Serological and conformational properties of E. coli K92 capsular polysaccharide and its N-propionylated derivative both illustrate that induced antibody does not recognize extended epitopes of polysialic acid: Implications for a comprehensive conjugate vaccine against groups B and C N. meningitidis

2002 ◽  
Vol 80 (8) ◽  
pp. 1055-1063 ◽  
Author(s):  
Robert A Pon ◽  
Nam Huan Khieu ◽  
Qing-Ling Yang ◽  
Jean-Robert Brisson ◽  
Harold J Jennings
Keyword(s):  
Molecular Dynamics ◽  
Immune Response ◽  
Conjugate Vaccine ◽  
Capsular Polysaccharide ◽  
Competitive Inhibition ◽  
Polysialic Acid ◽  
E Coli ◽  
Protective Epitope ◽  
Conformational Properties ◽  
Group B

The capsular polysaccharide of E. coli K92 (K92P) contains elements in common with the capsular polysaccharides of both groups B and C N. meningitidis, and may therefore form the basis of a bivalent vaccine. In an attempt to augment the cross-protective immune response to group B meningococci, the N-acetyl groups of the K92P were replaced by N-propionyl groups (NPrK92P) and conjugated to protein. This strategy had previously been applied with success to the poorly immunogenic capsular polysaccharide of group B meningococcus (GBMP), and the bactericidal epitope was found to be exclusively mimicked by extended helical segments of the NPrGBMP. The NPrK92P-conjugate, in relation to a K92P-conjugate, failed to enhance the response to GBMP but did generate a measurable response to NPrGBMP, but only at the expense of a greatly reduced GCMP response. Despite the presence of an immune response to NPrGBMP, the anti-NPrK92 serum was not bactericidal. Competitive inhibition studies with NPrGBMP oligosaccharides suggested the NPrK92 antibodies could not cross-react with the protective epitope on group B meningococci, as defined by extended helical segments of the NPrGBMP, but only recognized short non-bactericidal NPrGBMP epitopes. This hypothesis was supported from the conformational and molecular dynamics studies of the K92P, which demonstrated a lack of extended conformations that resemble the GBMP extended epitope. Indeed, the conformational properties of the K92P more closely resembled those of the GCMP, thereby explaining the observed moderate cross-protection of the K92P antiserum towards group C meningococci. Thus, on the basis of these results, it can be concluded that K92P, regardless of N-propionyl modification, will not serve as an effective single vaccine component against both groups B and C meningococci.Key words: conjugate vaccine, Neisseria meningitidis, polysialic acid, NMR, molecular dynamics.

scholarly journals N-Propionylated Group B Meningococcal Polysaccharide Mimics a Unique Bactericidal Capsular Epitope in Group B Neisseria meningitidis

1997 ◽  
Vol 185 (11) ◽  
pp. 1929-1938 ◽  
Author(s):  
Robert A. Pon ◽  
Michele Lussier ◽  
Qing-Ling Yang ◽  
Harold J. Jennings
Keyword(s):  
Conjugate Vaccine ◽  
Capsular Polysaccharide ◽  
Polysialic Acid ◽  
Passive Protection ◽  
E Coli ◽  
High Molecular Weight Form ◽  
Protective Epitope ◽  
Group B ◽  
Molecular Weight Form ◽  
Escherichia Coli K1

The N-propionylated group B meningococcal polysaccharide (NPrGBMP) mimics a unique protective epitope on the surface of group B meningococci (GBM) and Escherichia coli K1. Using a series of monoclonal antibodies (mAbs) induced by the NPrGBMP–monomeric tetanus toxoid (TT) conjugate vaccine it was demonstrated that mAbs having specificities for both extended and conventional short segments of the NPrGBMP were formed, but only the former were bactericidal, and/or gave passive protection against live challenge by GBM. The failure of mAbs specific for short epitopes to protect was further established when (NeuPr)4–TT was used as the vaccine. Of all the mAbs produced that were specific for short internal segments of the NPrGBMP, none were protective, despite the fact that most of them cross-react with the GBM capsular polysaccharide. In contrast, most of the protective mAbs produced by NPrGBMP– TT did not recognize the group B meningococcal polysaccharide (GBMP) unless it was present in its aggregated high molecular weight form. The bactericidal epitope mimicked by the NPrGBMP was shown to be ubiquitous in the capsule of both GBM and E. coli K1 using immunogold labeling techniques and, because of its unique properties, its identification could be significant in the development of a comprehensive conjugate vaccine against group B meningococcal meningitis. This is because most known human α(2–8)-polysialic acid self-antigens can be accommodated in 30–50 α(2–8)-linked sialic acid residues, which is roughly equivalent to an 11-kD length of the GBMP. It has been hypothesized that the formation of the protective epitope on the surface of GBM is due to the interaction of helical segments of the GBMP with another molecule and that the protective epitope is mimicked by the NPrGBMP. Support for the above hypothesis is provided by the fact that the protective NPrGBMP epitope has a similar unusual length dependency to that of the GBMP epitope.

scholarly journals Specificity of the Immune Response to a Modified Group B Meningococcal Polysaccharide Conjugate Vaccine

2006 ◽  
Vol 14 (1) ◽  
pp. 106-109 ◽  
Author(s):  
Samuel Moore ◽  
Esmé K. Farley ◽  
Peter C. Fusco ◽  
Francis Michon
Keyword(s):  
Immune Response ◽  
Conjugate Vaccine ◽  
Bactericidal Activity ◽  
Competitive Inhibition ◽  
Polysaccharide Vaccine ◽  
Killing Assay ◽  
Immunoaffinity Columns ◽  
Group B

ABSTRACT Antibodies to a modified group B meningococcal polysaccharide vaccine were examined for antigenic and functional specificities. Bactericidal determinants were investigated by using immunoaffinity columns and competitive inhibition of bactericidal activity in an in vitro killing assay. We conclude that nearly all of the vaccine-induced bactericidal activity is specific for the native polysaccharide.

scholarly journals Immunohistochemical localization of polysialic acid in tissue sections: differential binding to polynucleotides and DNA of a murine IgG and a human IgM monoclonal antibody.

1990 ◽  
Vol 38 (2) ◽  
pp. 209-215 ◽  
Author(s):  
M Husmann ◽  
J Roth ◽  
E A Kabat ◽  
C Weisgerber ◽  
M Frosch ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Capsular Polysaccharide ◽  
Polysialic Acid ◽  
Immunohistochemical Localization ◽  
Tissue Sections ◽  
Neural Cell Adhesion ◽  
Differential Binding ◽  
Group B ◽  
Unambiguous Detection

For immunolocalization of alpha(2-8)-linked polysialic acid, which forms part of the neural cell adhesion molecule (N-CAM), two monoclonal antibodies, MAb735 and IgMNOV, were employed. Both antibodies have previously been shown to bind the extremely low immunogenic capsular polysaccharide of group B meningococci, which also consists of alpha(2-8) polysialic acid, but not to other, even closely related forms of polysialic acid. Despite the identical polysaccharide specificity of these two MAb, we observed marked differences of the staining pattern in tissue sections. We showed that these differences in immunostaining were due to the crossreactivity of IgMNOV with polynucleotides and DNA. MAb735, however, was shown to react exclusively with alpha(2-8) polysialic acid. Moreover, the specificity of MAb735 proved to be unique among eleven other MAb directed against various bacterial polysaccharides, as it was the only one unreactive with polynucleotides. Thus, MAb735, the only IgG type mouse monoclonal antibody to polysialic acid thus far reported, can be considered a specific probe for the unambiguous detection of alpha(2-8) polysialic acid in tissue sections, and should therefore help to further elucidate the role of polysialic acid in developmental processes.

scholarly journals Epitopes Recognized by a Nonautoreactive Murine Anti-N-Propionyl Meningococcal Group B Polysaccharide Monoclonal Antibody

2005 ◽  
Vol 73 (4) ◽  
pp. 2123-2128 ◽  
Author(s):  
Gregory R. Moe ◽  
Apurva Dave ◽  
Dan M. Granoff
Keyword(s):  
Monoclonal Antibody ◽  
Capsular Polysaccharide ◽  
Polysialic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ionization Time ◽  
Protein Carriers ◽  
Protein Conjugate ◽  
Meningococcal Group ◽  
Group B ◽  
Antigenic Targets

ABSTRACT The capsular polysaccharide of Neisseria meningitidis group B (MBPS) is a polymer of alpha (2→8) N-acetyl neuraminic acid. The polysaccharide is chemically identical to an autoantigen, polysialic acid (PSA), and is a poor immunogen, even when conjugated to protein carriers. Immunization of mice with MBPS-protein conjugate vaccines, in which N-acetyl groups have been replaced by propionyl groups (N-Pr MBPS), elicits serum bactericidal antibodies. A subpopulation of these antibodies do not cross-react with human PSA. The reasons for the increased immunogenicity of N-Pr MBPS and the antigenic targets of the bactericidal nonautoreactive antibodies are unknown. In this study, we investigated the antigenic targets of a protective murine monoclonal antibody (MAb) prepared against a N-Pr MBPS-tetanus toxoid conjugate vaccine. Binding of the MAb to N-Pr MBPS (as demonstrated by an enzyme-linked immunosorbent assay) and bactericidal activity were inhibited by de-N-acetylated MBPS and re-N-acetylated MBPS, which indicate that N-propionyl groups are not obligatory determinants for binding. The results of affinity selection from a preparation of N-Pr MBPS and matrix-assisted laser desorption ionization-time of flight mass spectroscopic analysis indicated that the minimal epitope recognized by the MAb is a MBPS disaccharide containing one de-N-acetylated residue. Thus, the bacterial capsular epitope recognized by this bactericidal, nonautoreactive, anti-group-B MAb likely contains de-N-acetyl residues.

scholarly journals OC 8465 THE DEVELOPMENT OF A CONJUGATE VACCINE AGAINST GROUP B STREPTOCOCCUS: AN AFRICAN PERSPECTIVE

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A8.1-A8
Author(s):  
Seanette Wilson ◽  
Patrick Tippoo
Keyword(s):  
South Africa ◽  
Clinical Trial ◽  
Conjugate Vaccine ◽  
Capsular Polysaccharide ◽  
Disease Risk ◽  
Group B Streptococcus ◽  
International Health ◽  
Infant Deaths ◽  
Young Infants ◽  
Group B

BackgroundStreptococcus agalactiae, or group B streptococcus (GBS), is a gram-positive streptococcal bacterium that is well-recognised as one of the leading causes of infant death, particularly in the early neonatal period (the first week of life). An estimated one in five pregnant women around the world carries GBS bacteria in their gastrointestinal or genitourinary tracts and vertical transmission from colonised mothers can lead to invasive disease in their offspring. A recent study conservatively estimated that out of 410,000 GBS cases globally every year, there are at least 1 47 000 stillbirths and infant deaths. Despite being home to only 13% of the world’s population, Africa has the highest GBS disease burden, with 54% of estimated cases and 65% of stillbirths and infant deaths.An effective GBS vaccine, given during pregnancy, is a promising strategy to protect against GBS disease. Currently, no licensed vaccine exists to prevent it, but scientific evaluation of feasibility is favourable. The leading vaccine candidates are capsular polysaccharide-protein conjugate vaccines. Evidence suggests maternal immunisation with a safe and effective GBS vaccine may reduce the disease risk in neonates and young infants.The Biovac Institute was established as a private-public partnership and is the only Southern African vaccine manufacturer. Located in Cape Town, South Africa, Biovac’s mission is to become a leading vaccine developer and producer in South Africa to increase capacity in Africa which only has four other vaccine manufacturers.In collaboration with PATH, an international health organisation, and other partners, Biovac is developing a multivalent conjugate vaccine against GBS. The first stage of the project involves the development of biopharmaceutical manufacturing processes and analytical tests, the preparation of clinical trial product, and execution of a first-in-human clinical trial.This presentation will provide an overview of the project, progress to date, and the path to commercialisation.

scholarly journals Prevention and Cure of Systemic Escherichia coli K1 Infection by Modification of the Bacterial Phenotype

2004 ◽  
Vol 48 (5) ◽  
pp. 1503-1508 ◽  
Author(s):  
Naseem Mushtaq ◽  
Maria B. Redpath ◽  
J. Paul Luzio ◽  
Peter W. Taylor
Keyword(s):  
Escherichia Coli ◽  
Capsular Polysaccharide ◽  
Virulent Strain ◽  
Polysialic Acid ◽  
Intraperitoneal Administration ◽  
Systemic Infection ◽  
E Coli ◽  
Inhibition Of Growth ◽  
Old Rats ◽  
Prevention And Cure

ABSTRACT Escherichia coli is a common cause of meningitis and sepsis in the newborn infant, and the large majority of isolates from these infections produce a polysialic acid (PSA) capsular polysaccharide, the K1 antigen, that protects the bacterial cell from immune attack. We determined whether a capsule-depolymerizing enzyme, by removing this protective barrier, could alter the outcome of systemic infection in an animal model. Bacteriophage-derived endosialidase E (endoE) selectively degrades the PSA capsule on the surface of E. coli K1 strains. Intraperitoneal administration of small quantities of recombinant endoE (20 μg) to 3-day-old rats, colonized with a virulent strain of K1, prevented bacteremia and death from systemic infection. The enzyme had no effect on the viability of E. coli strains but sensitized strains expressing PSA to killing by the complement system. This study demonstrates the potential therapeutic efficacy of agents that cure infections by modification of the bacterial phenotype rather than by killing or inhibition of growth of the pathogen.

scholarly journals A human monoclonal macroglobulin with specificity for alpha(2----8)-linked poly-N-acetyl neuraminic acid, the capsular polysaccharide of group B meningococci and Escherichia coli K1, which crossreacts with polynucleotides and with denatured DNA.

1986 ◽  
Vol 164 (2) ◽  
pp. 642-654 ◽  
Author(s):  
E A Kabat ◽  
K G Nickerson ◽  
J Liao ◽  
L Grossbard ◽  
E F Osserman ◽  
...  
Keyword(s):  
Capsular Polysaccharide ◽  
Neuraminic Acid ◽  
Molecular Structures ◽  
Human Pathogens ◽  
E Coli ◽  
Group B ◽  
Antigen Antibody ◽  
Antibody Interactions ◽  
Escherichia Coli K1 ◽  
Horse Antiserum

We have described an IgM antibody from a patient with macroglobulinemia specifically reacting with poly-alpha(2----8)N-acetyl neuraminic acid (NeuNAc) the capsular polysaccharide of two important human pathogens, group B meningococcus and E. coli K1. This antibody has a narrowly defined specificity in its interactions with polysaccharides, being unable to bind poly-alpha(2----9)NeuNAc or alternating poly-alpha(2----8)alpha(2----9)NeuNAc. However, it shows interesting crossreactivity with seemingly unrelated polynucleotides and denatured DNA, supporting the hypothesis that charged groups with a given spacing may determine the specificity of antigen-antibody interactions on otherwise dissimilar molecular structures. Despite the crossreactivity with denatured DNA and polynucleotides, the antibody does not appear to have adverse effects in the patient. The antibody protects newborn rats against E. coli K1 infection, as well as the standard horse antiserum H46, and one would expect it to prove useful in humans as an adjunct to antibiotic therapy in infections with group B meningococcus and E. coli K1. We have attempted to clone the antibody-producing cells from peripheral blood, and have shown that the relevant cells are present and can be cultured.

scholarly journals Effects of Alum Adjuvant or a Booster Dose on Immunogenicity during Clinical Trials of Group B Streptococcal Type III Conjugate Vaccines

2001 ◽  
Vol 69 (11) ◽  
pp. 6696-6701 ◽  
Author(s):  
L. C. Paoletti ◽  
M. A. Rench ◽  
D. L. Kasper ◽  
D. Molrine ◽  
D. Ambrosino ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Conjugate Vaccine ◽  
Capsular Polysaccharide ◽  
Phase 1 ◽  
Geometric Mean ◽  
Healthy Adults ◽  
Conjugate Vaccines ◽  
Type Iii ◽  
Specific Igg ◽  
Group B

ABSTRACT Phase 1 and 2 clinical trials of group B streptococcal (GBS) capsular polysaccharide (CPS)-protein conjugate vaccines in healthy adults have demonstrated their safety and improved immunogenicity compared with uncoupled CPSs. Two recent trials sought to determine (i) whether adsorption of conjugate vaccine to aluminum hydroxide would improve immunogenicity and (ii) whether the CPS-specific immunoglobulin G (IgG) response could be boosted by administration of a second dose. Adsorption of GBS type III CPS-tetanus toxoid (III-TT) conjugate vaccine to alum did not improve the immune response to a 12.5-μg dose in healthy adult recipients. Four weeks after vaccination, the geometric mean antibody concentrations (GMCs) for the 15 recipients of III-TT with or without alum were 3.3 and 3.6 μg/ml, respectively. In the second trial, 36 healthy adults vaccinated previously with GBS III-TT conjugate were given a second 12.5-μg dose 21 months later. At 4 weeks after the second dose, the GMCs of type III CPS-specific IgG were similar to those measured 4 weeks after the primary vaccination, suggesting a lack of a booster response. However, 8 (22%) of the 36 participants who had undetectable III CPS-specific IgG (<0.05 μg/ml) before the first dose of III-TT conjugate exhibited a booster response to the second dose, with a fourfold-greater GMC of type III CPS-specific IgG than after the initial immunization. These results suggest that prior natural exposure to type III GBS or a related antigen may be responsible for the brisk IgG response to CPS noted in most adults after vaccination. However, a second dose of GBS III-TT conjugate vaccine may be required for adults whose initial CPS-specific IgG concentrations are very low and would also restore the initial peak-specific III CPS-IgG in responders to previous vaccination.

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