02. Beyond B Antigen Coverage: The Potential of the 4CMenB Vaccine for Cross-protection Against Pathogenic Neisseria Infections

Abstract Background Two human pathogenic Neisseria species exist: N. meningitidis (Nm) and N. gonorrhoeae (Ng). Although causing disparate clinical syndromes, invasive meningococcal disease (IMD) and gonorrhea, they are genetically similar and share key protein antigens. The 4CMenB vaccine, licensed against meningococcal B disease, comprises 4 antigenic components (factor H binding protein (fHbp), variant 1.1, subfamily B; Neisseria heparin binding antigen (NHBA) peptide 2; Neisserial adhesin A (NadA) variant 3; and Porin A (PorA) P1.4), and potentially protects against non-B invasive meningococcal and gonococcal strains. In this review, we summarize the similarities between these antigens and those in Nm serogroups A, C, W, X and Y and Ng. Methods Published data in humans were analyzed to conduct a narrative literature review of the potential extent of meningococcal vaccine-induced protection against non-B meningococcal strains and Ng. Techniques applied to indirectly measure this effect are based on genotype-phenotype modelling, strain coverage, bactericidal killing and direct impact on disease reduction. Results Data were identified from countries in America, Europe, Africa and Oceania. The genes encoding for fHbp and NHBA are also present in strains belonging to the five non-B serogroups, while NadA is present in several strains of serogroups C, W and Y, and PorA P1.4 mainly in serogroup W. At the genome level, Ng and Nm share up to 90% homology. Most of the outer membrane vesicle antigens, like PilQ, Omp85 (BamA), NspA, MtrE, MetQ, LbpA, PorB, FetA, OpcA and NHBA, are highly conserved in Ng. In addition, a synergistic effect might enhance immunogenicity against non-B serogroups as shown against serogroup B. Conclusion 4CMenB components are present and conserved in several Ng and Nm strains. Recent results demonstrate that 4CMenB reduces MenW disease incidence in infants and might generate cross-protection against other non-B serogroups. In addition, 4CMenB has been proven to be effective in reducing gonococcal infections in adolescents. Research on future genomic and proteomic characterizations of IMD and gonorrhea strains will provide information on the molecular basis of the underlying broad strain coverage, while informing decisions regarding prevention and immunization programmes. Disclosures Yara Ruiz Garcia, MSc, PhD, GSK group of companies (Employee) Woo-Yun Sohn, MD, GSK group of companies (Employee, Shareholder) Mariagrazia Pizza, Biological Sciences, PhD, GSK group of companies (Employee, Shareholder) Rafik Bekkat-Berkani, M.D, GSK group of companies (Employee, Shareholder)

Download Full-text

Characterization of Serogroup ANeisseria meningitidisfrom Invasive Meningococcal Disease Cases in Canada Between 1979 and 2006: Epidemiological Links to Returning Travellers

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2008/523021 ◽

2008 ◽

Vol 19 (3) ◽

pp. 227-232 ◽

Cited By ~ 2

Author(s):

Angela M Sloan ◽

Averil M Henderson ◽

Raymond SW Tsang

Keyword(s):

Meningococcal Disease ◽

Clonal Complex ◽

Disease Incidence ◽

Developing Nations ◽

Invasive Meningococcal Disease ◽

Protein Antigens ◽

Genes Encoding ◽

Returning Travellers ◽

The 1960S

INTRODUCTION: Serogroup ANeisseria meningitidishas repeatedly caused epidemics of invasive meningococcal disease (IMD) in developing nations since the 1960s. The present study is the first detailed study of serogroup A bacteria isolated in Canada.METHODS: Thirty-four serogroup A meningococcal isolates collected from individuals with IMD in Canada between 1979 and 2006 were characterized by serology and multilocus sequence typing of seven housekeeping enzyme genes and genes encoding three outer membrane protein antigens.RESULTS: Isolates were assigned to either the sequence type (ST)-1 or the ST-5 clonal complex. Clones within the ST-1 complex were recovered between 1979 and 1992, while clones of the ST-5 complex were isolated between 1987 and 2006; respectively, they accounted for 70.6% and 29.4% of all isolates studied. Isolates of the ST-1 complex were characterized by serosubtype antigen P1.3 or P1.3,6 with PorB allele 60 (serotype 4) and FetA sequence F5-1, while isolates of the ST-5 complex were characterized by serosubtype antigen P1.9 with PorB allele 47 (also serotype 4) and FetA sequence F3-1.CONCLUSIONS: The Canadian serogroup A IMD isolates likely originated in travellers returning from hyperendemic or epidemic areas of the globe where serogroup A bacteria circulate. Although the Canadian cases of serogroup A IMD were caused by clones known to have caused epidemics in developing countries, disease incidence remained low in Canada.

Download Full-text

The Serogroup B Meningococcal Vaccine Bexsero Elicits Antibodies to Neisseria gonorrhoeae

Clinical Infectious Diseases ◽

10.1093/cid/ciy1061 ◽

2018 ◽

Vol 69 (7) ◽

pp. 1101-1111 ◽

Cited By ~ 24

Author(s):

Evgeny A Semchenko ◽

Aimee Tan ◽

Ray Borrow ◽

Kate L Seib

Keyword(s):

Neisseria Gonorrhoeae ◽

Membrane Vesicle ◽

Vaccination Campaign ◽

Cross Reactivity ◽

Factor H ◽

Heparin Binding ◽

Meningococcal Vaccine ◽

Western Blots ◽

Recombinant Antigens ◽

High Level

Abstract Background Neisseria gonorrhoeae and Neisseria meningitidis are closely-related bacteria that cause a significant global burden of disease. Control of gonorrhoea is becoming increasingly difficult, due to widespread antibiotic resistance. While vaccines are routinely used for N. meningitidis, no vaccine is available for N. gonorrhoeae. Recently, the outer membrane vesicle (OMV) meningococcal B vaccine, MeNZB, was reported to be associated with reduced rates of gonorrhoea following a mass vaccination campaign in New Zealand. To probe the basis for this protection, we assessed the cross-reactivity to N. gonorrhoeae of serum raised to the meningococcal vaccine Bexsero, which contains the MeNZB OMV component plus 3 recombinant antigens (Neisseria adhesin A, factor H binding protein [fHbp]-GNA2091, and Neisserial heparin binding antigen [NHBA]-GNA1030). Methods A bioinformatic analysis was performed to assess the similarity of MeNZB OMV and Bexsero antigens to gonococcal proteins. Rabbits were immunized with the OMV component or the 3 recombinant antigens of Bexsero, and Western blots and enzyme-linked immunosorbent assays were used to assess the generation of antibodies recognizing N. gonorrhoeae. Serum from humans immunized with Bexsero was investigated to assess the nature of the anti-gonococcal response. Results There is a high level of sequence identity between MeNZB OMV and Bexsero OMV antigens, and between the antigens and gonococcal proteins. NHBA is the only Bexsero recombinant antigen that is conserved and surfaced exposed in N. gonorrhoeae. Bexsero induces antibodies in humans that recognize gonococcal proteins. Conclusions The anti-gonococcal antibodies induced by MeNZB-like OMV proteins could explain the previously-seen decrease in gonorrhoea following MeNZB vaccination. The high level of human anti-gonococcal NHBA antibodies generated by Bexsero vaccination may provide additional cross-protection against gonorrhoea.

Download Full-text

Characterization of InvasiveNeisseria meningitidisfrom Atlantic Canada, 2009 To 2013: With Special Reference to the Nonpolysaccharide Vaccine Targets (Pora, Factor H Binding Protein,NeisseriaHeparin-Binding Antigen andNeisseriaAdhesin A)

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2015/393659 ◽

2015 ◽

Vol 26 (6) ◽

pp. 299-304 ◽

Cited By ~ 4

Author(s):

Raymond SW Tsang ◽

Dennis KS Law ◽

Rita R Gad ◽

Tim Mailman ◽

Gregory German ◽

...

Keyword(s):

Clonal Analysis ◽

Factor H ◽

Vaccine Antigen ◽

Atlantic Canada ◽

Successful Implementation ◽

Heparin Binding ◽

Antigen Peptide ◽

Genes Encoding ◽

Adequate Coverage

BACKGROUND: Serogroup BNeisseria meningitidis(MenB) has always been a major cause of invasive meningococcal disease (IMD) in Canada. With the successful implementation of a meningitis C conjugate vaccine, the majority of IMD in Canada is now caused by MenB.OBJECTIVE: To investigate IMD case isolates in Atlantic Canada from 2009 to 2013. Data were analyzed to determine the potential coverage of the newly licensed MenB vaccine.METHODS: Serogroup, serotype and serosubtype antigens were determined from IMD case isolates. Clonal analysis was performed using multilocus sequence typing. The protein-based vaccine antigen genes were sequenced and the predicted peptides were investigated.RESULTS: The majority of the IMD isolates were MenB (82.5%, 33 of 40) and, in particular, sequence type (ST)-154 B:4:P1.4 was responsible for 47.5% (19 of 40) of all IMD case isolates in Atlantic Canada. Isolates of this clone expressed the PorA antigen P1.4 and possessed thenhbagenes encoding forNeisseriaheparin-binding antigen peptide 2, which together matched exactly with two of the four components of the new four-component meningococcal B vaccine. Nineteen MenB isolates had two antigenic matches, another five MenB and one meningitis Y isolate had one antigenic match. This provided 75.8% (25 of 33) potential coverage for MenB, or a 62.5% (25 of 40) overall potential coverage for IMD.CONCLUSION: From 2009 to 2013, IMD in Atlantic Canada was mainly caused by MenB and, in particular, the B:4:P1.4 ST-154 clone, which accounted for 47.5% of all IMD case isolates. The new four-component meningococcal B vaccine appeared to offer adequate coverage against MenB in Atlantic Canada.

Download Full-text

Genetic Distribution of Noncapsular Meningococcal Group B Vaccine Antigens in Neisseria lactamica

Clinical and Vaccine Immunology ◽

10.1128/cvi.00090-13 ◽

2013 ◽

Vol 20 (9) ◽

pp. 1360-1369 ◽

Cited By ~ 12

Author(s):

Jay Lucidarme ◽

Stefanie Gilchrist ◽

Lynne S. Newbold ◽

Stephen J. Gray ◽

Edward B. Kaczmarski ◽

...

Keyword(s):

Outer Membrane ◽

Membrane Vesicle ◽

Geographic Region ◽

Factor H ◽

Heparin Binding ◽

Content Type ◽

Vaccine Responses ◽

Neisseria Lactamica ◽

Genetic Distribution ◽

Group B

ABSTRACTThe poor immunogenicity of the meningococcal serogroup B (MenB) capsule has led to the development of vaccines targeting subcapsular antigens, in particular the immunodominant and diverse outer membrane porin, PorA. These vaccines are largely strain specific; however, they offer limited protection against the diverse MenB-associated diseases observed in many industrialized nations. To broaden the scope of its protection, the multicomponent vaccine (4CMenB) incorporates a PorA-containing outer membrane vesicle (OMV) alongside relatively conserved recombinant protein components, including factor H-binding protein (fHbp),Neisseriaadhesin A (NadA), and neisserial heparin-binding antigen (NHBA). The expression of PorA is unique to meningococci (Neisseria meningitidis); however, many subcapsular antigens are shared with nonpathogenic members of the genusNeisseriathat also inhabit the nasopharynx. These organisms may elicit cross-protective immunity against meningococci and/or occupy a niche that might otherwise accommodate pathogens. The potential for 4CMenB responses to impact such species (and vice versa) was investigated by determining the genetic distribution of the primary 4CMenB antigens among diverse members of the common childhood commensal,Neisseria lactamica. All the isolates possessednhbabut were devoid offhbpandnadA. Thenhbaalleles were mainly distinct from but closely related to those observed among a representative panel of invasive MenB isolates from the same broad geographic region. We made similar findings for the immunogenic typing antigen, FetA, which constitutes a major part of the 4CMenB OMV. Thus, 4CMenB vaccine responses may impact or be impacted by nasopharyngeal carriage of commensal neisseriae. This highlights an area for further research and surveillance should the vaccine be routinely implemented.

Download Full-text

Rapid Genetic Grouping of Factor H-Binding Protein (Genome-Derived Neisserial Antigen 1870), a Promising Group B Meningococcal Vaccine Candidate

Clinical and Vaccine Immunology ◽

10.1128/cvi.00097-06 ◽

2006 ◽

Vol 13 (7) ◽

pp. 758-763 ◽

Cited By ~ 23

Author(s):

Peter T. Beernink ◽

Arunas Leipus ◽

Dan M. Granoff

Keyword(s):

Amino Acid ◽

Quantitative Pcr ◽

Binding Protein ◽

Regulatory Protein ◽

Amino Acid Sequences ◽

Factor H ◽

Protein Vaccine ◽

Protein Antigens ◽

Genes Encoding ◽

Group B

ABSTRACT The most important antigen component of a promising multicomponent group B meningococcal recombinant protein vaccine is based on genome-derived neisserial antigen 1870, which recently was renamed factor H-binding protein (FHBP) to reflect one of its critical functions as a complement regulatory protein. Neisseria meningitidis strains can be subdivided into three FHBP variant groups based on divergence of FHBP amino acid sequences. Within each variant group, amino acid sequences are >90% conserved. To develop an FHBP-based group B vaccine, it is important to know the distribution of FHBP variant 1, 2, and 3 strains in different geographic regions, since antibodies against FHBP are bactericidal against strains within the homologous group but show minimal activity against strains from other groups. We have devised a high-throughput, quantitative PCR-based method that allows rapid and precise assignment of FHBP genes into each of the three major variant lineages. Among 48 group B isolates from patients hospitalized in California in 2003 to 2004, 83%, 13%, and 4%, respectively, had variant 1, 2, and 3 genes. Thus, a vaccine based on the variant 1 protein has the potential to prevent the majority of cases of group B disease. The quantitative PCR-based method will be useful for determining and monitoring the prevalence of meningococcal isolates with genes encoding different FHBP variant proteins. The technique also is suitable for monitoring variation of genes encoding other protein antigens targeted for vaccination.

Download Full-text

Meningococcal Outer Membrane Vesicle Composition-Dependent Activation of the Innate Immune Response

Infection and Immunity ◽

10.1128/iai.00635-16 ◽

2016 ◽

Vol 84 (10) ◽

pp. 3024-3033 ◽

Cited By ~ 17

Author(s):

Afshin Zariri ◽

Joep Beskers ◽

Bas van de Waterbeemd ◽

Hendrik Jan Hamstra ◽

Tim H. E. Bindels ◽

...

Keyword(s):

Innate Immunity ◽

Outer Membrane ◽

Lipid A ◽

Membrane Vesicle ◽

Outer Membrane Vesicles ◽

Factor H ◽

Innate Immune ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Detergent Treatment

Meningococcal outer membrane vesicles (OMVs) have been extensively investigated and successfully implemented as vaccines. They contain pathogen-associated molecular patterns, including lipopolysaccharide (LPS), capable of triggering innate immunity. However,Neisseria meningitidiscontains an extremely potent hexa-acylated LPS, leading to adverse effects when its OMVs are applied as vaccines. To create safe OMV vaccines, detergent treatment is generally used to reduce the LPS content. While effective, this method also leads to loss of protective antigens such as lipoproteins. Alternatively, genetic modification of LPS can reduce its toxicity. In the present study, we have compared the effects of standard OMV isolation methods using detergent or EDTA with those of genetic modifications of LPS to yield a penta-acylated lipid A (lpxL1andpagL) on thein vitroinduction of innate immune responses. The use of detergent decreased both Toll-like receptor 4 (TLR4) and TLR2 activation by OMVs, while the LPS modifications reduced only TLR4 activation. Mutational removal of PorB or lipoprotein factor H binding protein (fHbp), two proteins known to trigger TLR2 signaling, had no effect, indicating that multiple TLR2 ligands are removed by detergent treatment. Detergent-treated OMVs andlpxL1OMVs showed similar reductions of cytokine profiles in the human monocytic cell line MM6 and human dendritic cells (DCs). OMVs with the alternative penta-acylated LPS structure obtained after PagL-mediated deacylation showed reduced induction of proinflammatory cytokines interleukin-6 (IL-6) and IL-1β but not of IP-10, a typical TRIF-dependent chemokine. Taken together, these data show that lipid A modification can be used to obtain OMVs with reduced activation of innate immunity, similar to what is found after detergent treatment.

Download Full-text

Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms

Mediators of Inflammation ◽

10.1080/09511920410001713529 ◽

2004 ◽

Vol 13 (3) ◽

pp. 181-187 ◽

Cited By ~ 45

Author(s):

Joanna Balding ◽

Wendy J. Livingstone ◽

Judith Conroy ◽

Lesley Mynett-Johnson ◽

Donald G. Weir ◽

...

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Disease Incidence ◽

Strong Association ◽

Tnf Α ◽

Genes Encoding ◽

Inflammatory Processes ◽

Inflammatory Bowel ◽

Cytokine Gene Polymorphisms

THE mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n=172) and healthy controls (n=389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-α-308 polymorphism (p=0.0135). There was also variation in the frequency of IL-6-174 and TNF-α-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p=0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.

Download Full-text

4CMenB vaccine induces elite cross-protective human antibodies that compete with human factor H for binding to meningococcal fHbp

PLoS Pathogens ◽

10.1371/journal.ppat.1008882 ◽

2020 ◽

Vol 16 (10) ◽

pp. e1008882

Author(s):

Daniele Veggi ◽

Federica Bianchi ◽

Laura Santini ◽

Paola Lo Surdo ◽

Chelsy C. Chesterman ◽

...

Keyword(s):

Human Factor ◽

Factor H ◽

Human Antibodies ◽

4Cmenb Vaccine

Download Full-text

A Critical Threshold of Meningococcal Factor H Binding Protein Expression Is Required for Increased Breadth of Protective Antibodies Elicited by Native Outer Membrane Vesicle Vaccines

Clinical and Vaccine Immunology ◽

10.1128/cvi.00542-10 ◽

2011 ◽

Vol 18 (5) ◽

pp. 736-742 ◽

Cited By ~ 31

Author(s):

Oliver Koeberling ◽

Isabel Delany ◽

Dan M. Granoff

Keyword(s):

Outer Membrane ◽

Binding Protein ◽

Membrane Vesicle ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Factor H ◽

Critical Threshold ◽

Recombinant Strains ◽

Endotoxin Activity ◽

Group B

ABSTRACTNative outer membrane vesicles (NOMV) (not detergent treated), which are prepared from recombinant strains with attenuated endotoxin activity and overexpressed factor H binding protein (fHbp), elicited broad serum bactericidal antibody responses in mice. The amount of overexpressed fHbp required for optimal immunogenicity is not known. In this study we prepared NOMV vaccines from LpxL1 knockout (ΔLpxL1) mutants with penta-acylated lipooligosaccharide and attenuated endotoxin activity. The recombinant strains had wild-type (1×) fHbp expression or were engineered for 3-fold- or 10-fold-increased fHbp expression (3× or 10× fHbp). Control vaccines included NOMV from ΔLpxL1/ΔfHbp mutants or recombinant fHbp. In mice, only the 10× fHbp NOMV vaccine elicited significantly higher serum IgG anti-fHbp antibody titers than the corresponding 1× fHbp NOMV or recombinant fHbp vaccine. The 10× fHbp NOMV vaccine also elicited higher bactericidal responses (P< 0.05) against five group B strains with heterologous PorA than the recombinant fHbp or 1× fHbp NOMV vaccine. The 3× fHbp NOMV vaccine gave higher bactericidal titers against only one strain. Serum bactericidal titers in mice immunized with the control ΔfHbp NOMV vaccines were <1:10, and bactericidal titers in mice immunized with the 10× fHbp NOMV vaccine were <1:10 after adsorption of anti-fHbp antibodies. Mixing antiserum to NOMV vaccines from fHbp knockout mutants with antiserum to recombinant fHbp did not increase anti-fHbp bactericidal titers. Thus, a critical threshold of increased fHbp expression is required for NOMV vaccines to elicit broad serum bactericidal responses, and the antibodies conferring protection are directed primarily at fHbp.

Download Full-text

174 EPIDERMAL GROWTH FACTORS AND CALBINDIN-D9k GENE EXPRESSIONS DURING PREGANCY IN THE PORCINE UTERUS

Reproduction Fertility and Development ◽

10.1071/rdv20n1ab174 ◽

2008 ◽

Vol 20 (1) ◽

pp. 167

Author(s):

Y.-J. Kim ◽

E.-M. Jung ◽

G.-S. Lee ◽

S.-H. Hyun ◽

E.-B. Jeung

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Transforming Growth Factor ◽

Expression Patterns ◽

Negative Control ◽

Heparin Binding ◽

Gene Expressions ◽

Calbindin D9k ◽

Genes Encoding ◽

Epidermal Growth

To stably maintain pregnancy, several genes are expressed in the uterus. In particular, the endometrial expression of genes encoding growth factors appears to play a key role in maternal–fetal communication. Previous studies have characterized the endometrial expression kinetics of the genes encoding epidermal growth factor (EGF), its receptor (EGFR), transforming growth factor-alpha (TGF-α), amphiregulin (Areg), heparin-binding (Hb) EGF, and calbindin-D9k (CaBP-9k) in the pig during implantation. Here, we further characterized the expression patterns of these molecules during the entire porcine pregnancy. Porcine (n = 3 per PD) were collected at pregnancy days (PD) 12, 15, 30, 60, 90, and 110 and subjected to semi-quantitative RT-PCR. The data were analyzed with a nonparametric one-way analysis of variance using the Kruskal-Wallis test, followed by Dunnett's test for multiple comparisons to the negative control. EGF and EGFR showed similar expression patterns, being highly expressed around implantation time and then disappearing. TGF-α and Areg expression levels rose steadily until they peaked at PD30, after which they gradually decreased to PD12 levels. The Areg mRNA expression pattern was confirmed by real-time PCR, and similar Areg protein expression patterns were observed. Immunohistochemical analysis of PD60 uteri revealed Areg in the glandular and luminal epithelial cells. Hb-EGF was steadily expressed throughout the entire pregnancy while CaBP-9k was expressed strongly on PD12, and then declined sharply in PD15 before recovering slightly for the remainder of the pregnancy. Thus, the EGF family may play a key role during implantation in pigs. In addition, CaBP-9k may help maintain uterine quiescence during pregnancy by sequestering cytoplasmic Ca2+.

Download Full-text