Synthetic Toll-like receptor agonists for the development of powerful malaria vaccines: a patent review
TL;DR: TLR agonists are promising adjuvants for the development of effective malaria vaccine, allowing for both innate inflammatory responses as well as the induction of adaptive immunity.
Abstract: Introduction: Currently, there is no efficient vaccine available against clinical malaria. However, continuous efforts have been committed to develop powerful antimalarial vaccine by discovery of n...
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TL;DR: A new bifunctional layer-by-layer (LbL) construct made by combining a permanent microbicidal polyelectrolyte multilayered (PEM) base film with a hydrolytically degradable PEM top film that offers controlled and localized delivery of therapeutics is presented.
Abstract: Here we present a new bifunctional layer-by-layer (LbL) construct made by combining a permanent microbicidal polyelectrolyte multilayered (PEM) base film with a hydrolytically degradable PEM top film that offers controlled and localized delivery of therapeutics. Two degradable film architectures are presented: (1) bolus release of an antibiotic (gentamicin) to eradicate initial infection at the implant site, or (2) sustained delivery of an anti-inflammatory drug (diclofenac) to cope with inflammation at the site of implantation due to tissue injury. Each degradable film was built on top of a permanent base film that imparts the implantable device surface with microbicidal functionality that prevents the formation of biofilms. Controlled-delivery of gentamicin was demonstrated over hours and that of diclofenac over days. Both drugs retained their efficacy upon release. The permanent microbicidal base film was biocompatible with A549 epithelial cancer cells and MC3T3-E1 osteoprogenitor cells, while also pre...
97 citations
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TL;DR: Use of this platform to deliver a model whole‐protein vaccine with optimized release kinetics resulted in >10‐fold increases in antigen‐specific T‐cell and humoral immune responses relative to traditional parenteral needle‐based immunization.
Abstract: Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local infl ammatory responses in the skin, which are correlated with enhanced immune responses. Here, we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profi les present during natural acute infections. An approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base is reported. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1‐2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in > 10-fold increases in antigen-specifi c T-cell and humoral immune responses relative to traditional parenteral needle-based immunization. compared with traditional parenteral immunization approaches targeting less immunogenic tissues such as muscle (reviewed elsewhere). [ 1 ] Microneedle vaccination has in many cases also outperformed hypodermic needle-based delivery to the skin, suggesting the importance of factors relating to microneedle delivery itself, such as the infl ammatory state generated by micrometer-scale wounding following microneedle insertion. [ 2 , 3 ] Unrelated studies have begun to reveal the importance of antigen and adjuvant delivery kinetics in the developing immune response, both within the context of vaccination and in natural responses to infection. [ 4‐7 ] For example, the magnitude, functionality, and phenotype of CD8 + T-cell responses can be shaped by immunizations where antigen or adjuvant delivery kinetics are controlled over multi-week periods, with persistent antigenic and infl ammatory signals eliciting stronger responses than transient bolus vaccine exposure. [ 4 , 5 ] These fi ndings are consistent with known differences in the natural immunity generated against transient versus persistent pathogens, indicating specifi c mechanisms of immunity that may be exploited through engineered kinetics to yield greater vaccine effi cacy. We have recently begun to explore the combination of these two approaches for enhancing immunogenicity, through the
91 citations
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TL;DR: This perspective will highlight the recent discoveries in this field emphasizing the role of TLR isoforms in different diseases, the therapeutic effect of their natural and synthetic modulators and will discuss insights for the future exploitation of TLRs modulators in human health.
Abstract: Toll-like receptors (TLRs) are a class of proteins that recognize pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs), and they are involved in the regulation of innate immune system. These transmembrane receptors, localized at the cellular or endosomal membrane, trigger inflammatory processes through either myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathways. In the last decades, extensive research has been performed on TLR modulators and their therapeutic implication under several pathological conditions, spanning from infections to cancer, from metabolic disorders to neurodegeneration and autoimmune diseases. This Perspective will highlight the recent discoveries in this field, emphasizing the role of TLRs in different diseases and the therapeutic effect of their natural and synthetic modulators, and it will discuss insights for the future exploitation of TLR modulators in human health.
22 citations
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TL;DR: A detailed SAR in TLR2 agonistic scaffolds and also covered the design and chemistry for the conjugation of TLR 2 agonists to antigens, carbohydrates, polymers, and fluorophores are elaborated in this paper.
Abstract: Toll-like receptors (TLRs) are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) in microbial species. Among the various TLRs, TLR2 has a special place due to its ability to sense the widest repertoire of PAMPs owing to its heterodimerization with either TLR1 or TLR6, broadening its ligand diversity against pathogens. Various scaffolds are reported to activate TLR2, which include naturally occurring lipoproteins, synthetic lipopeptides, and small heterocyclic molecules. We described a detailed SAR in TLR2 agonistic scaffolds and also covered the design and chemistry for the conjugation of TLR2 agonists to antigens, carbohydrates, polymers, and fluorophores. The approaches involved in delivery of TLR2 agonists such as lipidation of antigen, conjugation to polymers, phosphonic acids, and other linkers to achieve surface adsorption, liposomal formulation, and encapsulating nanoparticles are elaborated. The crystal structure analysis and computational modeling are also included with the structural features that facilitate TLR2 activation.
5 citations
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TL;DR: The results confirmed that the R-stereochemistry at the thio-glycerol lipopeptide core was preferred for maximal TLR2/6 activity, as reflected in Th1 immune deviation, higher antibody levels and enhanced vaccine protection against a lethal influenza challenge.
Abstract: Lipopeptides including diacylated Pam2CSK4 as well as triacylated Pam3CSK4 act as ligands of toll-like receptor (TLR)-2, a promising target for the development of vaccine adjuvants. The highly investigated Pam2CSK4 and Pam3CSK4, despite their aqueous solubility have not performed well as vaccine adjuvants which may be attributable to potential denaturation of protein antigens by these cationic surfactant-like lipopeptides. In the present investigation, we synthesized (R), (S) and racemic Pam2CS(OMe) analogs and their N-acetyl derivatives without the tetralysine component to systematically investigate the effect of stereochemistry at the thio-glycerol lipopeptide core of these lipopeptide based TLR2 agonists. The resulting compounds were compared using TLR2 reporter cell-based assays and the ability of the synthesized lipopeptides to stimulate cytokine production (IL-6, IL-10 and TNF-α) by freshly collected human PBMCs and CD40 and CD86 expressions by mouse spleen cells was also investigated. Notably, few synthesized lipopeptides were found to be potent TLR2/6 agonists, inducing cytokine production and upregulating CD40 and CD86 expressions. The TLR2/6 agonistic lipopeptides were further assessed for vaccine adjuvant effects in mice. The results confirmed that the R-stereochemistry at the thio-glycerol lipopeptide core was preferred for maximal TLR2/6 activity, as reflected in Th1 immune deviation, higher antibody levels and enhanced vaccine protection against a lethal influenza challenge.
3 citations
References
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TL;DR: Rapid progress that has recently improved the understanding of the molecular mechanisms that mediate TLR signalling is reviewed.
Abstract: One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. Here, we review the rapid progress that has recently improved our understanding of the molecular mechanisms that mediate TLR signalling.
7,430 citations
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TL;DR: The role of PRRs, their signaling pathways, and how they control inflammatory responses are discussed.
Abstract: Infection of cells by microorganisms activates the inflammatory response. The initial sensing of infection is mediated by innate pattern recognition receptors (PRRs), which include Toll-like receptors, RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors. The intracellular signaling cascades triggered by these PRRs lead to transcriptional expression of inflammatory mediators that coordinate the elimination of pathogens and infected cells. However, aberrant activation of this system leads to immunodeficiency, septic shock, or induction of autoimmunity. In this Review, we discuss the role of PRRs, their signaling pathways, and how they control inflammatory responses.
5,827 citations
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TL;DR: The role played by TLRs in mounting protective immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition is focused on.
Abstract: Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to microbial pathogens. TLR-mediated recognition of components derived from a wide range of pathogens and their role in the subsequent initiation of innate immune responses is widely accepted; however, the recent discovery of non-TLR PRRs, such as C-type lectin receptors, NOD-like receptors, and RIG-I-like receptors, suggests that many aspects of innate immunity are more sophisticated and complex. In this review, we will focus on the role played by TLRs in mounting protective immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition.
2,754 citations
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TL;DR: Possible areas of application for polyelectrolyte shells range from the pharmaceutical, food, cosmetic, and paint industries to catalysis and microcrystallization.
Abstract: Exact control of the film thickness of polyelectrolyte shells (a transmission electron microscopy image is shown) is achieved by colloid-templated consecutive adsorption of polyanions and polycations followed by decomposition of the templating core. Possible areas of application for these shells range from the pharmaceutical, food, cosmetic, and paint industries to catalysis and microcrystallization.
1,715 citations
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TL;DR: The state of the art in the adjuvant field is reviewed, future directions of adjUvant development are explored, some of the impediments and barriers to development and registration of new human adjuvants are examined and some of those barriers are examined are examined.
Abstract: The problem with pure recombinant or synthetic antigens used in modern day vaccines is that they are generally far less immunogenic than older style live or killed whole organism vaccines. This has created a major need for improved and more powerful adjuvants for use in these vaccines. With few exceptions, alum remains the sole adjuvant approved for human use in the majority of countries worldwide. Although alum is able to induce a good antibody (Th2) response, it has little capacity to stimulate cellular (Th1) immune responses which are so important for protection against many pathogens. In addition, alum has the potential to cause severe local and systemic side-effects including sterile abscesses, eosinophilia and myofascitis, although fortunately most of the more serious side-effects are relatively rare. There is also community concern regarding the possible role of aluminium in neurodegenerative diseases such as Alzheimer's disease. Consequently, there is a major unmet need for safer and more effective adjuvants suitable for human use. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally-delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. Each of these areas are highly specialized with their own unique needs in respect of suitable adjuvant technology. This paper reviews the state of the art in the adjuvant field, explores future directions of adjuvant development and finally examines some of the impediments and barriers to development and registration of new human adjuvants.
874 citations
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