Aceptación y desigualdades socioeconómicas en la vacunación frente a meningococo B en la Comunidad de Madrid en el periodo anterior a su inclusión en el calendario / Acceptance and socioeconomic inequalities in meningococcal B vaccination in the community of Madrid prior to its inclusion in the immunization schedule

Introducción: La principal medida de prevención frente a la enfermedad meningocócica invasiva es la vacunación. El objetivo de este estudio es evaluar la aceptabilidad y las desigualdades socioeconómicas en el acceso a la vacuna frente a meningococo B (MenB) en la Comunidad de Madrid en el periodo previo a la introducción de la misma en el calendario. Materiales y métodos: Se realizó un estudio observacional descriptivo en la cohorte de niños/as nacidos entre 2016 y 2019, de tipo ecológico, empleando registros poblacionales electrónicos. Se describieron las coberturas de vacunación, se analizaron los factores asociados al estado vacunal, se describieron las distribuciones espaciales de cobertura de vacunación y de índice de privación (IP) y se analizó la asociación entre ambas mediante regresión espacial. Resultados: Se observó una tendencia creciente de las coberturas de primovacunación, pasando de un 44% en la cohorte de nacidos en el año 2016 a un 68% en la cohorte de 2019. Se encontró asociación estadísticamente significativa entre el estado vacunal y el IP (OR de primovacunación en zonas con IP5 respecto a zonas con IP1: 0,38; IC 95%: 0,39-0,50; p<0,001). El análisis espacial mostró correlación inversa entre el IP y la cobertura de vacunación. Conclusiones: El ascenso de las coberturas de esta vacuna muestra aceptación por parte de la población. La relación entre nivel socioeconómico y cobertura de vacunación confirma la existencia de una desigualdad en salud, y subraya la importancia de su inclusión en el calendario.(AU)

Introduction: The main preventive measure against invasive meningococcal disease is vaccination. The aim of our study was to evaluate the acceptability of the meningococcal B (MenB) vaccine and socioeconomic inequalities in the access to the vaccine in the Community of Madrid in the period prior to its introduction in the immunization schedule. Materials and methods: We conducted an observational and ecological descriptive study in the cohort of children born between 2016 and 2019 using population-based electronic records. We calculated the vaccination coverage and analysed factors associated with vaccination status, determined the spatial distribution of vaccination coverage and the deprivation index (DI) and assessed the association between them by means of spatial regression. Results: We observed an increasing trend in primary vaccination coverage, from 44% in the cohort born in 2016 to 68% in the 2019 cohort. We found a statistically significant association between vaccination status and the DI (OR of primary vaccination in areas with DI5 compared to areas with DP1, 0.38; 95% confidence interval: 0.39-0.50; P<.001). The spatial analysis showed an inverse correlation between the DI and vaccination coverage. Conclusions: The rise in the coverages of the MenB vaccine shows acceptance by the population. The association between socioeconomic level and vaccination coverage confirms the existence of health inequality and underlines the importance including this vaccine in the immunization schedule.(AU)

Acute kidney injury in a mouse model of meningococcal disease.

INTRODUCTION: Meningococcal disease is associated with high mortality. When acute kidney injury (AKI) occurs in patients with severe meningococcal disease, it is typically attributable to sepsis, although meningococcal disease and lipopolysaccharide release are rarely investigated. Therefore, we evaluated renal tissue in a mouse model of meningococcal disease. METHODS: Female BALB/c mice were induced to AKI by meningococcal challenge. Markers of renal function were evaluated in infected and control mice. RESULTS: In the infected mice, serum concentrations of tumor necrosis factor alpha, interferon gamma, interleukins (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12), and granulocyte-macrophage colony-stimulating factor were elevated, as was renal interstitial infiltration with lymphocytes and neutrophils (p < 0.01 for the latter). Histological analysis showed meningococcal microcolonies in the renal interstitium, without acute tubular necrosis. Infected mice also showed elevated renal expression of toll-like receptor 2, toll-like receptor 4, and Tamm-Horsfall protein. The expression of factors in the intrinsic pathway of apoptosis was equal to or lower than that observed in the control mice. Urinary sodium and potassium were also lower in infected mice, probably due to a tubular defect. CONCLUSION: Our findings corroborate those of other studies of AKI in sepsis. To our knowledge, this is the first time that meningococci have been identified in renal interstitium and that the resulting apoptosis and inflammation have been evaluated. However, additional studies are needed in order to elucidate the mechanisms involved.

Intracluster correlation coefficients in a large cluster randomized vaccine trial in schools: Transmission and impact of shared characteristics.

Cluster randomized trials (cRCT) to assess vaccine effectiveness incorporate indirect effects of vaccination, helping to inform vaccination policy. To calculate the sample size for a cRCT, an estimate of the intracluster correlation coefficient (ICC) is required. For infectious diseases, shared characteristics and social mixing behaviours may increase susceptibility and exposure, promote transmission and be a source of clustering. We present ICCs from a school-based cRCT assessing the effectiveness of a meningococcal B vaccine (Bexsero, GlaxoSmithKline) on reducing oropharyngeal carriage of Neisseria meningitidis (Nm) in 34,489 adolescents from 237 schools in South Australia in 2017/2018. We also explore the contribution of shared behaviours and characteristics to these ICCs. The ICC for carriage of disease-causing Nm genogroups (primary outcome) pre-vaccination was 0.004 (95% CI: 0.002, 0.007) and for all Nm was 0.007 (95%CI: 0.004, 0.011). Adjustment for social behaviours and personal characteristics reduced the ICC for carriage of disease-causing and all Nm genogroups by 25% (to 0.003) and 43% (to 0.004), respectively. ICCs are also reported for risk factors here, which may be outcomes in future research. Higher ICCs were observed for susceptibility and/or exposure variables related to Nm carriage (having a cold, spending ≥1 night out socializing or kissing ≥1 person in the previous week). In metropolitan areas, nights out socializing was a highly correlated behaviour. By contrast, smoking was a highly correlated behaviour in rural areas. A practical example to inform future cRCT sample size estimates is provided.

Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals.

Dysregulation of complement activation causes a number of diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. These conditions can be treated with monoclonal antibodies (mAbs) that bind to the complement component C5 and prevent formation of the membrane attack complex (MAC). While MAC is involved in uncontrolled lysis of erythrocytes in these patients, it is also required for serum bactericidal activity (SBA), i.e. clearance of encapsulated bacteria. Therefore, terminal complement blockage in these patients increases the risk of invasive disease by Neisseria meningitidis more than 1000-fold compared to the general population, despite obligatory vaccination. It is assumed that alternative instead of terminal pathway inhibition reduces the risk of meningococcal disease in vaccinated individuals. To address this, we investigated the SBA with alternative pathway inhibitors. Serum was collected from adults before and after vaccination with a meningococcal serogroup A, C, W, Y capsule conjugate vaccine and tested for meningococcal killing in the presence of factor B and D, C3, C5 and MASP-2 inhibitors. B meningococci were not included in this study since the immune response against protein-based vaccines is more complex. Unsurprisingly, inhibition of C5 abrogated killing of meningococci by all sera. In contrast, both factor B and D inhibitors affected meningococcal killing in sera from individuals with low, but not with high bactericidal anti-capsular titers. While the anti-MASP-2 mAb did not impair SBA, inhibition of C3 impeded meningococcal killing in most, but not in all sera. These data provide evidence that vaccination can provide protection against invasive meningococcal disease in patients treated with alternative pathway inhibitors.

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.

Intranasal immunization with a rNMB0315 and combination adjuvants induces protective immunity against Neisseria meningitidis serogroup B in mice.

Neisseria meningitidis (N. meningitidis) is a human-specific pathogen and a major cause of meningitis and septicemia with a high case fatality rate. N. meningitidis may penetrate the nasopharyngeal mucosal membrane and cause severe meningitis, a mucosal immune response plays a key role in the defense against meningococcal infections. Our previous study demonstrated that N. meningitidis serogroup B 0315 (NMB0315) was a vaccine candidate against N. meningitidis serogroup B (NMB) through parenteral immunization. In this study, immunopotentiators (C48/80 or CpG-ODN) were loaded into chitosan nanoparticle (Chi NP) to form combination adjuvants (Chi-CpG NP and Chi-C48/80 NP) and adopted to enhance the immunogenicity of NMB0315 through intranasal immunization. The experimental results have indicated that both Chi-CpG NP and Chi-C48/80 NP are effective mucosal adjuvants for the induction of significantly higher rNMB0315-specific IgG, IgG1, IgG2a and sIgA antibodies. Meanwhile, Chi-CpG NP and Chi-C48/80 NP could change the ratio of IgG1/IgG2a, inducing a more balanced cellular/humoral immune response. Chi-CpG NP and Chi-C48/80 NP also boosted interleukin-4 (IL-4), interferon-γ (IFN-γ) and interleukin-17 A (IL-17A) production by splenocytes. The bactericidal antibodies have been detected in sera from mice immunized with rNMB0315 + Chi-CpG NP and rNMB0315 + Chi-C48/80 NP. Overall, the combination adjuvants could be applicable to the development of a mucosal vaccine against NMB.

Use of Cost-Effectiveness Analyses for Decisions About Vaccination Programs for Meningococcal Disease in the United States, United Kingdom, The Netherlands, and Canada.

INTRODUCTION: Meningococcal vaccines to protect against invasive meningococcal disease (IMD) vary in terms of vaccine technology and serogroup coverage (Polysaccharide MnACWY, conjugated C and ACWY, outer membrane vesicle-based or protein-based B vaccines), and the national recommendations for each of them vary in terms of target population and number of doses. We sought to understand factors associated with the evolution of meningococcal vaccination program recommendations in four countries with formal evaluation processes: the UK, US, the Netherlands, and Canada. AREAS COVERED: A targeted review of published literature and internet sources for the four countries relating to meningococcal vaccination decision-making was conducted. The review focused on the impact of cost-effectiveness analyses on vaccine policy decisions and the extent to which variation in incidence of IMD and its potential catastrophic consequences influenced policy decisions.The evolution of meningococcal vaccine recommendations in the four countries was mainly driven by changes in vaccine availability and changes in serogroup incidence. Public pressure due to the catastrophic nature of IMD influenced recommendations. The role of cost-effectiveness analyses varied across the 4 countries. EXPERT OPINION: The value of implementing meningococcal vaccination programs should be assessed using factors beyond those included in traditional cost-effectiveness analyses.

Outer membrane vesicle vaccines.

Outer Membrane Vesicles (OMV) have received increased attention in recent years as a vaccine platform against bacterial pathogens. OMV from Neisseria meningitidis serogroup B have been extensively explored. Following the success of the MeNZB OMV vaccine in controlling an outbreak of N. meningitidis B in New Zealand, additional research and development resulted in the licensure of the OMV-containing four-component 4CMenB vaccine, Bexsero. This provided broader protection against multiple meningococcal B strains. Advances in the field of genetic engineering have permitted further improvements in the platform resulting in increased yields, reduced endotoxicity and decoration with homologous and heterologous antigens to enhance immuno genicity and provide broader protection. The OMV vaccine platform has been extended to many other pathogens. In this review, we discuss progress in the development of the OMV vaccine delivery platform, highlighting successful applications, together with potential challenges and gaps.

Genomic surveillance of Neisseria meningitidis serogroup B invasive strains: Diversity of vaccine antigen types, Brazil, 2016-2018.

BACKGROUND: Neisseria meningitidis serogroup B remains a prominent cause of invasive meningococcal disease (IMD) in Brazil. Because two novel protein-based vaccines against serogroup B are available, the main purpose of this study was to provide data on the diversity and distribution of meningococcal vaccine antigen types circulating in Brazil. METHODOLOGY: Genetic lineages, vaccine antigen types, and allele types of antimicrobial-associated resistance genes based on whole-genome sequencing of a collection of 145 Neisseria meningitidis serogroup B invasive strains recovered in Brazil from 2016 to 2018 were collected. RESULTS: A total of 11 clonal complexes (ccs) were identified among the 145 isolates, four of which were predominant, namely, cc461, cc35, cc32, and cc213, accounting for 72.0% of isolates. The most prevalent fHbp peptides were 24 (subfamily A/variant 2), 47 (subfamily A/variant 3), 1 (subfamily B/variant 1) and 45 (subfamily A/variant 3), which were predominantly associated with cc35, cc461, cc32, and cc213, respectively. The NadA peptide was detected in only 26.2% of the isolates. The most frequent NadA peptide 1 was found almost exclusively in cc32. We found seven NHBA peptides that accounted for 74.5% of isolates, and the newly described peptide 1390 was the most prevalent peptide exclusively associated with cc461. Mutated penA alleles were detected in 56.5% of the isolates, whereas no rpoB and gyrA mutant alleles were found. CONCLUSION: During the study period, changes in the clonal structure of circulating strains were observed, without a predominance of a single hyperinvasive lineage, indicating that an epidemiologic shift has occurred that led to a diversity of vaccine antigen types in recent years in Brazil.

Coletiva de imprensa: anúncios do Governo SP - 02/10/2020

O Governador João Doria anunciou nesta sexta-feira (2) o início da Campanha de Vacinação de Poliomielite e Multivacinação a partir da próxima segunda-feira (5). O objetivo é atualizar a carteirinha de vacinação de crianças e adolescentes entre 0 e 14 anos de idade, reforçando a proteção contra paralisia infantil (polio) nos menores de 5 anos. “É de extrema importância que todos estejam atentos à imunização e façam uso desta facilidade que o Governo do Estado, através da Secretaria de Saúde e das Secretarias Municipais de Saúde, oferecem gratuitamente à população de São Paulo. A vacinação é o meio mais eficaz e seguro de proteção contra doenças graves”, afirmou Doria. Para garantir a prevenção contra a poliomielite, pais ou responsáveis por crianças entre 1 ano a menores de 5 anos deverão levar os pequenos para receber a “gotinha” (vacina oral, VOP). A meta é alcançar cobertura vacinal de 95% de um total de 2,2 milhões de crianças (ou seja, pelo menos 2,1 milhões). A revacinação contribui com a redução do risco de reintrodução do vírus no Brasil – hoje, há circulação no Afeganistão e Paquistão. Simultaneamente, a campanha de multivacinação será focada na atualização de carteiras vacinais de crianças e adolescentes de 0 a 14 anos. A finalidade é que pessoas nessa faixa etária recebam doses de vacinas importantes e que podem estar pendentes, garantindo assim a devida proteção contra vírus que circulam no território. “Estas campanhas foram criadas justamente para incentivar a ida aos postos de saúde e, assim, garantir a proteção adequada”, afirma o Secretário de Estado da Saúde, Jean Gorinchteyn. Os pais ou responsáveis devem levar as crianças a um dos 5 mil postos de saúde localizados nos municípios de SP com a carteira de vacinação em mãos para que um profissional avalie quais doses precisarão ser aplicadas, tanto para eventual situação de atraso, falta ou necessidade de reforço. A medida contribui para melhorar as coberturas vacinais, que têm oscilado nos últimos anos. No total, serão oferecidas 14 tipos de vacinas que protegem contra cerca de 20 doenças: BCG (tuberculose); rotavírus (diarreia); poliomelite oral e intramuscular (paralisia infantil); pentavalente (difteria, tétano, coqueluche, hepatite B, Haemophilus influenza tipo b – Hib); pneumocócica; meningocócica; DTP; tríplice viral (sarampo, caxumba e rubéola); HPV (previne o câncer de colo de útero e verrugas genitais); além das vacinas contra febre amarela, varicela e hepatite A. Além disso, neste ano, também passou a integrar o SUS uma nova vacina, já inserida na campanha: Meningo ACWY, que protege contra meningite e infecções generalizadas, causadas pela bactéria meningococo dos tipos A, C, W e Y. Somando todos os tipos de vacinas, são mais de 5,2 milhões distribuídas nos postos do estado para aplicação na população-alvo. Serão mobilizados cerca de 30 mil profissionais de saúde até o dia 30 de outubro, prazo definido pelo Ministério da Saúde na campanha nacional. O Dia de Mobilização (“Dia D”) será 17 de outubro, com postos abertos no sábado. “A imunização correta garante a proteção contra complicações provocadas por diferentes tipos de vírus e, consequentemente, reduz casos e mortes. As campanhas contribuem para erradicação e para a eliminação do risco de reintrodução de doenças no território”, explica a diretora de Imunização da Secretaria, Núbia Araújo. A tabela completa com relação das vacinas, faixas etárias previstas para receber as doses e dados de cobertura está disponível no link: https://www.saopaulo.sp.gov.br/wp-content/uploads/2020/10/tabelavacinacao.pdf. No geral, são indicadas coberturas vacinais de 90% e 95% para proteção efetiva da população, mas tais índices não têm sido atingidos devido à baixa adesão. Alguns exemplos de cobertura inferior registrada em 2019, conforme dados disponíveis em sistema do PNI (Programa Nacional de Imunizações) são: menincoccócica C (87,28%), pentavalente (71,77%), poliomielite (86,16%), e tríplice viral (91,37% na primeira dose e 82% na segunda dose). Os dados preliminares de 2020, até agosto, indicam a importância de melhorar os índices. “Temos acompanhado os dados da cobertura vacinal em todo o estado e estamos em alerta com os baixos alcances. A Campanha de Multivacinação será um auxílio para aumentarmos a proteção e minimizarmos as chances de que as doenças retornem. Nosso objetivo é que o Estado de São Paulo tenha a maior cobertura vacinal entre os estados do país”, ressalta a coordenadora do Programa Estadual de Vacinação, Helena Sato.

Immunological fingerprint of 4CMenB recombinant antigens via protein microarray reveals key immunosignatures correlating with bactericidal activity.

Serogroup B meningococcus (MenB) is a leading cause of meningitis and sepsis across the world and vaccination is the most effective way to protect against this disease. 4CMenB is a multi-component vaccine against MenB, which is now licensed for use in subjects >2 months of age in several countries. In this study, we describe the development and use of an ad hoc protein microarray to study the immune response induced by the three major 4CMenB antigenic components (fHbp, NHBA and NadA) in individual sera from vaccinated infants, adolescents and adults. The resulting 4CMenB protein antigen fingerprinting allowed the identification of specific human antibody repertoire correlating with the bactericidal response elicited in each subject. This work represents an example of epitope mapping of the immune response induced by a multicomponent vaccine in different age groups with the identification of protective signatures. It shows the high flexibility of this microarray based methodology in terms of high-throughput information and minimal volume of biological samples needed.

Antibody persistence following meningococcal ACWY conjugate vaccine licensed in the European Union by age group and vaccine.

INTRODUCTION: Meningococcal disease caused by Neisseria meningitidis is a major cause of meningitis and septicemia with high rates of morbidity and mortality worldwide. MenACWY-TT and MenACWY-CRM197 are meningococcal conjugate vaccines approved for use in children and adults in the UK. The aim of this review was to evaluate and compare antibody responses and persistence in different age groups after MenACWY-TT and MenACWY-CRM197. AREAS COVERED: Randomized trials showed that MenACWY-TT is immunogenic at all ages. MenACWY-CRM197 is immunogenic for infants and adults, but there is a lack of data for children aged 1 to 2 years. Studies on MenACWY-TT indicated that serum bactericidal antibody (SBA) utilizing baby rabbit complement (rSBA) titers were significantly higher and more stable than SBA using human complement (hSBA) titers, compared with hSBA titers, which were lower and declined more rapidly by 1 year following post-primary MenACWY-TT and MenACWY-CRM197 vaccination, especially for MenA. EXPERT OPINION: MenACWY-TT and MenACWY-CRM197 are both well tolerated and induce similar antibody persistence and immunogenicity against all four serogroups for individuals more than one year old. rSBA assay is a more robust assay than the hSBA assay when vaccinating with MenACWY-TT, while rSBA and hSBA assays had similar antibody persistence when vaccinating with MenACWY-CRM197.

Safety and Immunogenicity of a Quadrivalent Meningococcal Conjugate Vaccine in Healthy Meningococcal-Naïve Children 2-9 Years of Age: A Phase III, Randomized Study.

BACKGROUND: Invasive meningococcal disease is a major cause of meningitis in children. An investigational meningococcal (serogroups A, C, Y, and W) tetanus toxoid conjugate vaccine (MenACYW-TT) could offer protection against invasive meningococcal disease in this population. This phase III study assessed the immunogenicity and safety of MenACYW-TT in children compared with a licensed quadrivalent meningococcal vaccine conjugated with diphtheria protein CRM197 (MenACWY-CRM). METHODS: Healthy children 2-9 years of age in the United States, including Puerto Rico, were randomized (1:1) to receive MenACYW-TT (n = 499) or MenACWY-CRM (n = 501) (NCT03077438). Meningococcal antibody titers to the 4 vaccine serogroups were measured using a serum bactericidal antibody assay with human complement (hSBA) before and at day 30 after vaccination. Noninferiority between the vaccine groups was assessed by comparing seroresponse rates (postvaccination titers ≥1:16 when prevaccination titers were <1:8, or ≥4-fold increase if prevaccination titers were ≥1:8) to the 4 serogroups at day 30. Safety was monitored. RESULTS: The proportion of participants achieving seroresponse at day 30 in the MenACYW-TT group was noninferior to the MenACWY-CRM group (A: 55.4% vs. 47.8%; C: 95.2% vs. 47.8%; W: 78.8% vs. 64.1%; Y: 91.5% vs. 79.3%, respectively). Geometric mean titers for serogroups C, W, and Y were higher with MenACYW-TT than for MenACWY-CRM. Both vaccines were well-tolerated and had similar safety profiles. CONCLUSIONS: MenACYW-TT was well-tolerated in children and achieved noninferior immune responses to MenACWY-CRM against each of the 4 vaccine serogroups.

Difference in virulence between Neisseria meningitidis serogroups W and Y in transgenic mice.

BACKGROUND: Neisseria meningitidis serogroups W and Y are the most common serogroups causing invasive meningococcal disease in Sweden. The majority of cases are caused by the serogroup W UK 2013 strain of clonal complex (cc) 11, and subtype 1 of the serogroup Y, YI strain of cc23. In this study, virulence factors of several lineages within cc11 and cc23 were investigated in transgenic BALB/c mice expressing human transferrin. Transgenic mice were infected intraperitoneally with serogroup W and Y isolates. Levels of bacteria and the proinflammatory cytokine CXCL1 were determined in blood collected 3 h and 24 h post-infection. Apoptosis was investigated in immune cells from peritoneal washes of infected mice. Adhesion and induction of apoptosis in human epithelial cells were also scored. RESULTS: The levels of bacteraemia, CXCL1, and apoptosis were higher in serogroup W infected mice than in serogroup Y infected mice. Serogroup W isolates also induced higher levels of apoptosis and adhesion in human epithelial cells. No significant differences were observed between different lineages within cc11 and cc23. CONCLUSIONS: N. meningitidis Serogroup W displayed a higher virulence in vivo in transgenic mice, compared to serogroup Y. This was reflected by higher bacteremia, proinflammatory activity, and ability to induce apoptosis in mouse immune cells and human epithelial cells.

Meningococcal factor H binding protein as immune evasion factor and vaccine antigen.

Factor H binding protein (fHbp) is a key virulence factor of Neisseria meningitidis and a main component of the two licensed vaccines against serogroup B meningococcus (Bexsero and Trumenba). fHbp is a surface-exposed lipoprotein that enables the bacterium to survive in human blood by binding the human complement regulator factor H (fH). When used as vaccine, the protein induces antibodies with potent bactericidal activity. While the fHbp gene is present in the majority of N. meningitidis serogroup B isolates, the expression level varies up to 15 times between different strains and more than 700 different sequence variants have been described. Antigenically, the protein has been divided into three variants or two subfamilies. The 3D structure of fHbp alone, in combination with fH or in complex with bactericidal antibodies, has been key to understanding the molecular details of the protein. In this article, we will review the biochemical and immunological properties of fHbp, and its key role in meningococcal pathogenesis, complement regulation, and immune evasion.

Serogroup A meningococcal conjugate vaccines: building sustainable and equitable vaccine strategies.

INTRODUCTION: For well over 100 years, meningococcal disease due to serogroup A Neisseria meningitidis (MenA) has caused severe epidemics globally, especially in the meningitis belt of sub-Saharan Africa. AREAS COVERED: The article reviews the background and identification of MenA, the global and molecular epidemiology of MenA, and the outbreaks of MenA in the African meningitis belt. The implementation (2010) of an equitable MenA polysaccharide-protein conjugate vaccine (PsA-TT, MenAfriVac) and the strategy to control MenA in sub-Saharan Africa is described. The development of a novel multi-serogroup meningococcal conjugate vaccine (NmCV-5) that includes serogroup A is highlighted. The PubMed database (1996-2019) was searched for studies relating to MenA outbreaks, vaccine, and immunization strategies; and the Neisseria PubMLST database of 1755 MenA isolates (1915-2019) was reviewed. EXPERT OPINION: Using strategies from the successful MenAfriVac campaign, expanded collaborative partnerships were built to develop a novel, low-cost multivalent component meningococcal vaccine that includes MenA. This vaccine promises greater sustainability and is directed toward global control of meningococcal disease in the African meningitidis belt and beyond. The new WHO global roadmap addresses the continuing problem of bacterial meningitis, including meningococcal vaccine prevention, and provides a framework for further reducing the devastation of MenA.

Understanding immunogenicity assessments for meningococcal serogroup B vaccines.

Invasive meningococcal disease (IMD) is a potentially devastating infection associated with high mortality and long-term sequelae; however, vaccines are available to protect against the five common disease-causing serogroups (A, B, C, W, and Y). Because traditional field efficacy clinical trials were not feasible due to low IMD incidence that necessitates a very large number of participants, serum bactericidal antibody (SBA) assays using rabbit (rSBA) or human (hSBA) complement were established as in vitro surrogates of meningococcal vaccine efficacy and are now routinely used to support vaccine licensure. Specifically, rSBA assays have been used to evaluate responses to meningococcal capsular polysaccharide-protein conjugate vaccines against serogroups A, C, W, and Y; the accepted correlate of protection for rSBA assays is a titer ≥1:8. Importantly, because the bacterial capsular polysaccharide antigen is conserved across strains, only one test strain that expresses an invariant polysaccharide capsule for each serogroup is required to assess coverage. rSBA assays are unsuitable for subcapsular protein-based serogroup B (MenB) vaccines, and therefore, hSBA assays have been used for licensure; titers ≥1:4 are considered the correlate of protection against IMD for hSBA. In contrast to MenACWY vaccines, because bacterial surface proteins are antigenically variable, MenB vaccines must be tested with hSBA assays using multiple test strains that represent the antigenic diversity of disease-causing isolates. As this complexity regarding SBA assessment methods can make data interpretation difficult, herein we describe the use of hSBA assays to evaluate MenB vaccine efficacy and to support licensure. In addition, we highlight how the two recently approved MenB vaccines differ in their use of hSBA assays in clinical studies to demonstrate broad protection against MenB IMD.

Human genetics of meningococcal infections.

Neisseria meningitidis is a leading cause of bacterial septicaemia and meningitis worldwide. Meningococcal disease is rare but can be life threatening with a tendency to affect children. Many studies have investigated the role of human genetics in predisposition to N. meningitidis infection. These have identified both rare single-gene mutations as well as more common polymorphisms associated with meningococcal disease susceptibility and severity. These findings provide clues to the pathogenesis of N. meningitidis, the basis of host susceptibility to infection and to the aetiology of severe disease. From the multiple discoveries of monogenic complement deficiencies to the associations of complement factor H and complement factor H-related three polymorphisms to meningococcal disease, the complement pathway is highlighted as being central to the genetic control of meningococcal disease. This review aims to summarise the current understanding of the host genetic basis of meningococcal disease with respect to the different stages of meningococcal infection.

Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms.

Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea, while Neisseria meningitidis is an important cause of bacterial meningitis and sepsis. Complement is a central arm of innate immune defenses and plays an important role in combating Neisserial infections. Persons with congenital and acquired defects in complement are at a significantly higher risk for invasive Neisserial infections such as invasive meningococcal disease and disseminated gonococcal infection compared to the general population. Of note, Neisseria gonorrhoeae and Neisseria meningitidis can only infect humans, which in part may be related to their ability to evade only human complement. This review summarizes the epidemiologic and clinical aspects of Neisserial infections in persons with defects in the complement system. Mechanisms used by these pathogens to subvert killing by complement and preclinical studies showing how these complement evasion strategies may be used to counteract the global threat of meningococcal and gonococcal infections are discussed.

Safety of MenACWY-CRM vaccine exposure during pregnancy.

BACKGROUND: Although the meningococcal conjugate MenACWY-CRM vaccine is not approved for use in pregnant women, unintentional exposure during pregnancy can occur, especially during early pregnancy among women of child-bearing age. This study provides safety information about inadvertent MenACWY-CRM vaccination during pregnancy. METHODS: The evaluated population consisted of pregnant female members of Kaiser Permanente Southern California who inadvertently received MenACWY-CRM at 11-21 years of age during 09/30/2011-06/30/2013 within 28 days prior to conception or during pregnancy. Chart abstraction was conducted to identify pregnancy and birth outcomes, including spontaneous and induced abortions, preterm births, low weight births, and major congenital malformations (MCMs). RESULTS: There were 92 women who received MenACWY-CRM during the pregnancy exposure period, mainly during the first trimester (76.1%). Hispanics represented the largest race/ethnicity category (68.5%). Among the known pregnancy outcomes (n = 66; excluding induced abortions and unknown pregnancy outcomes), the prevalence of spontaneous abortions was 18.2% (n = 12). Among live born infants (n = 55; from 54 pregnancies), 14.5% (n = 8) were born preterm (<37 weeks gestation) and 9.1% (n = 5) had a low birthweight (<2500 g). The prevalence rate of MCMs among live born infants (n = 55) was 1.8% (n = 1). CONCLUSIONS: This study provides baseline prevalence estimates of spontaneous abortions, preterm births, low weight births, and MCMs among women inadvertently exposed to MenACWY-CRM during the pregnancy period. These estimates appear to be comparable with U.S. background prevalence estimates.