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1.
Vaccine ; 40(52): 7676-7692, 2022 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-36376214

RESUMEN

Syphilis continues to be a significant public health concern worldwide. The disease is endemic in many low- and middle-income countries, and rates have risen sharply in high-income countries over the last decade. The continued prevalence of infectious and congenital syphilis worldwide highlights the need for the development of an effective syphilis vaccine to complement public health measures for syphilis control. The complex, multi-stage course of syphilis infection necessitates a holistic approach to the development of an effective vaccine, in which immunization prevents both the localized stage of infection (typified by the highly infectious chancre) and the disseminated stages of infection (typified by the secondary rash, neurosyphilis, and destructive tertiary lesions, as well as congenital syphilis). Inhibiting development of the infectious chancre would reduce transmission thus providing community- level protection, while preventing dissemination would provide individual-level protection by reducing serious sequelae and may also provide community level protection by reducing shedding during secondary syphilis. In the current study we build upon prior investigations which demonstrated that immunizations with individual, well characterized T. pallidum TprK, TprC, and Tp0751 peptides elicits partial protection against infection in the animal model. Specifically, we show here that immunization with a TprC/TprK/Tp0751 tri-antigen cocktail protects animals from progressive syphilis lesions and substantially inhibits dissemination of the infection.


Asunto(s)
Chancro , Sífilis Congénita , Sífilis , Animales , Treponema pallidum , Sífilis/prevención & control , Carga Bacteriana , Vacunas Bacterianas , Inmunización
2.
Nanoscale ; 12(4): 2515-2523, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31930264

RESUMEN

The growing shift to subunit antigen vaccines underscores the need for adjuvants that can enhance the magnitude and quality of immune response. Aluminum salts or alums are the first adjuvants with a long history of clinical use. Alum predominantly induces T helper 2 (TH2) type immunity in animal models, characterized by antibody production with little to no induction of antigen-specific T cells. The lack of cell-mediated or T helper 1 (TH1) immunity makes alum adjuvants ineffective in mounting durable responses against diseases like tuberculosis, malaria and HIV. Here we show that the clinically approved adjuvant, Alhydrogel, reformulated as a stable nanoparticle (nanoalum) with the anionic polymer polyacrylic acid (PAA) induces structure-dependent TH1 response against the recombinant tuberculosis antigen ID93. We found that PAA adsorption to Alhydrogel was a key parameter affecting nanoalum adjuvanticity. Adsorption depended on various factors, most notably formulation pH, and directly correlated with immunological response in mice, enhancing known hallmarks of a murine TH1 type response: induction of antigen-specific IFN-γ secreting CD4+ T cells and IgG2c subclass of antibodies. Our results demonstrate a correlation between a measurable nanoalum property and immunological response, providing a structural basis to derive a beneficial immunological outcome from a clinically approved adjuvant.


Asunto(s)
Resinas Acrílicas/química , Linfocitos T CD4-Positivos/citología , Diferenciación Celular/efectos de los fármacos , Nanopartículas/química , Células TH1/citología , Adsorción , Compuestos de Aluminio/química , Hidróxido de Aluminio/química , Óxido de Aluminio/química , Animales , Citocinas/metabolismo , Femenino , Concentración de Iones de Hidrógeno , Inmunoglobulina G/química , Ratones , Ratones Endogámicos C57BL , Tamaño de la Partícula , Fosfatos/química , Polímeros/química , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X
3.
Front Immunol ; 11: 578715, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33732227

RESUMEN

Asiatic schistosomiasis caused by Schistosoma japonicum is a neglected tropical disease resulting in significant morbidity to both humans and animals - particularly bovines - in endemic areas. Infection with this parasite leads to less healthy herds, causing problems in communities which rely on bovines for farming, milk and meat production. Additionally, excretion of parasite eggs in feces perpetuates the life cycle and can lead to human infection. We endeavored to develop a minimally purified, inexpensive, and effective vaccine based on the 80 kDa large subunit of the calcium activated neutral protease (calpain) from S. japonicum (Sj-p80). Here we describe the production of veterinary vaccine-grade Sj-p80 at four levels of purity and demonstrate in a pilot study that minimally purified antigen provides protection against infection in mice when paired with a low-cost veterinary adjuvant, Montanide™ ISA61 VG. Preliminary data demonstrate that the vaccine is immunogenic with robust antibody titers following immunization, and vaccination resulted in a reduction of parasite eggs being deposited in the liver (23.4-51.4%) and intestines (1.9-55.1%) depending on antigen purity as well as reducing the ability of these eggs to hatch into miracidia by up to 31.6%. We therefore present Sj-p80 as a candidate vaccine antigen for Asiatic schistosomiasis which is now primed for continued development and testing in bovines in endemic areas. A successful bovine vaccine could play a major role in reducing pathogen transmission to humans by interrupting the parasitic life cycle and improving quality of life for people living in endemic countries.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antígenos Helmínticos/farmacología , Desarrollo de Medicamentos , Vacunas Antiprotozoos/farmacología , Schistosoma japonicum/patogenicidad , Esquistosomiasis Japónica/prevención & control , Drogas Veterinarias/farmacología , Adyuvantes Inmunológicos/economía , Animales , Anticuerpos Antihelmínticos/sangre , Antígenos Helmínticos/economía , Antígenos Helmínticos/inmunología , Bovinos , Análisis Costo-Beneficio , Modelos Animales de Enfermedad , Costos de los Medicamentos , Femenino , Interacciones Huésped-Patógeno , Inmunogenicidad Vacunal , Ratones Endogámicos C57BL , Recuento de Huevos de Parásitos , Proyectos Piloto , Vacunas Antiprotozoos/economía , Schistosoma japonicum/inmunología , Esquistosomiasis Japónica/parasitología , Esquistosomiasis Japónica/transmisión , Vacunación , Drogas Veterinarias/economía
4.
Phytomedicine ; 64: 152927, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31465981

RESUMEN

BACKGROUND: Next to aluminum salts, squalene nanoemulsions comprise the most widely employed class of adjuvants in approved vaccines. Despite their importance, the mechanisms of action of squalene nanoemulsions are not completely understood, nor are the structure/function requirements of the oil composition. PURPOSE: In this study, we build on previous work that compared the adjuvant properties of nanoemulsions made with different classes of oil structures to squalene nanoemulsion. Here, we introduce nanoemulsions made with polyprenols derived from species of the Pinaceae family as novel vaccine adjuvant compositions. In contrast with long-chain triglycerides that do not efficiently enhance an immune response, both polyprenols and squalene are comprised of multimeric isoprene units, which may represent an important structural property of oils in nanoemulsions with adjuvant properties. STUDY DESIGN: Oils derived from species of the Pinaceae family were formulated in nanoemulsions, with or without a synthetic Toll-like receptor 4 (TLR4) ligand, and characterized regarding physicochemical and biological activity properties in comparison to squalene nanoemulsions. METHODS: Oils were extracted from species of the Pinaceae family and used to prepare oil-in-water nanoemulsions by microfluidization. Emulsion droplet diameter stability was characterized by dynamic light scattering. Nanoemulsions were evaluated for in vitro biological activity using human whole blood, and in vivo biological activity in mouse, pig, and ferret models when combined with pandemic influenza vaccine antigens. RESULTS: Nanoemulsions comprised of Pinaceae-derived polyprenol oils demonstrated long-term physical stability, stimulated cytokine production from human cells in vitro, and promoted antigen-specific immune responses in various animal models, particularly when formulated with the TLR4 ligand glucopyranosyl lipid adjuvant (GLA). CONCLUSION: Pinaceae-derived nanoemulsions are compatible with inclusion of a synthetic TLR4 ligand and promote antigen-specific immune responses to pandemic influenza antigens in mouse, pig, and ferret models.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Pinaceae/química , Aceites de Plantas/farmacología , Poliprenoles/farmacología , Escualeno/farmacología , Adyuvantes Inmunológicos/química , Animales , Emulsiones , Femenino , Hurones , Humanos , Gripe Humana/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Aceites de Plantas/química , Poliprenoles/química , Organismos Libres de Patógenos Específicos , Escualeno/química , Porcinos , Receptor Toll-Like 4/inmunología
5.
J Immunol ; 201(1): 98-112, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29769270

RESUMEN

The involvement of innate receptors that recognize pathogen- and danger-associated molecular patterns is critical to programming an effective adaptive immune response to vaccination. The synthetic TLR4 agonist glucopyranosyl lipid adjuvant (GLA) synergizes with the squalene oil-in-water emulsion (SE) formulation to induce strong adaptive responses. Although TLR4 signaling through MyD88 and TIR domain-containing adapter inducing IFN-ß are essential for GLA-SE activity, the mechanisms underlying the synergistic activity of GLA and SE are not fully understood. In this article, we demonstrate that the inflammasome activation and the subsequent release of IL-1ß are central effectors of the action of GLA-SE, as infiltration of innate cells into the draining lymph nodes and production of IFN-γ are reduced in ASC-/- animals. Importantly, the early proliferation of Ag-specific CD4+ T cells was completely ablated after immunization in ASC-/- animals. Moreover, numbers of Ag-specific CD4+ T and B cells as well as production of IFN-γ, TNF-α, and IL-2 and Ab titers were considerably reduced in ASC-/-, NLRP3-/-, and IL-1R-/- mice compared with wild-type mice and were completely ablated in TLR4-/- animals. Also, extracellular ATP, a known trigger of the inflammasome, augments Ag-specific CD4+ T cell responses, as hydrolyzing it with apyrase diminished adaptive responses induced by GLA-SE. These data thus demonstrate that GLA-SE adjuvanticity acts through TLR4 signaling and NLRP3 inflammasome activation to promote robust Th1 and B cell responses to vaccine Ags. The findings suggest that engagement of both TLR and inflammasome activators may be a general paradigm for induction of robust CD4 T cell immunity with combination adjuvants such as GLA-SE.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antígenos/inmunología , Linfocitos B/inmunología , Inflamasomas/inmunología , Células TH1/inmunología , Receptor Toll-Like 4/inmunología , Vacunas/inmunología , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Proteínas Adaptadoras de Señalización CARD/genética , Femenino , Glucósidos/inmunología , Inmunidad Humoral , Interferón beta/inmunología , Interferón gamma/inmunología , Interleucina-1beta/metabolismo , Interleucina-2/inmunología , Lípido A/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptores Tipo I de Interleucina-1/genética , Escualeno/inmunología , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/inmunología , Vacunación
6.
Expert Rev Vaccines ; 15(5): 619-27, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26651503

RESUMEN

Schistosomiasis is a neglected tropical disease (NTD) of public health importance. Despite decades of implementation of mass praziquantel therapy programs and other control measures, schistosomiasis has not been contained and continues to spread to new geographic areas. A schistosomiasis vaccine could play an important role as part of a multifaceted control approach. With regards to vaccine development, many biological bottlenecks still exist: the lack of reliable surrogates of protection in humans; immune interactions in co-infections with other diseases in endemic areas; the potential risk of IgE responses to antigens in endemic populations; and paucity of appropriate vaccine efficacy studies in nonhuman primate models. Research is also needed on the role of modern adjuvants targeting specific parts of the innate immune system to tailor a potent and protective immune response for lead schistosome vaccine candidates with the long-term aim to achieve curative worm reduction. This review summarizes the current status of schistosomiasis vaccine development.


Asunto(s)
Descubrimiento de Drogas/tendencias , Esquistosomiasis/prevención & control , Vacunas/inmunología , Vacunas/aislamiento & purificación , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Primates
7.
J Biol Chem ; 280(23): 22053-9, 2005 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-15814612

RESUMEN

A unique feature of the Toxoplasma gondii purine salvage pathway is the expression of two isoforms of the hypoxanthine-xanthine-guanine phosophoribosyltransferase (HXGPRT) of the parasite encoded by a single genetic locus. These isoforms differ in the presence or absence of a 49-amino acid insertion (which is specified by a single differentially spliced exon) but exhibit similar substrate specificity, kinetic characteristics, and temporal expression patterns. To examine possible functional differences between the two HXGPRT isoforms, fluorescent protein fusions were expressed in parasites lacking the endogenous hxgprt gene. Immunoblot analysis of fractionated cell extracts and fluorescence microscopy indicated that HXGPRT-I (which lacks the 49-amino acid insertion) is found in the cytosol, whereas HXGPRT-II (which contains the insertion) localizes to the inner membrane complex (IMC) of the parasite. Simultaneous expression of both isoforms resulted in the formation of hetero-oligomers, which distributed between the cytosol and IMC. Chimeric constructs expressing N-terminal peptides from either isoform I (11 amino acids) or isoform II (60 amino acids) fused to a chloramphenicol acetyl transferase (CAT) reporter demonstrated that the N-terminal domain of isoform II is both necessary and sufficient for membrane association. Metabolic labeling experiments with transgenic parasites showed that isoform II or an isoform II-CAT fusion protein (but not isoform I or isoform I-CAT) incorporate [(3)H]palmitate. Mutation of three adjacent cysteine residues within the isoform II-targeting domain to serines blocked both palmitate incorporation and IMC attachment without affecting enzyme activity, demonstrating that acylation of N-terminal isoform II cysteine residues is responsible for the association of HXGPRT-II with the IMC.


Asunto(s)
Pentosiltransferasa/química , Toxoplasma/enzimología , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Membrana Celular/metabolismo , Cisteína/química , Citosol/metabolismo , ADN Complementario/metabolismo , Exones , Biblioteca de Genes , Immunoblotting , Inmunoprecipitación , Cinética , Microscopía Fluorescente , Datos de Secuencia Molecular , Ácidos Palmíticos/metabolismo , Péptidos/química , Isoformas de Proteínas , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/química , Homología de Secuencia de Aminoácido , Fracciones Subcelulares , Especificidad por Sustrato , Factores de Tiempo , Transgenes
8.
J Immunol ; 169(7): 3545-54, 2002 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-12244144

RESUMEN

To design side chain variants for modulation of immunogenicity, we modeled the complex of the HLA-A2 molecule with an immunodominant peptide, E75, from the HER-2/neu protooncogene protein recognized by CTL. We identified the side chain orientation of E75. We modified E75 at the central Ser(5) (E75 wild-type), which points upward, by removing successively the HO (variant S5A) and the CH2-OH (variant S5G). Replacement of the OH with an aminopropyl (CH2)3-NH3 (variant S5K) maintained a similar upward orientation of the side chain. S5A and S5G were stronger stimulators while S5K was a weaker stimulator than E75 for induction of lytic function, indicating that the OH group and its extension hindered TCR activation. S5K-CTL survived longer than did CTL induced by E75 and the variants S5A and S5G, which became apoptotic after restimulation with the inducer. S5K-CTL also recognized E75 endogenously presented by the tumor by IFN-gamma production and specific cytolysis. S5K-CTL expanded at stimulation with E75 or with E75 plus agonistic anti-Fas mAb. Compared with S5K-CTL that had been restimulated with the inducer S5K, S5K-CTL stimulated with wild-type E75 expressed higher levels of E75(+) TCR and BCL-2. Activation of human tumor-reactive CTL by weaker agonists than the nominal Ag, followed by expansion with the nominal Ag, is a novel approach to antitumor CTL development. Fine tuning of activation of tumor-reactive CTL by weak agonists, designed by molecular modeling, may circumvent cell death or tolerization induced by tumor Ag, and thus, may provide a novel approach to the rational design of human cancer vaccines.


Asunto(s)
Sustitución de Aminoácidos/inmunología , Antígenos de Neoplasias/inmunología , Citotoxicidad Inmunológica , Epítopos de Linfocito T/inmunología , Genes erbB-2/inmunología , Antígeno HLA-A2/inmunología , Fragmentos de Péptidos/inmunología , Linfocitos T Citotóxicos/inmunología , Adyuvantes Inmunológicos/síntesis química , Adyuvantes Inmunológicos/farmacología , Alanina/genética , Presentación de Antígeno , Apoptosis/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Adhesión Celular/inmunología , Línea Celular , Supervivencia Celular/inmunología , Epítopos de Linfocito T/química , Epítopos de Linfocito T/farmacología , Glicina/genética , Antígeno HLA-A2/química , Humanos , Interferón gamma/biosíntesis , Activación de Linfocitos , Lisina/genética , Modelos Moleculares , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/farmacología , Serina/genética , Linfocitos T Citotóxicos/citología , Células Tumorales Cultivadas
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