Induction of a protective capsular polysaccharide antibody response to a multiepitope DNA vaccine encoding a peptide mimic of meningococcal serogroup C capsular polysaccharide

Prinz, Deborah M.; Smithson, S. Louise; Kieber‐Emmons, Thomas; Westerink, M. A. Julie

doi:10.1046/j.1365-2567.2003.01732.x

Cited by 22 publications

(18 citation statements)

References 89 publications

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“…For a peptide to succeed as an immunogen that can generate a specific anticarbohydrate antibody response, carbohydratepeptide cross-reactivity must translate into immunogenic mimicry (i.e., the ability of a crossreactive peptide to elicit that same antibody, or functionally similar ones). Immunogenic mimicry of carbohydrate epitopes by peptides has been previously reported (22)(23)(24)(25)(26)(49)(50)(51), which suggests that cross-reacting peptides may elicit antibodies functionally equivalent to those elicited by carbohydrate epitopes. In contrast, our preliminary immunization of rabbits with recombinant 2G12.1 phage produced a significant antipeptide response but no crossreactivity with gp120, indicating that 2G12.1 elicits an antibody response that is qualitatively different from 2G12 (see Supplemental Table 3 and Supplemental Fig.…”

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confidence: 92%

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

Menéndez

Calarese

Stanfield³

et al. 2008

FASEB j.

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MAb 2G12 neutralizes HIV-1 by binding with high affinity to a cluster of high-mannose oligosaccharides on the envelope glycoprotein, gp120. Screening of phage-displayed peptide libraries with 2G12 identified peptides that bind specifically, with K d s ranging from 0.4 to 200 μM. The crystal structure of a 21-mer peptide ligand in complex with 2G12 Fab was determined at 2.8 Å resolution. Comparison of this structure with previous structures of 2G12-carbohydrate complexes revealed striking differences in the mechanism of 2G12 binding to peptide vs. carbohydrate. The peptide occupies a site different from, but adjacent to, the primary carbohydrate-binding site on 2G12, and makes only slightly fewer contacts to the Fab than Man 9 GlcNAc 2 (51 vs. 56, respectively). However, only two antibody contacts with the peptide are hydrogen bonds in contrast to six with Man 9 GlcNAc 2 , and only three of the antibody residues that interact with Man 9 GlcNAc 2 also contact the peptide. Thus, this mechanism of peptide binding to 2G12 does not support structural mimicry of the native carbohydrate epitope on gp120, since it neither replicates the oligosaccharide footprint on the antibody nor most of the contact residues. Moreover, 2G12.1 peptide is not an immunogenic mimic of the 2G12 epitope, since antisera produced against it did not bind gp120.-Menendez, A., Calarese, D. A., Stanfield, R. L., Chow, K. C., Scanlan, C. N., Kunert, R., Katinger, H., Burton, D. R., Wilson, I. A., Scott, J. K. A peptide inhibitor of HIV-1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHuman monoclonal antibody (MAb) 2G12 efficiently neutralizes a broad range of HIV-1 primary isolates in vitro (1-3) and protects from in vivo viral challenge in macaques in combination with other antibodies (4-6). MAb 2G12 binds with high affinity to a unique, conserved epitope on the HIV-1 envelope that is formed by a cluster of N-linked, high-mannose glycan groups on the "silent" face of gp120 (7-10). Crystal structures of 2G12 Fab alone, and in complex with oligosaccharides Man 9 GlcNAc 2 and Manα1-2Man, revealed that two Fab monomers assemble into an interlocked, domain-swapped dimer, that forms an extensive, multivalent binding surface (11). Four Man 9 GlcNAc 2 moieties were observed bound to the Fab dimer in the crystal structure, occupying the two canonical antigen-binding sites, and two novel ones located at the assembled interface of the two interlocked V H domains. Since the identification of its epitope, MAb 2G12 has received significant attention as a template for HIV-1 vaccine development. Considerable effort has been directed at characterizing its oligosaccharide-binding profile (12)(13)(14)(15), and the generation of novel antigens in the form of synthetic oligomannoses (13,16,17) or short, synthetic glycopeptides (18-20). In an attempt to generate immunogens that elicit 2G12-like antibodies, we chose to isolate peptides t...

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confidence: 92%

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

Menéndez

Calarese

Stanfield³

et al. 2008

FASEB j.

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“…The demonstration that this approach can induce cross-reactive antibodies has already been achieved for a number of other micro-organisms. Westerink and collaborators obtained an anti-meningococcal group C capsular polysaccharide response by vaccination with a peptide spanning the CDR3 domain of an antiidiotypic antibody mimicking the anti-meningococcal group C capsular polysaccharide [10,11]. Phalipon et al selected immunogenic peptide mimics from a phage-display library using monoclonal antibodies specific for the O-antigen of Shigella flexneri serotype 5a lipopolysaccharide.…”

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confidence: 99%

“…Antibodies in each of the sera bound the peptide and in each case binding was inhibited by prior incubation of the serum with 9V polysaccharide, (25, 27 and 37% inhibition). The sequences of the peptides selected by biopanning with mAb 206, F-5 are presented in Table 1.mAb Db3G9 selected seven positive phage clones from four rounds of biopanning phage-displayed peptide libraries (MP2,10,13,14,15, 17 and 18). Figure 2 shows the reactivity of the phage-displayed peptides to the mAb in ELISA.…”

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Peptide mimics of two pneumococcal capsular polysaccharide serotypes (6B and 9V) protect mice from a lethal challenge with Streptococcus pneumoniae

et al. 2009

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Anti-polysaccharide immunity is a key facet of protection against several bacterial pathogens. Problems exist with current polysaccharide vaccines and alternative strategies that deliver a protective response are needed. We have identified immunological peptide mimics of type 6B and 9V pneumococcal capsular polysaccharides that could be used as vaccine antigens. Peptides mimicking antigenic properties of serotype 6B capsular polysaccharide were obtained from a phage-displayed peptide library expressing dodecameric peptides, using a human monoclonal antibody (Db3G9). A murine monoclonal antibody (206, F-5) against the serotype 9V capsular polysaccharide identified three peptide mimotopes from the dodecameric peptide library and one from a random pentadecameric peptide library. In ELISA, binding of 206, F-5 and Db3G9 to phage displaying the selected mimotopes was significantly inhibited by type-specific pneumococcal polysaccharide. Peptides were conjugated to keyhole limpet haemocyanin and were used to immunise mice. Two peptides, MP13 and MP7, induced specific anti-6B and 9V polysaccharide antibodies, respectively. Mice immunised with MP7-keyhole limpet hemocyanin or MP13-keyhole limpet hemocyanin conjugate were significantly and specifically protected against a lethal challenge with pneumococci of the appropriate serotype. This study provides strong in vivo evidence that peptide mimics are alternatives to polysaccharide vaccines.Key words: Mimotope . Peptide . Polysaccharide . Streptococcus pneumoniae .Vaccine IntroductionStreptococcus pneumoniae (the pneumococcus) remains a major cause of morbidity and mortality worldwide, causing diseases such as pneumonia, septicaemia, meningitis and otitis media [1]. It is well known that protective immunity to S. pneumoniae can result from the development of specific antibodies against pneumococcal capsular polysaccharides. In 1983 a vaccine (Pneumovax) composed of a mixture of 23 capsular serotypes was licensed for use [1]. Unfortunately, this vaccine has proved to be ineffective for the most at risk groups, particularly infants. Problems arise because polysaccharide antigens cannot be To circumvent the T-independence problem, major research efforts focused on a vaccine in which protein is chemically conjugated to polysaccharide. In this form the polysaccharide is converted to a T-dependent antigen. This increases its immunogenicity and stimulates immunological memory. Recently, a conjugate vaccine (Prevenar) composed of seven capsular serotypes was licensed for use in infants. Undoubtedly, the conjugate vaccine has been successful in reducing invasive pneumococcal disease in children [3][4][5]. However, the purification of polysaccharide, the need for multiple protein conjugations and the quality control issues make this a very expensive approach. Added to this is the question of the very restricted serotype coverage by the vaccine and the possibility that the low serotype coverage increases the opportunity for serotype replacement [6][7][8][9].An alternative approach is...

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“…Such peptide mimics have been proposed as potential surrogate antigens of carbohydrates for vaccine development against several microorganisms (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) and tumors (22)(23)(24)(25). Indeed, because of their ease of production and their intrinsic immunogenic properties, peptide mimotopes may have several advantages over incorporating complex carbohydrate haptens issued from bacterial cell cultures or low yielding syntheses.…”

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confidence: 99%

“…Panning and screening phage display libraries with mAbs has identified peptide mimics of surface carbohydrate structures of several pathogens and tumors that have also been used as immunogens to elicit cross-reactive carbohydrate-directed responses (11,(13)(14)(15)(16). However, only a few peptide mimics of surface carbohydrate structures have been shown to induce a protective immune response (17)(18)(19)(20)(21)(22)(23).…”

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confidence: 99%

Development of Peptide Mimics of a Protective Epitope of Vibrio cholerae Ogawa O-antigen and Investigation of the Structural Basis of Peptide Mimicry

Dharmasena

Jewell

Taylor

2007

Journal of Biological Chemistry

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As an alternative approach toward the development of a cholera vaccine, the potential of peptide mimics of Vibrio cholerae lipopolysaccharide (LPS) to elicit cross-reactive immune responses against LPS was investigated. Two closely related protective monoclonal antibodies, S-20-4 and A-20-6, which are specific for Ogawa O-antigen (O-specific polysaccharide; O-SP) of V. cholerae O1, were used as the target antibodies (Abs) to pan phage display libraries under different elution conditions. Six phage clones identified from S-20-4 panning showed significant binding to both S-20-4 and A-20-6. Thus, it is likely that these phage-displayed peptides mimic an important conformational epitope of Ogawa antigens and are not simply functionally recognized by S-20-4. Each of the six phage clones that could bind to both monoclonal antibodies also competed with LPS for binding to S-20-4, suggesting that the peptides bind close to the paratope of the Ab. In order to predict how these peptide mimics interact with S-20-4 compared with its carbohydrate counterpart, one peptide mimic, 4P-8, which is one of the highest affinity binders and shares motifs with several other peptide mimics, was selected for further studies using computer modeling methods and site-directed mutagenesis. These studies suggest that 4P-8 is recognized as a hairpin structure that mimics some O-SP interactions with S-20-4 and also makes unique ligand interactions with S-20-4. In addition, 4P-8-KLH was able to elicit anti-LPS Abs in mice, but the immune response was not vibriocidal or protective. However, boosting with 4P-8-KLH after immunizing with LPS prolonged the LPS-reactive IgG and IgM Ab responses as well as vibriocidal titers and provided a much greater degree of protection than priming with LPS alone.Cholera is a severe diarrheal disease caused by the bacterium Vibrio cholerae, which is prevalent in many developing countries. According to the World Health Organization, an estimated 120,000 deaths occur from cholera worldwide each year. Although the establishment of clean water and food, adequate personal hygiene, and sanitation are the long term solutions for cholera control, in the short term, sufficient improvements in these areas are difficult to achieve in most cholera-endemic areas. Meanwhile, there is an urgent need for improved vaccines as an additional public health tool for cholera prevention (1). Since the affected population is very poor, development of an inexpensive vaccine is most desirable.Currently available vaccines for cholera are based on killed, whole cell, or live attenuated formulations. The killed, whole cell (WC and WCrBS) vaccines provide only partial short term protection. The live, attenuated strains, such as CVD 103-HgR, have greatly improved efficacy in North American volunteers but have not been proven efficacious in field trials (1, 2). However, field trials of the live attenuated strain Peru-15 have proven to be safe, immunogenic, and efficacious (3). An approach that could serve as an alternative or be used to augment e...

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Induction of a protective capsular polysaccharide antibody response to a multiepitope DNA vaccine encoding a peptide mimic of meningococcal serogroup C capsular polysaccharide

Cited by 22 publications

References 89 publications

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120

Peptide mimics of two pneumococcal capsular polysaccharide serotypes (6B and 9V) protect mice from a lethal challenge with Streptococcus pneumoniae

Development of Peptide Mimics of a Protective Epitope of Vibrio cholerae Ogawa O-antigen and Investigation of the Structural Basis of Peptide Mimicry

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