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1.
PLoS One ; 16(10): e0254330, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34648533

RESUMO

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.


Assuntos
Infecções Meningocócicas/imunologia , Vacinas Meningocócicas/imunologia , Neisseria meningitidis/imunologia , Adolescente , Análise por Conglomerados , Feminino , Humanos , Masculino , Fatores de Risco , Instituições Acadêmicas , Austrália do Sul , Vacinação
2.
Int J Mol Sci ; 22(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638530

RESUMO

Outer Membrane Vesicles (OMV) constitute a promising platform for the development of efficient vaccines. OMV can be decorated with heterologous antigens (proteins or polysaccharides), becoming attractive novel carriers for the development of multicomponent vaccines. Chemical conjugation represents a tool for linking antigens, also from phylogenetically distant pathogens, to OMV. Here we develop two simple and widely applicable conjugation chemistries targeting proteins or lipopolysaccharides on the surface of Generalized Modules for Membrane Antigens (GMMA), OMV spontaneously released from Gram-negative bacteria mutated to increase vesicle yield and reduce potential reactogenicity. A Design of Experiment approach was used to identify optimal conditions for GMMA activation before conjugation, resulting in consistent processes and ensuring conjugation efficiency. Conjugates produced by both chemistries induced strong humoral response against the heterologous antigen and GMMA. Additionally, the use of the two orthogonal chemistries allowed to control the linkage of two different antigens on the same GMMA particle. This work supports the further advancement of this novel platform with great potential for the design of effective vaccines.


Assuntos
Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Vesículas Extracelulares/imunologia , Proteínas de Protozoários/imunologia , Vacinas Protozoárias/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/química , Vacinas Bacterianas/biossíntese , Feminino , Lipopolissacarídeos/imunologia , Camundongos , Neisseria meningitidis/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/química , Vacinas Protozoárias/biossíntese , Salmonella typhimurium/imunologia , Shigella sonnei/imunologia
3.
Epidemiol Infect ; 149: e90, 2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33814028

RESUMO

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.


Assuntos
Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/imunologia , Neisseria meningitidis/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antivirais/sangue , Vacina contra Varicela/administração & dosagem , Vacina contra Varicela/imunologia , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Feminino , Vacinas Anti-Haemophilus/administração & dosagem , Vacinas Anti-Haemophilus/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/imunologia , Humanos , Imunogenicidade da Vacina , Lactente , Masculino , Vacina contra Sarampo-Caxumba-Rubéola/administração & dosagem , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Vacina Antipólio de Vírus Inativado/administração & dosagem , Vacina Antipólio de Vírus Inativado/imunologia , Segurança , Sorogrupo , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/imunologia
4.
Biochem J ; 478(8): 1485-1509, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33881487

RESUMO

Carbohydrate-binding antibodies play diverse and critical roles in human health. Endogenous carbohydrate-binding antibodies that recognize bacterial, fungal, and other microbial carbohydrates prevent systemic infections and help maintain microbiome homeostasis. Anti-glycan antibodies can have both beneficial and detrimental effects. For example, alloantibodies to ABO blood group carbohydrates can help reduce the spread of some infectious diseases, but they also impose limitations for blood transfusions. Antibodies that recognize self-glycans can contribute to autoimmune diseases, such as Guillain-Barre syndrome. In addition to endogenous antibodies that arise through natural processes, a variety of vaccines induce anti-glycan antibodies as a primary mechanism of protection. Some examples of approved carbohydrate-based vaccines that have had a major impact on human health are against pneumococcus, Haemophilus influeanza type b, and Neisseria meningitidis. Monoclonal antibodies specifically targeting pathogen associated or tumor associated carbohydrate antigens (TACAs) are used clinically for both diagnostic and therapeutic purposes. This review aims to highlight some of the well-studied and critically important applications of anti-carbohydrate antibodies.


Assuntos
Síndrome de Guillain-Barré/imunologia , Infecções por Haemophilus/imunologia , Meningite Meningocócica/imunologia , Pneumonia Pneumocócica/imunologia , Polissacarídeos/imunologia , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/uso terapêutico , Autoanticorpos/biossíntese , Autoanticorpos/sangue , Vacinas Bacterianas/biossíntese , Vacinas Bacterianas/uso terapêutico , Sequência de Carboidratos , Síndrome de Guillain-Barré/patologia , Infecções por Haemophilus/microbiologia , Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/biossíntese , Vacinas Anti-Haemophilus/uso terapêutico , Haemophilus influenzae/imunologia , Humanos , Meningite Meningocócica/microbiologia , Meningite Meningocócica/prevenção & controle , Neisseria meningitidis/imunologia , Vacinas Pneumocócicas/biossíntese , Vacinas Pneumocócicas/uso terapêutico , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/prevenção & controle , Polissacarídeos/antagonistas & inibidores , Polissacarídeos/química , Streptococcus pneumoniae/imunologia
5.
J Immunol Methods ; 493: 113037, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33722512

RESUMO

Traditional ELISA-based protein analysis has been predicated on the assumption that proteins bind randomly to the solid surface of the ELISA plate polymer (polystyrene or polyvinyl chloride). Random adherence to the plate ensures equal access to all faces of the protein, an important consideration when evaluating immunogenicity of polyclonal serum samples as well as when examining the cross-reactivity of immune serum against different antigenic variants of a protein. In this study we demonstrate that the soluble form of the surface lipoprotein transferrin binding protein B (TbpB) from three different bacterial pathogens (Neisseria meningitidis, Actinobacillus pleuropneumoniae, and Mannheimia haemolytica) bind the ELISA plate in a manner that consistently obscures the transferrin binding face of the proteins' N-lobe. In order to develop a non-biased ELISA where all faces of the protein are accessible, the strong interaction between biotin and avidin has been exploited by adding a biotin tag to these proteins during Escherichia coli-based cytoplasmic expression and utilizing streptavidin or neutravidin coated ELISA plates for protein capture and display. The use of avidin coated ELISA plates also allows for rapid purification of biotin-tagged proteins from crude E. coli lysates, removing the requirement of prior affinity purification of each protein to be included in the ELISA-based analyses. In proof of concept experiments we demonstrate the utility of this approach for evaluating immunogenicity and cross-reactivity of serum from mice and pigs immunized with TbpBs from human and porcine pathogens.


Assuntos
Actinobacillus pleuropneumoniae/química , Ensaio de Imunoadsorção Enzimática , Mannheimia haemolytica/química , Neisseria meningitidis/química , Proteína B de Ligação a Transferrina/imunologia , Actinobacillus pleuropneumoniae/imunologia , Avidina/química , Avidina/imunologia , Biotina/química , Biotina/imunologia , Mannheimia haemolytica/imunologia , Neisseria meningitidis/imunologia , Poliestirenos/química , Cloreto de Polivinila/química , Proteína B de Ligação a Transferrina/química
6.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33544069

RESUMO

Invasive meningococcal disease (IMD) is a major cause of meningitis and septicaemia worldwide. The switches in serogroup predominance contribute to the unpredictable nature of the disease with significant health impacts. The aim of this study was to determine the epidemiological profile of IMD in Rio Grande do Sul, Santa Catarina and Paraná, three states in the south of Brazil. All meningitis cases confirmed by clinical and/or laboratory criteria notified to the national information system for notifiable diseases between 2015 and 2019 were analysed. Proportions of serogroup and incidence by age were calculated. A total of 17 894 cases of IMD were reported during this period. Of these, 9029 cases (50 %) were due to serogroup C. Furthermore, serogroup W was responsible for almost half of the cases among children younger than 5 years old during 2017 and 2018, with an overall incidence of 33.3 cases per 100 000 infants. Despite the reduction in serogroup C after the introduction of meningococcal C conjugate vaccine into a childhood immunization programme in Brazil, it remains a significant healthcare issue in the south of the country. Changes in disease epidemiology were observed and serogroup W was the most common among children below 5 years of age in 2017 and 2018. Although future cost-effectiveness studies are necessary, our results could have future implications for meningococcal vaccination programmes.


Assuntos
Programas de Imunização/estatística & dados numéricos , Infecções Meningocócicas/epidemiologia , Infecções Meningocócicas/prevenção & controle , Distribuição por Idade , Brasil/epidemiologia , Monitoramento Epidemiológico , Imunização , Programas de Imunização/tendências , Incidência , Infecções Meningocócicas/microbiologia , Vacinas Meningocócicas/administração & dosagem , Neisseria meningitidis/classificação , Neisseria meningitidis/imunologia , Neisseria meningitidis/isolamento & purificação , Sorogrupo
7.
Int Immunopharmacol ; 93: 107411, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33548582

RESUMO

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.


Assuntos
Antígenos Virais/administração & dosagem , Vacinas Bacterianas/imunologia , Infecções Meningocócicas/imunologia , Nanopartículas/administração & dosagem , Neisseria meningitidis/imunologia , Adjuvantes Imunológicos , Administração Intranasal , Animais , Antígenos Virais/química , Quitosana/química , Citocinas/metabolismo , Feminino , Humanos , Imunidade , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Sorogrupo , Vacinação
8.
Pediatr Infect Dis J ; 40(4): 375-381, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33591079

RESUMO

BACKGROUND: Overall, there are over 30 different sexually transmitted infections with Neisseria gonorrhoeae being the third most frequent with a reported 78 million cases per year. Gonococcal infection causes genital inflammation, which can be a risk factor for others sexually transmitted infections, particularly human immunodeficiency virus. Gonorrhea is a treatable disease, but recently an increase in antibiotic resistance has been of concern. There are currently no vaccines available. However, parenteral vaccination with anti N. meningitidis serogroup B vaccine has been reported to decrease the incidence of gonococcal burden in New Zealand and in Cuba despite the fact that parenteral vaccination is not deemed to induce mucosal IgA. Here we explore possible mechanisms of protection against gonococcal infection through parenteral meningococcal B vaccination. METHODS: Ninety-two serum, saliva and oropharyngeal swabs samples of young adults (healthy and Neisseria carriers) of the internal higher school were obtained. They have been vaccinated with VA-MENGOC-BC (MBV) during their infancy and boosted with a third dose during this study. Serum and saliva samples were analyzed by ELISA and Western blot to measured IgG and IgA antibodies against N. meningitidis and N. gonorrhoeae antigens. N. meningitidis carriers were determined by standard microbiologic test. In addition, we reviewed epidemiologic data for N. meningitidis and N. gonorrhoeae infections in Cuba. RESULTS: Epidemiologic data show the influence of MBV over gonorrhea incidence suggesting to be dependent of sexual arrival age of vaccines but not over syphilis. Laboratorial data permit the detection of 70 and 22 noncarriers and carriers of N. meningitidis, respectively. Serum anti-MBV antigens (PL) responses were boosted by a third dose and were independent of carriage stages, but saliva anti-PL IgA responses were only present and were significant induced in carriers subjects. Carriers boosted with a third dose of MBV induced similar antigonococcal and -PL saliva IgA and serum IgG responses; meanwhile, serum antigonococcal IgG was significantly lower. In saliva, at least 2 gonococcal antigens were identified by Western blot. Finally, gonococcal-specific mucosal IgA antibody responses, in addition to the serum IgG antibodies, might contributed to the reduction of the incidence of N. gonorrhoeae. We hypothesize that this might have contributed to the observed reductions of the incidence of N. gonorrhoeae. CONCLUSION: These results suggest a mechanism for the influence of a Proteoliposome-based meningococcal BC vaccine on gonococcal incidence.


Assuntos
Anticorpos Antibacterianos/sangue , Gonorreia/prevenção & controle , Imunidade nas Mucosas/imunologia , Vacinas Meningocócicas/imunologia , Neisseria gonorrhoeae/imunologia , Neisseria meningitidis/imunologia , Vacinação/métodos , Adolescente , Reações Cruzadas , Cuba/epidemiologia , Feminino , Gonorreia/epidemiologia , Humanos , Incidência , Injeções Intramusculares , Masculino , Vacinas Meningocócicas/administração & dosagem , Proteolipídeos/administração & dosagem , Proteolipídeos/química , Proteolipídeos/imunologia , Saliva/imunologia , Sorogrupo , Adulto Jovem
9.
Virulence ; 12(1): 389-403, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33459578

RESUMO

Neisseria meningitidis (meningococcus) is a common bacterial colonizer of the human nasopharynx but can occasionally cause very severe systemic infections with rapid onset. Meningococci are able to degrade IgA encountered during colonization of mucosal membranes using their IgA1-specific serine protease. During systemic infection, specific IgG can induce complement-mediated lysis of the bacterium. However, meningococcal immune evasion mechanisms in thwarting IgG remain undescribed. In this study, we report for the first time that the meningococcal IgA1-specific serine protease is able to degrade IgG3 in addition to IgA. The IgG3 heavy chain is specifically cleaved in the lower hinge region thereby separating the antigen binding part from its effector binding part. Through molecular characterization, we demonstrate that meningococcal IgA1-specific serine protease of cleavage type 1 degrades both IgG3 and IgA, whereas cleavage type 2 only degrades IgA. Epidemiological analysis of 7581 clinical meningococcal isolates shows a significant higher proportion of cleavage type 1 among isolates from invasive cases compared to carrier cases, regardless of serogroup. Notably, serogroup W cc11 which is an increasing cause of invasive meningococcal disease globally harbors almost exclusively cleavage type 1 protease. Our study also shows an increasing prevalence of meningococcal isolates encoding IgA1P cleavage type 1 compared to cleavage type 2 during the observed decade (2010-2019). Altogether, our work describes a novel mechanism of IgG3 degradation by meningococci and its association to invasive meningococcal disease.


Assuntos
Imunoglobulina G/metabolismo , Neisseria meningitidis/enzimologia , Neisseria meningitidis/genética , Serina Endopeptidases/metabolismo , Serina Proteases/metabolismo , Humanos , Imunoglobulina G/imunologia , Infecções Meningocócicas/microbiologia , Neisseria meningitidis/imunologia , Neisseria meningitidis/patogenicidade , Serina/metabolismo , Serina Proteases/genética , Serina Proteases/imunologia
10.
Lancet Infect Dis ; 21(5): 688-696, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33428870

RESUMO

BACKGROUND: The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate. METHODS: In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A [NadA]), NZ98/254 (porin A), and 44/76-SL (factor H binding protein [fHbp]). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus [MenC], Haemophilus influenzae b [Hib], tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov, NCT02482636, and is complete. FINDINGS: Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5-98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2-97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0-92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5-94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions. INTERPRETATION: These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important. FUNDING: Bill & Melinda Gates Foundation and the National Institute for Health Research.


Assuntos
Esquemas de Imunização , Imunogenicidade da Vacina/imunologia , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/imunologia , Animais , Anticorpos Antibacterianos , Humanos , Lactente , Vacinas Meningocócicas/administração & dosagem , Neisseria meningitidis/imunologia , Neisseria meningitidis Sorogrupo C , Vacinas Pneumocócicas , Coelhos , Toxoide Tetânico , Reino Unido , Vacinação , Vacinas Conjugadas/imunologia
11.
PLoS Pathog ; 16(12): e1008602, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33290434

RESUMO

There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development.


Assuntos
Proteção Cruzada/imunologia , Vacinas Meningocócicas/farmacologia , Neisseria gonorrhoeae/imunologia , Animais , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/imunologia , Estudos de Casos e Controles , Reações Cruzadas/imunologia , Feminino , Gonorreia/imunologia , Humanos , Soros Imunes/imunologia , Imunização/métodos , Masculino , Infecções Meningocócicas/microbiologia , Vacinas Meningocócicas/imunologia , Vacinas Meningocócicas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neisseria meningitidis/imunologia , Neisseria meningitidis Sorogrupo B/imunologia , Estudos Retrospectivos , Sorogrupo , Vacinação/métodos
12.
Proc Natl Acad Sci U S A ; 117(47): 29795-29802, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33158970

RESUMO

Meningococcal meningitis remains a substantial cause of mortality and morbidity worldwide. Until recently, countries in the African meningitis belt were susceptible to devastating outbreaks, largely attributed to serogroup A Neisseria meningitidis (MenA). Vaccination with glycoconjugates of MenA capsular polysaccharide led to an almost complete elimination of MenA clinical cases. To understand the molecular basis of vaccine-induced protection, we generated a panel of oligosaccharide fragments of different lengths and tested them with polyclonal and monoclonal antibodies by inhibition enzyme-linked immunosorbent assay, surface plasmon resonance, and competitive human serum bactericidal assay, which is a surrogate for protection. The epitope was shown to optimize between three and six repeating units and to be O-acetylated. The molecular interactions between a protective monoclonal antibody and a MenA capsular polysaccharide fragment were further elucidated at the atomic level by saturation transfer difference NMR spectroscopy and X-ray crystallography. The epitope consists of a trisaccharide anchored to the antibody via the O- and N-acetyl moieties through either H-bonding or CH-π interactions. In silico docking showed that 3-O-acetylation of the upstream residue is essential for antibody binding, while O-acetate could be equally accommodated at three and four positions of the other two residues. These results shed light on the mechanism of action of current MenA vaccines and provide a foundation for the rational design of improved therapies.


Assuntos
Epitopos/imunologia , Meningite Meningocócica/prevenção & controle , Vacinas Meningocócicas/imunologia , Neisseria meningitidis/imunologia , Polissacarídeos Bacterianos/imunologia , Acetilação , Adolescente , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/imunologia , Criança , Ensaios Clínicos Fase II como Assunto , Cristalografia por Raios X , Feminino , Humanos , Imunogenicidade da Vacina , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/imunologia , Masculino , Meningite Meningocócica/imunologia , Meningite Meningocócica/microbiologia , Vacinas Meningocócicas/uso terapêutico , Simulação de Acoplamento Molecular , Estudos Multicêntricos como Assunto , Polissacarídeos Bacterianos/química , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorogrupo , Ensaios de Anticorpos Bactericidas Séricos , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/uso terapêutico
13.
Vaccine ; 38(48): 7674-7682, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33082014

RESUMO

Outer membrane vesicles (OMVs) of Neisseria meningitidis contain important antigens to trigger an immune response against meningococci and have been studied as vaccines compounds. The immune response to a vaccine may be affected by its constitution and route of administration. Therefore, Swiss mice were immunized by different routes with OMVs of N. meningitidis B with dimethyl dioctadecyl ammonium bromide in bilayer fragments (DDA-BF) or aluminum hydroxide (AH) as adjuvants. The adjuvants and different routes were compared regarding the immune responses by ELISA, western blot, delayed type hypersensitivity (DTH) and histopathologic analysis. The antigenic preparation generated humoral and cellular immune responses. In quantitative analyzes, in general, AH was superior to DDA-BF. However, analysis such as IgG avidity index, bactericidal activity and immunoblot, revealed no important differences regarding the adjuvant or route of immunization. Regarding the parameters tested, it was not possible to define a superiority between the adjuvants and routes of immunization proposed by this study.


Assuntos
Anticorpos Antibacterianos , Neisseria meningitidis , Adjuvantes Imunológicos , Hidróxido de Alumínio , Animais , Proteínas da Membrana Bacteriana Externa , Imunização , Camundongos , Neisseria meningitidis/imunologia
14.
Viruses ; 12(10)2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036278

RESUMO

The highly conserved extracellular domain of the transmembrane protein M2 (M2e) of the influenza A virus is a promising target for the development of broad-spectrum vaccines. However, M2e is a poor immunogen by itself and must be linked to an appropriate carrier to induce an efficient immune response. In this study, we obtained recombinant mosaic proteins containing tandem copies of M2e fused to a lipopeptide from Neisseria meningitidis surface lipoprotein Ag473 and alpha-helical linkers and analyzed their immunogenicity. Six fusion proteins, comprising four or eight tandem copies of M2e flanked by alpha-helical linkers, lipopeptides, or a combination of both of these elements, were produced in Escherichia coli. The proteins, containing both alpha-helical linkers and lipopeptides at each side of M2e repeats, formed nanosized particles, but no particulate structures were observed in the absence of lipopeptides. Animal study results showed that proteins with lipopeptides induced strong M2e-specific antibody responses in the absence of external adjuvants compared to similar proteins without lipopeptides. Thus, the recombinant M2e-based proteins containing alpha-helical linkers and N. meningitidis lipopeptide sequences at the N- and C-termini of four or eight tandem copies of M2e peptide are promising vaccine candidates.


Assuntos
Proteínas de Bactérias/imunologia , Vírus da Influenza A/imunologia , Proteínas de Fusão de Membrana/imunologia , Proteínas Recombinantes de Fusão/imunologia , Vacinas Sintéticas/imunologia , Proteínas da Matriz Viral/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Lipopeptídeos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Neisseria meningitidis/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Domínios Proteicos/imunologia
15.
PLoS Pathog ; 16(10): e1008882, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33007046

RESUMO

Neisseria meningitidis serogroup B (MenB) is the leading cause of meningococcal meningitis and sepsis in industrialized countries, with the highest incidence in infants and adolescents. Two recombinant protein vaccines that protect against MenB are now available (i.e. 4CMenB and MenB-fHbp). Both vaccines contain the Factor H Binding Protein (fHbp) antigen, which can bind the Human Factor H (fH), the main negative regulator of the alternative complement pathway, thus enabling bacterial survival in the blood. fHbp is present in meningococcal strains as three main variants which are immunologically distinct. Here we sought to obtain detailed information about the epitopes targeted by anti-fHbp antibodies induced by immunization with the 4CMenB multicomponent vaccine. Thirteen anti-fHbp human monoclonal antibodies (mAbs) were identified in a library of over 100 antibody fragments (Fabs) obtained from three healthy adult volunteers immunized with 4CMenB. Herein, the key cross-reactive mAbs were further characterized for antigen binding affinity, complement-mediated serum bactericidal activity (SBA) and the ability to inhibit binding of fH to live bacteria. For the first time, we identified a subset of anti-fHbp mAbs able to elicit human SBA against strains with all three variants and able to compete with human fH for fHbp binding. We present the crystal structure of fHbp v1.1 complexed with human antibody 4B3. The structure, combined with mutagenesis and binding studies, revealed the critical cross-reactive epitope. The structure also provided the molecular basis of competition for fH binding. These data suggest that the fH binding site on fHbp v1.1 can be accessible to the human immune system upon immunization, enabling elicitation of human mAbs broadly protective against MenB. The novel structural, biochemical and functional data are of great significance because the human vaccine-elicited mAbs are the first reported to inhibit the binding of fH to fHbp, and are bactericidal with human complement. Our studies provide molecular insights into the human immune response to the 4CMenB meningococcal vaccine and fuel the rationale for combined structural, immunological and functional studies when seeking deeper understanding of the mechanisms of action of human vaccines.


Assuntos
Anticorpos/imunologia , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Meningite Meningocócica/imunologia , Vacinas Meningocócicas/administração & dosagem , Neisseria meningitidis/imunologia , Adulto , Anticorpos/sangue , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Fator H do Complemento/imunologia , Fator H do Complemento/metabolismo , Humanos , Meningite Meningocócica/metabolismo , Meningite Meningocócica/microbiologia , Meningite Meningocócica/prevenção & controle
16.
Expert Rev Vaccines ; 19(8): 745-754, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32897762

RESUMO

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.


Assuntos
Formação de Anticorpos/imunologia , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/administração & dosagem , Adulto , Fatores Etários , Animais , Pré-Escolar , União Europeia , Humanos , Imunogenicidade da Vacina , Lactente , Infecções Meningocócicas/imunologia , Vacinas Meningocócicas/imunologia , Neisseria meningitidis/imunologia , Coelhos , Ensaios Clínicos Controlados Aleatórios como Assunto , Vacinação
17.
Infect Immun ; 88(12)2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-32958529

RESUMO

Factor H binding protein (FHbp) is an important Neisseria meningitidis virulence factor that binds a negative regulator of the alternative complement pathway, human factor H (FH). Binding of FH increases meningococcal resistance to complement-mediated killing. FHbp also is reported to prevent interaction of the antimicrobial peptide (AMP) LL-37 with the meningococcal surface and meningococcal killing. FHbp is a target of two licensed group B-directed meningococcal (MenB) vaccines. We found a new FHbp variant, peptide allele identification no. 896 (ID 896), was highly expressed by an emerging meningococcal pathotype, the nonencapsulated urethritis clade (US_NmUC). This clade has been responsible for outbreaks of urethritis in multiple U.S. cities since 2015, other mucosal infections, and cases of invasive meningococcal disease. FHbp ID 896 is a member of the variant group 1 (subfamily B), bound protective anti-FHbp monoclonal antibodies, bound high levels of human FH, and enhanced the resistance of the clade to complement-mediated killing in low levels of human complement likely present at human mucosal surfaces. Interestingly, expression of FHbp ID 896 resulted in augmented killing of the clade by LL-37. FHbp ID 896 of the clade was recognized by antibodies elicited by FHbp in MenB vaccines.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Meningite Meningocócica/imunologia , Vacinas Meningocócicas/imunologia , Neisseria meningitidis/metabolismo , Uretrite/imunologia , Uretrite/microbiologia , Sequência de Aminoácidos , Antígenos de Bactérias/química , Antígenos de Bactérias/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Sobrevivência Celular/genética , Fator H do Complemento/imunologia , Bases de Dados Genéticas , Genômica , Humanos , Infecções Meningocócicas , Neisseria meningitidis/genética , Neisseria meningitidis/imunologia , Neisseria meningitidis/patogenicidade , Neisseria meningitidis Sorogrupo B/imunologia , Neisseria meningitidis Sorogrupo B/isolamento & purificação , Filogenia , Ligação Proteica , Alinhamento de Sequência
18.
Microb Genom ; 6(9)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32776867

RESUMO

We studied population genomics of 486 Neisseria meningitidis isolates causing meningitis in the Netherlands during the period 1979-2003 and 2006-2013 using whole-genome sequencing to evaluate the impact of a hyperendemic period of serogroup B invasive disease. The majority of serogroup B isolates belonged to ST-41/44 (41 %) and ST-32 complex (16 %). Comparing the time periods, before and after the decline of serogroup B invasive disease, there was a decrease of ST-41/44 complex sequences (P=0.002). We observed the expansion of a sub-lineage within ST-41/44 complex sequences being associated with isolation from the 1979-2003 time period (P=0.014). Isolates belonging to this sub-lineage expansion within ST-41/44 complex were marked by four antigen allele variants. Presence of these allele variants was associated with isolation from the 1979-2003 time period after correction for multiple testing (Wald test, P=0.0043 for FetA 1-5; P=0.0035 for FHbp 14; P=0.012 for PorA 7-2.4 and P=0.0031 for NHBA two peptide allele). These sequences were associated with 4CMenB vaccine coverage (Fisher's exact test, P<0.001). Outside of the sub-lineage expansion, isolates with markedly lower levels of predicted vaccine coverage clustered in phylogenetic groups showing a trend towards isolation in the 2006-2013 time period (P=0.08). In conclusion, we show the emergence and decline of a sub-lineage expansion within ST-41/44 complex isolates concurrent with a hyperendemic period in meningococcal meningitis. The expansion was marked by specific antigen peptide allele combinations. We observed preliminary evidence for decreasing 4CMenB vaccine coverage in the post-hyperendemic period.


Assuntos
Antígenos de Bactérias/genética , Meningite Meningocócica/microbiologia , Neisseria meningitidis/imunologia , Sequenciamento Completo do Genoma/métodos , Adolescente , Variação Genética , Genoma Bacteriano , Humanos , Metagenômica , Taxa de Mutação , Neisseria meningitidis/classificação , Neisseria meningitidis/genética , Neisseria meningitidis/isolamento & purificação , Países Baixos , Filogenia , Seleção Genética
19.
Pediatr Infect Dis J ; 39(10): 955-960, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32852352

RESUMO

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.


Assuntos
Imunogenicidade da Vacina , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/imunologia , Vacinas Combinadas/imunologia , Anticorpos Antibacterianos/sangue , Criança , Pré-Escolar , Método Duplo-Cego , Drogas em Investigação/administração & dosagem , Humanos , Infecções Meningocócicas/imunologia , Vacinas Meningocócicas/administração & dosagem , Neisseria meningitidis/imunologia , Porto Rico , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/imunologia , Estados Unidos , Vacinação , Vacinas Combinadas/administração & dosagem , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia
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