Structure–Activity Relationship for the Development of a Self-Adjuvanting Mucosally Active Lipopeptide Vaccine against Streptococcus pyogenes

Zaman, Mehfuz; Abdel–Aal, Abu-Baker M.; Fujita, Yoshio; Ziora, Zyta M.; Batzloff, Michael R.; Good, Michael F.; Tóth, István

doi:10.1021/jm301074n

Cited by 44 publications

(40 citation statements)

References 40 publications

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“…23,33 Similarly, vaccine constructs (1, 2, 4 and 5) encompassed of LAAs C16 (single/ double copies) formed nanoparticles as determined by DLS and TEM (Table 1). Extreme particles size distribution of vaccine constructs 3 and 4 were illustrated in TEM images where their size ranging from 20 nm to 300 nm.…”

Section: Discussionmentioning

confidence: 95%

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Self-adjuvanting vaccine against group A streptococcus: Application of fibrillized peptide and immunostimulatory lipid as adjuvant

Azmi

Fuaad

Giddam

et al. 2014

Bioorganic & Medicinal Chemistry

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Peptides are of great interest to be used as vaccine antigens due to their safety, ease of manufacturing and specificity in generating immune response. There have been massive discoveries of peptide antigens over the past decade. However, peptides alone are poorly immunogenic, which demand co-administration with strong adjuvant to enhance their immunogenicity. Recently, fibril-forming peptides such as Q11 and lipoamino acid-based carrier have been identified to induce substantial immune responses when covalently linked to peptide epitope. In this study, we have incorporated either Q11 or lipoamino acids to a peptide epitope (J14) derived from M protein of group A streptococcus to develop self-adjuvanting vaccines. J14, Q11 and lipoamino acids were also conjugated together in a single vaccine construct in an attempt to evaluate the synergy effect of combining multiple adjuvants. Physicochemical characterization demonstrated that the vaccine constructs folded differently and self-assembled into nanoparticles. Significantly, only vaccine constructs containing double copies of lipoamino acids (regardless in conjugation with Q11 or not) were capable to induce significant dendritic cells uptake and subsequent J14-specific antibody responses in non-sizes dependent manners. Q11 had minimal impact in enhancing the immunogenicity of J14 even when it was used in combination with lipoamino acids. These findings highlight the impact of lipoamino acids moiety as a promising immunostimulant carrier and its number of attachment to peptide epitope was found to have a profound effect on the vaccine immunogenicity.

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Section: Discussionmentioning

confidence: 95%

“…19,20 Currently, many efforts have been made towards the development of vaccine delivery systems that utilizes J14 as a major protective epitope. [21][22][23] Herein, several potentially self-adjuvanting vaccine candidates incorporating J14 conjugation to Q11 or LAAs C16 (either single or double copies) have been synthesized (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Self-adjuvanting vaccine against group A streptococcus: Application of fibrillized peptide and immunostimulatory lipid as adjuvant

Azmi

Fuaad

Giddam

et al. 2014

Bioorganic & Medicinal Chemistry

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“…However, peptide-based vaccines are not immunogenic and require the addition of adjuvants or a delivery system for optimum efficacy. Recently, the J14 B-cell peptide epitope, along with the P25 universal T-helper epitope, were introduced into the lipid core peptide (LCP) system to form vaccine candidates against GAS (Figure 1) [20,21]. This lipopeptide, when delivered with the cationic liposome, chitosan, and PLGA-based nanocarriers significantly improved immune responses over free LCP-1 upon mucosal immunizations [8,9,13,15,16].…”

Section: Resultsmentioning

confidence: 99%

Poly-L-lysine-coated nanoparticles are ineffective in inducing mucosal immunity against group a streptococcus

Marasini¹,

Giddam²,

Batzloff³

et al. 2017

Bio Chem Comp

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Background: Group A Streptococcus (GAS) can cause a range of maladies, from simple throat infections to lethal complication, such as rheumatic heart disease. The M-protein, a bacterial cell surface protein, is the major virulence factor ofGAS. Several attempts have been made over the past few decades to develop vaccines against GASthat employed peptides derived from the M-protein. One suchapproach used lipopeptides or lipid core peptide (LCP) systems that incorporated a B-cell epitope derived from the conserved region of the M-protein. Methods:In the present study, we prepared different biodegradable polymer [dextran, poly-(lacticcoglycolic-acid) (PLGA), and poly-L-lysine] nanoparticles (NPs)-based delivery systems for a lipopeptidevaccine candidate (LCP-1).The NPs were characterised by their size, charge, morphology, antigen-presenting cells (APCs) uptake and subsequent APCs maturations efficacy, followed by in vivo nasal immunisation in mice. Results:All produced NPs ranged in size from 100-205 nm, and their charge varied depending upon the nature of polymer. A high APCs uptake efficacy for dextran and poly-L-lysine NPswere observed, compared to PLGA NPs. Despite the high uptake by APCs, dextran and poly-L-lysine NPs failed to improve APCs maturation that resulted in low antibody titres. In contrast, while LCP-1 encapsulated into PLGA showed low APCs uptake,it induced significant maturation of DCs and higher antibody titres compared to other NPs. Conclusions: Positively-charged poly-L-lysine NPswere non-immunogenic, while negatively charged PLGA NPs induced similar responses to antigens adjuvanted with cholera toxin B (CTB).

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“…This peptide is derived from a conserved fragment of Group A streptococcal M-protein that has a tendency to adopt a helical conformation and has been widely used for the development of peptide based vaccines [31][32][33]. The second B-cell epitope, 88/30 (DNGKAIYERARERALQELGP), was derived from the N-terminal hyper variable region of GAS M-protein, and has a tendency to form random coil rather than an ordered conformation.…”

Section: Resultsmentioning

confidence: 99%

pH-triggered peptide self-assembly into fibrils: a potential peptide-based subunit vaccine delivery platform

Skwarczynski¹,

Kowapradit²,

Ziora³

et al. 2013

Bio Chem Comp

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Background: Peptide-based subunit vaccines require strong adjuvants (immunostimulant) for therapeutic potency. There is strong demand for the discovery of new safe adjuvants and vaccine delivery systems that can be produced in a highly controlled manner. The pH dependent self-assembly of isopeptide derivatives into fibrils has been reported. Appropriately designed fibrils may have adjuvanting potency. Methods: Isopeptides conjugated to B-cell peptide epitopes (antigens) were synthesized. Properties of the resultant conjugates and their ability to undergo O-N intramolecular acyl migration reaction were analysed by HPLC, circular dichroism, and transmission electron microscopy. Results: The conjugates were converted to "parent" peptides via the pH-triggered O-N acyl migration reaction. The parent peptides aggregated into fibrils. The differences in conjugates composition resulted in different fibril morphology. Aggregation of produced peptides induced desired secondary conformation of antigens (peptide epitopes). Conclusions:The isopeptide approach presented herein may serve as a new self-adjuvanting delivery system for peptide-based vaccines. Such vaccines could be stable when stored in a non-aggregative form, and then converted on demand to the active form in pH-controlled manner. The use of a vaccine that is solely composed of endogenous components may reduce vaccine-associated side effects.

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Structure–Activity Relationship for the Development of a Self-Adjuvanting Mucosally Active Lipopeptide Vaccine against Streptococcus pyogenes

Cited by 44 publications

References 40 publications

Self-adjuvanting vaccine against group A streptococcus: Application of fibrillized peptide and immunostimulatory lipid as adjuvant

Self-adjuvanting vaccine against group A streptococcus: Application of fibrillized peptide and immunostimulatory lipid as adjuvant

Poly-L-lysine-coated nanoparticles are ineffective in inducing mucosal immunity against group a streptococcus

pH-triggered peptide self-assembly into fibrils: a potential peptide-based subunit vaccine delivery platform

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