Seroprevalence of meningococcal serogroup C bactericidal antibodies in the Portuguese population, a decade after vaccine introduction in the National Immunisation Programme.

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.

Enfermedad meningocócica invasiva por serogrupo C en la era posvacunal y fallos vacunales / Serogroup C invasive meningococcal disease in the post-vaccine era and vaccine failures

INTRODUCCIÓN: La incidencia de la enfermedad meningocócica invasiva (EMI) por serogrupo C ha disminuido desde la introducción de la vacunación sistemática el año 2000. El objetivo de este estudio es determinar los casos de EMI diagnosticados desde entonces y los fallos vacunales en los casos por serogrupo C. PACIENTES Y MÉTODOS: Análisis retrospectivo de pacientes diagnosticados de EMI confirmada por cultivo o reacción en cadena de la polimerasa, en un hospital infantil de tercer nivel de Barcelona, entre 2001 y 2018. Se analizó el número de dosis de vacuna recibidas y la edad, recogidos de la historia clínica y del carnet de vacunaciones. RESULTADOS: Se confirmaron 128 casos de EMI (7,1 casos/año; 70,3% en < 5 años). Se estudió el serogrupo en 125 casos (97,6%): 103 fueron B (82,4%), 10 fueron C (8%), uno fue 29E (0,8%) y uno fue Y (0,8%); solo 10 (8%) no fueron serogrupables. De los 10 pacientes con serogrupo C, 4 no estaban vacunados y en 3 la pauta fue incompleta en cuanto a número de dosis; 3 de ellos recibieron la pauta completa según la edad y el calendario vacunal vigente, por lo que se consideran fallos vacunales. Fallecieron 6 pacientes (tasa de letalidad: 4,7%): 5 por serogrupo B (letalidad: 4,8%) y uno por serogrupo C (letalidad: 10%). CONCLUSIONES: El serogrupo C representó solo el 8% de los casos de EMI en el periodo de estudio y los fallos vacunales de este serogrupo fueron del 30%

INTRODUCTION: The incidence of serogroup C invasive meningococcal disease (IMD) has decreased since the introduction of systematic vaccination in 2000. The aim of this study is to determine the number of serogroup C IMD cases diagnosed since then and the vaccine failures. PATIENTS AND METHODS: A retrospective analysis was performed on patients diagnosed with IMD by culture or polymerase chain reaction (PCR) in a maternity and childhood hospital in Barcelona between 2001 and 2018. An analysis was made of the number of vaccine doses and the age received, as well as on the medical records and vaccine cards. RESULTS: There were 128 confirmed cases of IMD (7.1 cases/year; 70.3 in < 5 years). The serogroup was studied in 125 (97.6%) cases, in which 103 (82.4%) were B, 10 (8%) were C, one (0.8%) was 29E, and one (0.8%) was Y, and only 10 (8%) were not able to be serogrouped. Of the 10 patients with serogroup C, 4 were not vaccinated, and in 3, the course was not complete as regards the number of doses. The other 3 received the complete course according to age and current calendar, and thus were considered vaccine failures. A total of 6 patients died (mortality rate: 4.7%), 5 due to serogroup B (mortality: 4.8%), and one due to serogroup C (mortality: 10%). CONCLUSIONS: Serogroup C only represented 8% of IMD cases in the period studied, with 30% of cases due to this serogroup being vaccine failures

An Update on Meningococcal Vaccination.

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.

Episodio maníaco tras la administración simultánea de 4 vacunas: relación temporal frente a relación causal. A propósito de un caso / Manic episode after the simultaneous administration of 4 vaccines: temporal relationship versus causal relationship. A case report

Ante un cambio radical en el comportamiento en un varón de 17 años, a las 12 horas de administrar, en el mismo día, las vacunas contra el Meningococo C, Hepatitis B, Triple Vírica y Varicela, y la detección de un cuadro maníaco a la semana, se sospechó que se tratase de un cuadro de encefalitis post-vacunal. A pesar de la ausencia de hallazgos patológicos en las exploraciones complementarias realizadas, y aunque en la literatura científica no se haya demostrado una asociación temporal a día de hoy, no podemos aceptar ni descartar con certeza la sospecha diagnóstica dado que no contamos con la serología infecciosa o un estudio de anticuerpos en líquido cefalorraquídeo. Los efectos secundarios graves tras vacunaciones no han quedado claramente demostrados, lo que sí está ampliamente demostrado es que la inmunidad adquirida es uno de los mayores logros de la medicina que ha ayudado a erradicar enfermedades potencialmente mortales

A radical behavioral change was observed in a 17-year-old male 12 hours after having received vaccines for Meningococcus C, Hepatitis B, Triple Viral and Varicella on the same day. Moreover a manic episode was detected one week later. It was suspected that this was a case of post-vaccinal encephalitis. In spite of the absence of pathological findings in the complementary explorations carried out and although a temporal association has not been demonstrated to date in the scientific literature, we can not be certain of this diagnostic suspicion since we do not have the infectious serology or a study of antibodies in central spinal fluid. Serious side effects after vaccinations have never been clearly demonstrated, while it has been widely demonstrated that the acquired immunity from these vaccines is one of the greatest achievements of medicine, and this has helped to eradicate life-threatening diseases

Higher mass meningococcal group C-tetanus toxoid vaccines conjugated with carbodiimide correlate with greater immunogenicity.

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.

Molecular surveillance of brazilian meningococcal isolates serogroup c in the pre and post-men-c-vaccination period: Emergence of ST-3780.

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.

Spatiotemporal Analysis of Serogroup C Meningococcal Meningitis Spread in Niger and Nigeria and Implications for Epidemic Response.

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.

Development and pre-clinical evaluation of a synthetic oligosaccharide-protein conjugate vaccine against Neisseria meningitidis serogroup C.

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.

Immunogenicity and Safety of a Quadrivalent Meningococcal ACWY-tetanus Toxoid Conjugate Vaccine 6 Years After MenC Priming as Toddlers.

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).

Development of meningococcal polysaccharide conjugate vaccine that can elicit long-lasting and strong cellular immune response with hepatitis B core antigen virus-like particles as a novel carrier protein.

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.

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

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

Use of saliva to monitor meningococcal vaccine responses: proposing a threshold in saliva as surrogate of protection.

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.

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

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

Development of a measure to assess vaccine confidence among men who have sex with men.

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.

Meningococcus serogroup C clonal complex ST-10217 outbreak in Zamfara State, Northern Nigeria.

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 21st 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.

Interconnected clusters of invasive meningococcal disease due to Neisseria meningitidis serogroup C ST-11 (cc11), involving bisexuals and men who have sex with men, with discos and gay-venues hotspots of transmission, Tuscany, Italy, 2015 to 2016.

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.

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

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.

Role of O-Acetylation in the Immunogenicity of Bacterial Polysaccharide Vaccines.

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.

Induction of salivary antibody levels in Dutch adolescents after immunization with monovalent meningococcal serogroup C or quadrivalent meningococcal serogroup A, C, W and Y conjugate vaccine.

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.