A DNA vaccine encoding a peptide mimic of Streptococcus pneumoniae serotype 4 capsular polysaccharide induces specific anti-carbohydrate antibodies in Balb/c mice

Lesinski, Gregory B.; Smithson, S. Louise; Srivastava, N C; Chen, Dexiang; Widera, Georg; Westerink, M. A. Julie

doi:10.1016/s0264-410x(00)00397-2

Cited by 67 publications

(42 citation statements)

References 51 publications

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“…The ability of the gun to deliver drugs is unsatisfactory. However, the PNI technique might be suitable for use in gene delivery, as confirmed by some studies using the PowderJect device (Lesinski et al, 2001).…”

Section: Discussionmentioning

confidence: 90%

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment

Wang

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:Insulin is widely used in treating diabetes, but still needs to be administered by needle injection. This study investigated a new needle-free approach for insulin delivery. A portable powder needleless injection (PNI) device with an automatic mechanical unit was designed. Its efficiency in delivering insulin was evaluated in alloxan-induced diabetic rabbits. The skin irritation caused by the device was investigated and the results were analyzed in relation to aerodynamic parameters. Inorganic salt-carried insulin powders had hypoglycemic effects, while raw insulin powders were not effective when delivered by PNI, indicating that salt carriers play an important role in the delivery of insulin via PNI. The relative delivery efficiency of phosphate-carried insulin powder using the PNI device was 72.25%. A safety assessment test showed that three key factors (gas pressure, cylinder volume, and nozzle distance) were related to the amount of skin irritation caused by the PNI device. Optimized injection conditions caused minimal skin lesions and are safe to use in practice. The results suggest that PNI has promising prospects as a novel technology for delivering insulin and other biological drugs.

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Section: Discussionmentioning

confidence: 90%

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment

Wang

et al. 2014

J. Zhejiang Univ. Sci. B

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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: 91%

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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“…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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confidence: 99%

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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A DNA vaccine encoding a peptide mimic of Streptococcus pneumoniae serotype 4 capsular polysaccharide induces specific anti-carbohydrate antibodies in Balb/c mice

Cited by 67 publications

References 51 publications

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment

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

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