 year) attained protective bactericidal antibody titers against serogroup C. Higher protection rates were achieved in older children. CONCLUSIONS In addition to prevention of meningococcal disease caused by homologous serogroup B strains, VA-MENGOC-BC should be considered for heterologous contexts. It is protective against serogroup C in all age groups. KEYWORDS Neisseria meningitidis, meningococcal disease, meningococcal vaccines, serogroup B meningococcus, serogroup C meningococcus, immunogenicity, bacterial outer membrane proteins, heterologous effects of vaccines, acellular vaccines, Cuba.

The incidence of infectious diseases caused by several bacterial pathogens such as Haemophilus influenzae type b, Streptococcus pneumoniae , and Neisseria meningitidis , has been dramatically reduced over the last 25 years through the use of glycoconjugate vaccines. The structures of the bacterial capsular polysaccharide (CPS) antigens, extracted and purified from microbial cultures and obtained with very high purity, show that many of them are decorated by O-acetyl groups. While these groups are often considered important for the structural identity of the polysaccharides, they play a major role in the functional immune response to some vaccines such as meningococcal serogroup A and Salmonella typhi Vi, but do not seem to be important for many others, such as meningococcal serogroups C, W, Y, and type III Group B Streptococcus . This review discusses the O-acetylation status of CPSs and its role in the immunological responses of these antigens.

The significant increase in the incidence rates and ongoing outbreaks of serogroup C meningococcal (MenC) disease, associated with the sequence type-103 complex, motivated the incorporation of the meningococcal C conjugate (MCC) vaccine in the routine immunization program in the State of Bahia, Brazil in early 2010, targeting children younger than 5 years of age. In its capital, Salvador, the program also included a catch-up campaign for individuals 10-24 years of age. We performed an observational, ecological study, analyzing data collected from 2007 to 2015, to compare the impact of these two immunization strategies on meningococcal disease incidence and mortality rates. In Salvador, following the vaccination program, a dramatic early impact on MenC disease and mortality rates could be observed, with significant reductions in incidence rates of MenC disease in all age groups, including individuals that were too old to have been vaccinated, indicating the presence of herd protection. Compared to the pre-vaccine period, a virtual disappearance of MenC disease was observed in 2015. However, in the state of Bahia (excluding the city of Salvador), no herd protection could be observed, with significant impact only among vaccine-eligible children within 5 years of introduction of the MCC vaccination program. These results highlight the importance of catch-up campaigns, including adolescents and young adults, to induce herd protection compared to immunization strategies restricted to infants and young children. This information is crucial for identifying optimal immunization policies and future strategies, focused on adolescents, to optimize the impact of MCC vaccination programs.

Background: Meningococcal infection starts with colonisation of the upper respiratory tract. Mucosal immunity is important for protection against acquisition and subsequent meningococcal carriage. In this study, we assessed salivary antibody levels against meningococcal serogroup A (MenA), W (MenW) and Y (MenY) after vaccination with a quadrivalent MenACWY conjugated vaccine. We also compared salivary meningococcal serogroup C (MenC) antibody levels after monovalent MenC and quadrivalent MenACWY conjugated vaccination., Methods: Healthy participants, who had received MenC conjugate vaccine between 14 months and 3 years of age, received a (booster) MenC or MenACWY vaccination at age 10-15 years. MenA-, MenC-, MenW- and MenY-polysaccharide (PS) specific IgG and IgA levels in saliva and serum and PS specific secretory component levels in saliva were measured using the fluorescent-bead-based multiplex immunoassay., Results: MenACYW vaccination increased salivary PS-specific IgA (2-fold) and IgG levels(>10-fold) for MenA, MenY, and MenW. After one year, salivary IgA levels had returned to baseline levels. Both vaccines induced an increase in salivary MenC-PS specific IgA (>3-fold) and IgG (>100-fold), with higher levels after MenC as compared to MenACWY vaccination. The antibody decay rate of MenC in saliva between one month and one year was similar for both vaccines. The overall correlation between serum and saliva IgA levels was low (R = 0.39, R = 0.58, R = 0.31, and R = 0.36 for MenA, MenC, MenW and MenY, respectively). Serogroup-PS specific IgG levels between serum and saliva correlated better (R ranged from 0.51 to 0.88)., Conclusions: Both primary (MenA, MenY, and MenW) and booster (MenC) parenteral meningococcal conjugate vaccination induced high salivary antibody levels. The strong correlation for MenC, MenW and MenY between saliva and serum IgG levels indicates that saliva might be used as a reliable tool to measure vaccine responses after both primary and booster meningococcal vaccination.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

High temperature is known to cause some instability in polysaccharide-protein conjugated vaccines and studies under stress conditions may be useful in determining whether short-term accidental exposure to undesired conditions can compromise product quality. In this study, we examined the structural stability of three industrial batches of Brazilian Meningococcal C conjugate bulk (MPCT) incubated at 4, 37, and 55 °C for 5 weeks. The effect of exposure to the storage temperatures was monitored by HPLC-SEC, CZE, CD and NMR techniques. The immunological significance of any physicochemical changes observed in MPCT was determined by SBA and ELISA assays of serum from immunized mice. Fluorescence emission spectra at 4 and 37 °C were similar among all samples and compatible with the native fold of the carrier protein. Fluorescence spectra of MPCT stored at 55 °C decreased in intensity and had a significant red-shift, indicating conformational changes. Far-UV CD spectra revealed a trend toward loss of structural conformation as storage temperature was increased to 55 °C. The NMR data showed modified signal intensity of the aromatic and aliphatic residues, mainly for samples incubated at 55 °C, suggesting a partial loss of tertiary structure. About 50% free saccharide content was found in bulks stored at 55 °C, but no difference was observed in the IgG or SBA titers. The present study showed physicochemical methods alone are insufficient to predict the biological activity of a MPCT conjugate vaccine without extensive validation against immunological data. However, they provide a sensitive means of detecting changes induced in a vaccine exposed to adverse environmental condition.

Background: The US Advisory Committee on Immunization Practices recommends a booster dose of quadrivalent meningococcal conjugate vaccine (MCV4) after initial immunization for patients at high risk for meningococcal infection., Methods: The International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT) P1065 trial evaluated the use of MCV4 in human immunodeficiency virus (HIV)-infected children and youth. The final step of this trial was an open-label study of an MCV4 booster dose 3.5 years after primary MCV4 immunization. Antibody titers were evaluated at the time of the booster vaccine and 1, 4, and 24 weeks after the booster. Immunogenicity was measured by rabbit serum bactericidal antibody (rSBA) against each meningococcal serogroup. Immunologic memory was defined as either seroprotection (rSBA titer ≥1:128) or a ≥4-fold increase 1 week after the booster dose. Primary response was defined as either a ≥4-fold response or seropositivity 4 weeks after the booster in the absence of immunologic memory. Adverse events were assessed for 4 weeks after the booster dose., Results: Of 174 participants with serology results at entry and 1 and 4 weeks later, the percentage with protective antibody levels at entry varied according to serogroup, ranging from a low of 26% for serogroup C to a high of 68% for serogroup A. A memory response to at least 1 serogroup occurred in 98% of the participants: 93% each for serogroups A and Y, 88% for serogroup C, and 94% for serogroup W-135; 83% had a memory response to all 4 serogroups. Overall, rates of any memory or primary response were ≥90% for all serogroups. No serious adverse events were encountered., Conclusions: A booster dose of MCV4 elicited a memory response in 88% to 94% of previously immunized HIV-infected participants depending on serogroup, including those who lacked a protective titer level for that serogroup before booster vaccination., (© The Author 2017. Published by the Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Aims: Meningococcal 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 8-12years after different MCCV vaccination programs were launched and evaluated the impact of vaccination on seroprotection., Methods: Seroepidemiological 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≥3years 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., Results: Serum samples from 1880 subjects were collected. In total, 523 (27.8%) of the 1880 subjects and 446 (31.2%) of the 1430 subjects<30years (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 10-13years of age (20-21years old at the time of blood sampling). Those scheduled for immunization in infancy at 2, 4 and 6months of age (7-8years at blood sample) represented the lowest (7.1%, 95% CI 3.3-13.1) number of seroprotected subjects. Having received one vaccine dose after 12months 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., Conclusion: Only one in three subjects who were vaccinated with MCC vaccine was seroprotected after 8-12years. These findings emphasize that seroprevalence studies are essential to identify susceptible cohorts and to inform vaccine policy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The objective of this study was to evaluate the immunogenicity and safety of the novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroup A and C-tetanus toxoid conjugate vaccine (Hib-MenAC)., Methods: We conducted a non-inferiority, randomized, observer-blind, positive control clinical trial in 900 healthy infants aged between 3-5 months in Funing County, Jiangsu Province, China. Participants were randomly allocated, in a ratio of 2:1 (block = 6), to receive experimental combined Hib-MenAC vaccines co-administrated with placebo or the co-administration of licensed Hib vaccine and MenAC vaccine, according to a three-dose immunization schedule. The seroconversion of antibody titer against meningococcal serogroups A, C and Hib was the primary endpoint., Results: The experimental vaccines was non-inferior to the licensed two control vaccines. Participants receiving experimental Hib-MenAC vaccines showed a seroconversion rate of 99.0%, 96.1% and 97.7% for rSBA-MenA, rSBA-MenC and anti-PRP antibodies, respectively. The Hib-MenAC vaccine did not result in an increase in adverse reaction, and no serious adverse event was judged to be related to the vaccination., Conclusions: The novel combined Hib-MenAC conjugate vaccine was safe and highly immunogenic in infants aged between 3 to 5 months.

Meningococcus serogroup B (MenB), clonal complex 32 (cc 32), was the Brazilian epidemic strain of meningococcal disease (MD) in the 1990's. Currently, meningococcus serogroup C (MenC), cc 103, is responsible for most of the cases of the disease in Brazil. The aim of this study was to investigate the seroprevalence of bactericidal antibody (SBA) against representative epidemic strains of MenC, (N753/00 strain, C:23:P1.22,14-6, cc103) and MenB, (Cu385/83 strain, B:4,7:P1.15,19, cc32) in students and employees of a university hospital in the State of Rio Grande do Sul (RS, Brazil). A second MenC strain (N79/96, C:2b:P1.5-2,10, cc 8) was used as a prototype strain of Rio de Janeiro's outbreak that occurred in the 1990's. Our previous study showed a 9% rate of asymptomatic carriers in these same individuals. A second goal was to compare the SBA prevalence in meningococcal carriers and non-carriers. Fifty-nine percent of the studied population showed protective levels of SBA titers (log2≥2) against at least one of the three strains. About 40% of the individuals had protective levels of SBA against N753/00 and Cu385/83 strains. Nonetheless, only 22% of the individuals showed protective levels against N79/96 strain. Significantly higher antibody levels were seen in carriers compared to non-carriers (P≤0.009). This study showed that, similar to other States in Brazil, a MenC (23:P1.22,14-6, cc103) strain with epidemic potential is circulating in this hospital. Close control by the Epidemiological Surveillance Agency of RS of the number of cases of MD caused by MenC strains in the State is recommended to prevent a new disease outbreak.

Background: Routine infant immunization with meningococcal C conjugate (MCC) vaccination started in Brazil in November 2010, scheduled at three and five months plus a booster at 12-15months of age. No catch-up was implemented. We assessed the impact of vaccination on meningococcal C disease (MenC) four years after vaccination start in the National Immunization Program., Methods: We performed an ecological quasi-experimental design from 2008 to 2014 using a deterministic linkage between the National Notification and the National Reference Laboratory databases for meningitis. We conducted an interrupted time-series analysis considering Brazil except for Salvador municipality, because an epidemic of serogroup C disease occurred in this city, which prompted a mass vaccination campaign with catch-up for adolescents in 2010. Observed MenC rates in the post-vaccination period were compared to expected rates calculated from the pre-vaccination years. Results for Salvador were presented as descriptive data. An additional time-series analysis was performed for the state of São Paulo., Results: A total of 18,136 MenC cases were analyzed. The highest incidence rates were observed for infants aged <12months and no second incident peak was observed for adolescents. For Brazil, MenC rates were reduced by 67.2% (95%CI 43.0-91.4%) for infants <12months of age, 92.0% (77.3-106.8%) for the age-group 12-23months, and 64.6% (24.6-104.5%) for children aged 2-4years. For children 5-9years old, MenC rates reduced 19.2% (9.5-28.9%). Overall, 955 MenC cases were averted in Brazil in individuals aged <40years after MCC vaccination. Results from São Paulo State, mirror the patterns seen in Brazil., Conclusion: After four years of infants and toddlers vaccination start, MenC invasive disease reduced in the target population. This investigation provide a robust baseline to ascertain how much the upcoming catch-up dose in 12-13years of age will accelerate the decrease in MenC incidence rates among youths in Brazil., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Meningococcal C conjugate (MenC) vaccine was introduced as part of the Brazilian National Immunisation Program in 2010 for children < 1 year of age., Objectives: The study objective was to evaluate the impact of this vaccination strategy., Methods: An observational, mixed ecological and analytical study was conducted, based on time series panel data from surveillance records (2001-2013)., Findings: A total of 37,538 of meningococcal disease cases were recorded during the study period. Of these, 19,997 were attributed to serogroup C. A decrease in meningococcal disease serogroup C (MDC) incidence among children aged < 1 year [65.2%; 95% confidence interval (CI): 20.5-84.7%] and 1-4 years (46.9%; 95%CI: 14.6-79.1%) were found in the three years following vaccination introduction. Vaccination impact on the reduction of MDC incidence varied from 83.7% (95%CI: 51.1-100.0%) in the Midwest region to 56.7% (95%CI: 37.4-76.0%) in the Northeast region., Main Conclusions: Vaccination against MDC in Brazil had a positive impact on the population of children aged < 1 year, across all regions, and on the 1-4 year-old cohort. Nevertheless, in our view there is scope for improving the vaccination strategy adopted in Brazil.

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., (Copyright © 2017 American Society for Microbiology.)

Objective: To inform public health recommendations, we evaluated the effectiveness and efficiency of current and hypothetical surveillance and vaccine response strategies against Neisseria meningitidis C meningitis epidemics in 2015 in Niger., Methods: We analysed reports of suspected and confirmed cases of meningitis from the region of Dosso during 2014 and 2015. Based on a definition of epidemic signals, the effectiveness and efficiency of surveillance and vaccine response strategies were evaluated by calculating the number of potentially vaccine-preventable cases and number of vaccine doses needed per epidemic signal., Results: A total of 4763 weekly health area reports, collected in 90 health areas with 1282 suspected meningitis cases, were included. At a threshold of 10 per 100 000, the total number of estimated vaccine-preventable cases was 29 with district-level surveillance and vaccine response, 141 with health area-level surveillance and vaccination and 339 with health area-level surveillance and district-level vaccination. While being most effective, the latter strategy required the largest number of vaccine doses (1.8 million), similar to the strategy of surveillance and vaccination at district level (1.3 million), whereas the strategy of surveillance and vaccination at health area level would have required only 0.8 million doses. Thus, efficiency was lowest for district-level surveillance and highest for health area-level surveillance with district-level vaccination., Conclusion: In this analysis, we found that effectiveness and efficiency were higher at health area-level surveillance and district-level vaccination than for other strategies. Use of N. meningitidis C vaccines in a preventive strategy thus should be considered, in particular as most reactive vaccine response strategies in our analysis had little impact on disease burden., (© 2016 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Use of a polysaccharide vaccine challenge to demonstrate immunologic memory after priming with capsular group C meningococcal conjugate vaccines (MenCC) risks induction of immunologic hyporesponsiveness. For this reason, MenCC vaccines are now used as probes of immunologic memory, however, no studies have demonstrated their ability to distinguish primed from unprimed children., Methods: This study was part of a randomised controlled trial investigating the immunogenicity of a booster dose of the combined Haemophilus influenzae type b and MenC-tetanus toxoid vaccine (Hib-MenC-TT) in infants receiving reduced dose MenCC vaccine priming schedules (one MenC-CRM/MenC-TT or two MenC-CRM vaccine doses) compared with an unprimed group. Antibody kinetics were studied in a subset of 269 children by measuring changes in the MenC serum bactericidal antibody, using rabbit complement, (MenC rSBA) titres and MenC specific IgG memory B-cells before and at 6 and 28days following the 12month booster vaccination., Results: At 6days after the 12monthMenCC vaccine, the rise in MenC rSBA titres and MenC specific IgG memory B-cells of the primed groups were significantly higher than the infant MenCC naïve group. Participants primed with one MenC-TT dose had the highest increase in MenC rSBA titres compared with all other groups. The MenC rSBA titres at the 28th compared with the 6th day after boosting was significantly higher in those primed with a single MenC-TT/MenC-CRM vaccine in infancy compared with those who were not primed or who were primed with two doses of the MenC-CRM vaccine., Conclusion: Immunologic memory can be demonstrated by a MenCC booster vaccination but is affected by the type and number of MenCC doses used for infant priming. The MenC rSBA responses can be used to demonstrate successful immunologic priming., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Due to waning immunity, infant vaccination with meningococcal serogroup C conjugated (MenCC) vaccines is insufficient to maintain long-term individual protection. Adolescent booster vaccination is thought to offer direct protection against invasive meningococcal disease (IMD) but also to reduce meningococcal carriage and transmission and in this way establish herd protection in the population. Previously, we studied antibody levels after adolescent MenCC booster vaccination. In the present study, the adolescent vaccinees were revisited after three years to determine antibody persistence and to predict long-term protection., Methods: Meningococcal serogroup C tetanus toxoid conjugated (MenC-TT) vaccine was administered to 10-, 12- and 15-year old participants who had been primed nine years earlier with a single dose of MenC-TT vaccine. Blood samples were collected before, 1month, 1year and 3years after the adolescent booster vaccination. Functional antibody levels were measured with serum bactericidal assay using rabbit complement (rSBA). Meningococcal serogroup C polysaccharide and tetanus toxoid specific antibody levels were measured using fluorescent-bead-based multiplex immunoassay. Long-term protection was estimated using longitudinal multilevel antibody decay modeling., Results: Of the original 268 participants, 201 (75%) were revisited after 3years. All participants still had an rSBA titer above the protective threshold of ⩾8 and 98% ⩾128. The 15-year-olds showed the highest antibody titers. Using a bi-exponential decay model, the median time to fall below the protection threshold (rSBA titer <8) was 16.3years, 45.9years and around 270years following the booster for the 10-, 12- and 15-year-olds, respectively., Conclusions: After a first steep decline in antibody levels in the first year after the booster, antibody levels slowly declined between one and three years post-booster. A routine MenC-TT booster vaccination for adolescents in the Netherlands will likely provide long-term individual protection and potentially reduce the risk of resurgence of MenC disease in the general population., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To understand the level of bactericidal antibodies against Neisseria meningitidis and their rate of protection in children aged between 3 and 23 months, in Liuzhou, in 2012. Methods: Convenience sampling was performed in Liujiang, Rong'an and Sanjiang Counties from May through August, 2012. The inclusion criteria for 603 subjects were: Children aged between 3 and 23 months; no history of meningococcal meningitis; no vaccination against Neisseria meningitidis serogroup C; more than 30 days from the last vaccination against Neisseria meningitidis serogroup A. Demographic information and immunization history of the subjects were obtained using questionnaires. Venous blood samples (2.0 ml each) were collected and levels of Neisseria meningitides antibodies determined using a Serum Bactericidal Assay (SBA). The geometric mean titer (GMT) of serum bacterial antibodies was positive when it was greater than or equal to 1∶2 and protective when greater than 1∶8. Chi-square and Fisher's exact tests were used to compare differences in the positive and protective rates of serum antibodies of Neisseria meningitidis serogroup A and Neisseria meningitidis serogroup C, among children with different demographic characteristics. Kruskal-Wallis H test was used to compare differences in the GMT of serum antibodies of Neisseria meningitidis serogroup A and Neisseria meningitidis serogroup C, among children with different demographic characteristics. Results: Of 603 subjects, 325 (53.9%) were female and 278 (46.1%) were male; 276 (45.8%), 143 (23.7%) and 184 (30.5%) subjects were administered, respectively, no treatment, 1 dose vaccine and 2 doses vaccine. The GMT of serum antibodies against group A Neisseria meningitidis was 1∶1.11, the positive rate was 7.6% (46) and the protective rate was 2.0% (12). The GMT of antibodies in children receiving 1 vaccine dose was 1∶1.16 and the protective rate was 3.5% (5), both values higher than those in children receiving 2 vaccine doses (GMT: 1∶1.2, protective rate: 3.5% (5)). However, these differences were not statistically significant (GMT: H =0.64, P= 0.728; protective rate: Fisher's exact test, P= 0.080). The GMT of antibodies in children receiving 1 and 2 doses of meningococcal polysaccharide vaccines were 1∶1.12 and 1∶2.30, respectively (≤180 d). The GMT of serum antibodies for group C meningococcal vaccine was 1∶1.18 and its positive and protective rates were 14.6% (88) and 2.2% (13), respectively. Conclusion: Children aged between 3 and 23 months are susceptible to Neisseria meningitidis groups A and C. The immune effectiveness of group A meningococcal polysaccharide vaccine is relatively poor in this age group and their antibody levels decreased rapidly.

Conjugation of a small molecule immunopotentiator to antigens has been proposed to deliver the ligand to the receptor, localize its action and minimize systemic inflammation. However, the effect of conjugation of Toll like receptor 7 agonists (TLR7a) on the immunogenicity of carbohydrate-based vaccines is unknown. In this study we synthesized an anti-Neisseria meningitidis serogroup C (MenC) glycoconjugate vaccine composed of MenC oligosaccharide antigens covalently linked to the carrier protein CRM197, to which a TLR7a was in turn conjugated. This vaccine was able to activate in vitro the TLR7 comparably to the unconjugated ligand. The magnitude and the quality of the immune response against MenC capsular polysaccharide were evaluated in mice, comparing the MenC-CRM-TLR7a construct to a MenC-CRM197 vaccine, prepared through the same conjugation chemistry and co-administered with the unconjugated TLR7a. A commercially licensed anti-MenC glycoconjugate was used as further control to determine the influence of the coupling approach and the level of carbohydrate incorporation on the anti-MenC immune response. The possible additive effect of co-administration with Alum hydroxide (AlumOH) was also examined. The bactericidal titers against N. meningitidis were in agreement with the elicited anti-carbohydrate IgGs, and unequivocally showed that TLR7a conjugation to CRM197 enhanced the anti-MenC immune response. TLR7a conjugation induced a shift to a Th1 type response, as assessed by the increased IgG2a subclass production, both in the absence and in the presence of AlumOH. The increased immune response was clearly present only in the absence of AlumOH and was less pronounced than the co-administration of a licensed glycoconjugate with a standard dose of TLR7a-phosphonate adsorbed on the inorganic salt. The amount of MenC saccharide that was covalently linked to CRM197 after previous CRM197-TLR7a conjugation resulted in lower responses than achieved with conventional MenC-CRM197 glycoconjugation in the absence of TLR7a. As result, the benefit of the adjuvant conjugation in terms of anti-MenC immune response was jeopardized by the lower saccharide/protein ratio obtained in the MenC-CRM-TLR7a conjugate. While adsorption on AlumOH offers more flexibility in the administered dose of TLR7a, conjugation of the small molecule immunopotentiator could be particularly suited for vaccination routes such as skin delivery, where insoluble aluminum salts cannot be used because of their reactogenicity in this site., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: A 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., Methods: SCD 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., Results: For children primed under 2years of age rSBA titer ⩾8 was demonstrated in 53.3%, 21.7% and 35.0%, 2-3, 4-5, 6-8years, respectively, after vaccination, compared with 70.0%, 45.0% and 53.5%, respectively, for individuals primed at ages 2-13years. 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., Conclusion: Immunity 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.)., (Copyright © 2016 Tejedor et al.)

The degree of phosphorylation and phosphoethanolaminylation of lipid A on neisserial lipooligosaccharide (LOS), a major cell-surface antigen, can be correlated with inflammatory potential and the ability to induce immune tolerance in vitro. On the oligosaccharide of the LOS, the presence of phosphoethanolamine and sialic acid substituents can be correlated with in vitro serum resistance. In this study, we analyzed the structure of the LOS from 40 invasive isolates and 25 isolates from carriers of Neisseria meningitidis without disease. Invasive strains were classified as groups 1-3 that caused meningitis, septicemia without meningitis, and septicemia with meningitis, respectively. Intact LOS was analyzed by high resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Prominent peaks for lipid A fragment ions with three phosphates and one phosphoethanolamine were detected in all LOS analyzed. LOS from groups 2 and 3 had less abundant ions for highly phosphorylated lipid A forms and induced less TNF-α in THP-1 monocytic cells compared with LOS from group 1. Lipid A from all invasive strains was hexaacylated, whereas lipid A of 6/25 carrier strains was pentaacylated. There were fewer O-acetyl groups and more phosphoethanolamine and sialic acid substitutions on the oligosaccharide from invasive compared with carrier isolates. Bioinformatic and genomic analysis of LOS biosynthetic genes indicated significant skewing to specific alleles, dependent on the disease outcome. Our results suggest that variable LOS structures have multifaceted effects on homeostatic innate immune responses that have critical impact on the pathophysiology of meningococcal infections., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Various meningococcal conjugate vaccines exist against serogroups A, C, W and Y. A new protein-based vaccine targeting serogroup B (MenB) is also now available. The potential of such vaccines to drive serogroup replacement is considered a possible public health concern when implementing nationwide routine immunization programmes. The aim of this work was to investigate if and how serogroup replacement may occur following widespread vaccination with a MenB vaccine that may protect against carriage. To that end, we built a dynamic transmission model with age and serogroup stratification, focusing on European settings where most invasive meningococcal disease (IMD) cases are caused by serogroups B and C. For illustration purposes, the model was employed in 2 such settings: UK (England and Wales) and Czech Republic. Preliminary model-based projections suggest that, under strong serogroup competition for colonization, vaccine-induced serogroup replacement may occur even with a relatively low vaccine efficacy against serogroup B carriage (e.g., 20%), with potential subsequent increase in serogroup C IMD. The magnitude and speed of the model-projected serogroup C IMD increase depend on the MenB vaccination strategy, vaccine efficacy against carriage and the extent of any potential cross-protection against other serogroups. These analyses are neither exhaustive nor definitive, and focused on simulating potential population-level trends in IMD post-vaccination, under certain assumptions. Due to present inherent limitations and uncertainties, this study has limited quantitative value and is best regarded as an explorative qualitative modeling approach, to complement and challenge the current status quo, and suggest areas where collecting additional data may be essential.

Meningococcal serogroup C (MenC) vaccination of men who have sex with men (MSM) was temporarily recommended to control an outbreak of invasive MenC disease among MSM in Berlin in 2012-2013. Vaccination was offered to HIV-infected MSM free of charge; others had to request reimbursement or pay out of pocket. We aimed to assess (i) awareness and acceptance of this recommendation through an online survey of MSM, (ii) implementation through a survey of primary care physicians and analysis of vaccine prescriptions, and (iii) impact through analysis of notified cases. Among online survey respondents, 60% were aware of the recommendation. Of these, 39% had obtained vaccination (70% of HIV-infected, 13% of HIV-negative/non-tested MSM). Awareness of recommendation and vaccination were positively associated with HIV infection, primary care physicians' awareness of respondents' sexual orientation, and exposure to multiple information sources. Most (26/30) physicians informed clients about the recommendation. Physicians considered concerns regarding reimbursement, vaccine safety and lack of perceived disease risk as primary barriers. After the recommendation, no further outbreak-related cases occurred. To reach and motivate target groups, communication of a new outbreak-related vaccination recommendation should address potential concerns through as many information channels as possible and direct reimbursement of costs should be enabled.

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.

Background: Antibody levels wane rapidly after Meningococcal serogroup C conjugate (MenCC) vaccination in young children, rendering the need for an adolescent booster dose. It is not clear whether circulating memory B cells are associated with persistence of MenC-specific antibody levels., Methods: Measurement of MenC-specific IgG and IgA memory B cells and levels of serum and salivary MenC-specific IgG and IgA in healthy 10-, 12- and 15-year-olds prior to and one month and one year after a MenCC booster vaccination. All participants had received a primary MenCC vaccination nine years earlier., Results: The number of circulating MenC-specific IgG memory B cells prior to booster was low and not predictive for MenC-specific IgG responses in serum or saliva post-booster, whereas the number of MenC-specific IgA memory B cells pre-booster positively correlated with MenC-specific IgA levels in saliva post-booster (R = 0.5, P<0.05). The booster induced a clear increase in the number of MenC-specific IgG and IgA memory B cells. The number of MenC-PS-specific IgG memory B cells at 1 month post-booster was highest in the 12-year-olds. The number of MenC-specific memory B cells at one month post-booster showed no correlation with the rate of MenC-specific antibody decay throughout the first year post-booster., Conclusions: Circulating MenC-specific IgA memory B cells correlate with IgA responses in saliva, whereas circulating MenC-specific IgG memory B cells are not predictive for MenC-specific IgG responses in serum or saliva. Our results are suggestive for age-dependent differences in pre-existing memory against MenC.

Several outbreaks caused by Neisseria meningitidis group C have been occurred in different regions of Brazil. A conjugate vaccine for Neisseria meningitidis was produced by chemical linkage between periodate-oxidized meningococcal C polysaccharide and hydrazide-activated monomeric tetanus toxoid via a modified reductive amination conjugation method. Vaccine safety and immunogenicity tested in Phase I and II trials showed satisfactory results. Before starting Phase III trials, vaccine production was scaled up to obtain industrial lots under Good Manufacture Practices (GMP). Comparative analysis between data obtained from industrial and pilot scales of the meningococcal C conjugate bulk showed similar execution times in the scaling up production process without significant losses or alterations in the quality attributes of purified compounds. In conclusion, scale up was considered satisfactory and the Brazilian meningococcal conjugate vaccine production aiming to perform Phase III trials is feasible., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In September 2012, the New York City Department of Health and Mental Hygiene identified an outbreak of Neisseria meningitidis serogroup C invasive meningococcal disease among men who have sex with men (MSM). Twenty-two case-patients and 7 deaths were identified during August 2010-February 2013. During this period, 7 cases in non-MSM were diagnosed. The slow-moving outbreak was linked to the use of websites and mobile phone applications that connect men with male sexual partners, which complicated the epidemiologic investigation and prevention efforts. We describe the outbreak and steps taken to interrupt transmission, including an innovative and wide-ranging outreach campaign that involved direct, internet-based, and media-based communications; free vaccination events; and engagement of community and government partners. We conclude by discussing the challenges of managing an outbreak affecting a discrete community of MSM and the benefits of using social networking technology to reach this at-risk population.

Background: In 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., Aim: To 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., Methods: Nine 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., Results: Before 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., Conclusion: Parenteral 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)