Molecular adjuvants and immunomodulators: new approaches to immunization

Johnson, Arthur G.

doi:10.1128/cmr.7.3.277

Cited by 88 publications

(45 citation statements)

References 120 publications

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“…Chitin and chitosan are both components of fungal cell walls (10,11). Therefore, chitosan may provide a "danger signal" and be acting as an adjuvant, as do other conserved cellular components of microorganisms (27,28). In contrast, extracellular polysaccharides, such as gellan, can vary greatly from one bacteria to another (even within the same bacterial species), are often poorly immunogenic, and are not known to act as adjuvants.…”

Section: Discussionmentioning

confidence: 99%

Carbohydrate Biopolymers Enhance Antibody Responses to Mucosally Delivered Vaccine Antigens

Bacon

Makin²,

Sizer³

et al. 2000

Infect Immun

134

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Section: Discussionmentioning

confidence: 99%

Carbohydrate Biopolymers Enhance Antibody Responses to Mucosally Delivered Vaccine Antigens

Bacon

Makin²,

Sizer³

et al. 2000

Infect Immun

134

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“…The first microbial product discovered to bind TLRs was lipopolysaccharide (LPS) (234). Although LPS is a potent adjuvant for protein and carbohydrate antigens and induces both humoral and cellular immunity, its toxicity precludes its use in human vaccines (155). Investigators chemically modified lipid A by uncoupling its toxic effects while retaining its immunostimulatory effects (156).…”

Section: Special Considerations Adjuvantsmentioning

confidence: 99%

Coccidioidomycosis: Host Response and Vaccine Development

2004

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Coccidioidomycosis is caused by the dimorphic fungi in the genus Coccidioides. These fungi live as mycelia in the soil of desert areas of the American Southwest, and when the infectious spores, the arthroconidia, are inhaled, they convert into the parasitic spherule/endospore phase. Most infections are mild, but these organisms are frank pathogens and can cause severe lethal disease in fully immunocompetent individuals. While there is increased risk of disseminated disease in certain racial groups and immunocompromised persons, the fact that there are hosts who contain the initial infection and exhibit long-term immunity to reinfection supports the hypothesis that a vaccine against these pathogens is feasible. Multiple studies have shown that protective immunity against primary disease is associated with T-helper 1 (Th-1)-associated immune responses. The single best vaccine in animal models, formalin-killed spherules (FKS), was tested in a human trial but was not found to be significantly protective. This result has prompted studies to better define immunodominant Coccidioides antigen with the thought that a subunit vaccine would be protective. These efforts have defined multiple candidates, but the single best individual immunogen is the protein termed antigen 2/proline-rich antigen (Ag2/PRA). Studies in multiple laboratories have shown that Ag2/PRA as both protein and genetic vaccines provides significant protection against mice challenged systemically with Coccidioides. Unfortunately, compared to the FKS vaccine, it is significantly less protective as measured by both assays of reduction in fungal CFU and assays of survival. The capacity of Ag2/PRA to induce only partial protection was emphasized when animals were challenged intranasally. Thus, there is a need to define new candidates to create a multivalent vaccine to increase the effectiveness of Ag2/PRA. Efforts of genomic screening using expression library immunization or bioinformatic approaches to identify new candidates have revealed at least two new protective proteins, expression library immunization antigen 1 (ELI-Ag1) and a β-1,3-glucanosyltransferase (GEL-1). In addition, previously discovered antigens such as Coccidioides-specific antigen (CSA) should be evaluated in assays of protection. While studies have yet to be completed with combinations of the current candidates, the hypothesis is that with increased numbers of candidates in a multivalent vaccine, there will be increased protection. As the genome sequences of the two Coccidioides strains which are under way are completed and annotated, the effort to find new candidates can increase to provide a complete genomic scan for immunodominant proteins. Thus, much progress has been made in the discovery of subunit vaccine candidates against Coccidioides and there are several candidates showing modest levels of protection, but for complete protection against pulmonary challenge we need to continue the search for additional candidates

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“…Recently, the intrauterine administration of LPS in cattle was shown to facilitate clearance of chronic intrauterine infections associated with infertility (34). However, despite these potentially beneficial effects, the pharmacologic use of purified LPS (or lipid A) is precluded by its extreme toxicity; LPS is highly pyrogenic and promotes systemic inflammatory response syndrome (12). In an effort to uncouple the immunomodulatory effects of lipid A from its toxicity, Masihi et al (19) developed monophosphoryl lipid A (MLA); MLA comprises the lipid A portion of LPS from which the (R)-3-hydroxytetradecanoyl group and the 1-phosphate have been removed (24) by successive acid and base hydrolysis.…”

mentioning

confidence: 99%

Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge

et al. 2005

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A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.The toll-like receptors (TLRs) comprise an evolutionarily conserved receptor family that is capable of detecting and responding to microbial challenge (1). The TLRs recognize a variety of pathogen-specific components, including lipopolysaccharide (LPS), CpG DNA, and microbial membrane and cell wall components (20). Toll-like receptor 4 (TLR4) is critical for the recognition of LPS (30, 31), and considerable progress has recently been made in understanding the interaction of TLR4 with critical accessory molecules implicated in LPS recognition (8,9,17,21,22, 32,40,41). In this regard, it appears that LPS binding protein (LBP) promotes the binding of LPS to CD14, which in turn facilitates the association of the lipid A component of LPS with MD-2 to form a soluble complex that serves as an activating ligand for TLR4 on the cell surface. Binding of the MD-2/LPS complex to TLR4 results in the aggregation of TLR4 into lipid rafts and the activation of several distinct intracellular signaling pathways that results in increased transcription of many genes encoding cytokines, defensins, chemokines, and alpha/beta interferons (28, 38). These effector molecules determine a wide range of biological activities, including further production of cytokines, enhancement of microbicidal activity of phagocytic cells, and migration/maturation of dendritic cells (5,23,36).Before the discovery that LPS interacts with TLR4, evidence demonstrating the importance of innate immune activation in controlling infection with gram-neg...

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Molecular adjuvants and immunomodulators: new approaches to immunization

Cited by 88 publications

References 120 publications

Carbohydrate Biopolymers Enhance Antibody Responses to Mucosally Delivered Vaccine Antigens

Carbohydrate Biopolymers Enhance Antibody Responses to Mucosally Delivered Vaccine Antigens

Coccidioidomycosis: Host Response and Vaccine Development

Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge

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