RESUMEN

Control of complex parasites via vaccination remains challenging, with the current combination of vaccines and small drugs remaining the choice for an integrated control strategy. Studies conducted to date, are providing evidence that multicomponent vaccines will be needed for the development of protective vaccines against endo- and ectoparasites, though multicomponent vaccines require an in-depth understanding of parasite biology which remains insufficient for ticks. With the rapid development and spread of acaricide resistance in ticks, new targets for acaricide development also remains to be identified, along with novel targets that can be exploited for the design of lead compounds. In this study, we analysed the differential gene expression of Rhipicephalus microplus ticks that were fed on cattle vaccinated with a multi-component vaccine (Bm86 and 3 putative Bm86-binding proteins). The data was scrutinised for the identification of vaccine targets, small drug targets and novel pathways that can be evaluated in future studies. Limitations associated with targeting novel proteins for vaccine and/or drug design is also discussed and placed into the context of challenges arising when targeting large protein families and intracellular localised proteins. Lastly, this study provide insight into how Bm86-based vaccines may reduce successful uptake and digestion of the bloodmeal and overall tick fecundity.

RESUMEN

INTRODUCTION: Vaccines based on multiple antigens often induce an immune response, which is higher than that triggered by each single component, with antibodies acting cooperatively and synergistically in tackling the infection. AREAS COVERED: An interesting example is the antibody response induced by the 4CMenB vaccine, currently licensed for the prevention of Neisseria meningitidis serogroup B (MenB). It contains four antigenic components: Factor H binding protein (fHbp), Neisseria adhesin A (NadA), Neisserial Heparin Binding Antigen (NHBA), and Outer Membrane Vesicles (OMV). Monoclonal and polyclonal antibodies raised by vaccination with 4CMenB show synergistic activity in complement-dependent bacterial killing. This review summarizes published and unpublished data and provides evidence of the added value of multicomponent vaccines. EXPERT OPINION: The ability of 4CMenB vaccine to elicit antibodies targeting multiple surface-exposed antigens is corroborated by the recent data on real-world evidences. Bactericidal activity is generally mediated by antibodies that bind to antigens highly expressed on the bacterial surface and immunologically related. However, simultaneous binding of antibodies to various surface-exposed antigens can overcome the threshold density of antigen-antibody complexes needed for complement activation. The data discussed in this review highlight the interplay between antibodies targeting major and minor antigens and their effect on functionality. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers of studies with original data mentioned in the article: NCT00937521, NCT00433914, NCT02140762, and NCT02285777.

Asunto(s)

Infecciones Meningocócicas , Vacunas Meningococicas , Neisseria meningitidis Serogrupo B , Anticuerpos , Anticuerpos Antibacterianos , Antígenos Bacterianos , Humanos , Infecciones Meningocócicas/prevención & control

RESUMEN

Multiple sclerosis (MS) affects 2.3 million patients worldwide with no effective treatments available thus far. Depletion of autoreactive T-cells is considered the basis for immunotherapeutic approaches. For this purpose the peptides BV5S2, BV6S5, and BV13S1 have been identified as candidates for the development of a MS vaccine. Herein, the plant-based simultaneous production of these peptides is described as an effort to generate a new model of MS immunotherapy. A polyprotein comprising the sequence of the target peptides was designed having the picornaviral 2A sequence in between to mediate the release of the individual peptides upon translation. A codon optimized gene was cloned in vectors mediating constitutive (CaMV35S promoter) or inducible (AlcA promoter) expression. No transgenic tobacco plants were recovered from the constitutive vector suggesting toxicity of the target peptides. In contrast, several transformed lines were obtained with the inducible vector. The individual BV5S2, BV6S5, and BV13S1 peptides were detected in transformed lines upon ethanol-mediated induction and a quantitative analysis based on a OVA conjugate carrying the three peptides revealed accumulation levels up to 0.5 µg g-1 FW leaves. The plant-made peptides were able to induce humoral responses in orally immunized mice. This platform will be useful in the development of alternative immunotherapies against MS having low cost and safety as main attributes. Moreover the platform represents an attractive alternative for the expression of antigens having detrimental effects in plants.

Asunto(s)

Inmunoterapia , Esclerosis Múltiple/terapia , Fragmentos de Péptidos/genética , Plantas Modificadas Genéticamente/genética , Receptores de Antígenos de Linfocitos T/genética , Animales , Cisteína Endopeptidasas/genética , Expresión Génica , Vectores Genéticos , Humanos , Inmunización , Ratones , Esclerosis Múltiple/inmunología , Fragmentos de Péptidos/inmunología , Plantas Modificadas Genéticamente/metabolismo , Regiones Promotoras Genéticas/genética , Receptores de Antígenos de Linfocitos T/inmunología , Nicotiana/genética , Nicotiana/metabolismo , Vacunas de Subunidad/genética , Vacunas de Subunidad/inmunología , Proteínas Virales/genética

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The skin is an attractive tissue target for vaccination, as it is readily accessible and contains a dense population of antigen-presenting and immune-accessory cells. Microneedle arrays (MNAs) are emerging as an effective tool for in situ engineering of the cutaneous microenvironment to enable diverse immunization strategies. Here, we present novel dissolving undercut MNAs and demonstrate their application for effective multicomponent cutaneous vaccination. The MNAs are composed of micron-scale needles featuring pyramidal heads supported by undercut stem regions with filleted bases to ensure successful skin penetration and retention during application. Prior efforts to fabricate dissolving undercut microstructures were limited and required complex and lengthy processing and assembly steps. In the current study, we strategically combine three-dimensional (3D) laser lithography, an emerging micro-additive manufacturing method with unique geometric capabilities and nanoscale resolution, and micromolding with favorable materials. This approach enables reproducible production of dissolving MNAs with undercut microneedles that can be tip-loaded with multiple biocargos, such as antigen (ovalbumin) and adjuvant (Poly(I:C)). The resulting MNAs fulfill the geometric (sharp tips and smooth edges) and mechanical-strength requirements for failure-free penetration of human and murine skin to simultaneously deliver multicomponent (antigen plus adjuvant) vaccines to the same cutaneous microenvironment. Cutaneous vaccination of mice using these MNAs induces more potent antigen-specific cellular and humoral immune responses than those elicited by traditional intramuscular injection. Together, the unique geometric features of these undercut MNAs and the associated manufacturing strategy, which is compatible with diverse drugs and biologics, could enable a broad range of non-cutaneous and cutaneous drug delivery applications, including multicomponent vaccination.

Asunto(s)

Vacunación , Vacunas , Administración Cutánea , Animales , Sistemas de Liberación de Medicamentos , Ratones , Microinyecciones , Agujas , Piel

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Meningococcal serogroup B (MenB) has become the main cause of invasive meningococcal disease in industrialized countries in recent years. The diversity of MenB strains and poor immunogenicity of the MenB capsular polysaccharide have made vaccine development challenging. Two MenB vaccines, including factor H binding protein (fHbp) as a major antigenic component, are now licensed for use. In addition to fHbp variant 1, the multicomponent vaccine 4CMenB contains neisserial heparin binding antigen, Neisseria adhesin A, and outer membrane vesicles containing porin A. The vast majority of circulating MenB strains contain genes encoding at least one 4CMenB component and many express genes for more than one vaccine antigen. Recent studies have suggested that serum bactericidal activity is enhanced against strains that express two or more vaccine antigens. Bacterial killing may also occur when antibodies to vaccine components are collectively present at levels that would individually be sub-lethal. The evaluation of immune responses to separate vaccine components does not take cooperative activity into account and may underestimate the overall protection. Available data on 4CMenB effectiveness indicate that this multicomponent vaccine affords broad coverage and protection against MenB disease. 4CMenB also has the potential to protect against disease caused by non-MenB meningococci and Neisseria gonorrhoeae.

Asunto(s)

Infecciones Meningocócicas/prevención & control , Vacunas Meningococicas/administración & dosificación , Neisseria meningitidis Serogrupo B/inmunología , Animales , Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/genética , Antígenos Bacterianos/inmunología , Proteínas de la Membrana Bacteriana Externa/administración & dosificación , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas Portadoras/administración & dosificación , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Humanos , Infecciones Meningocócicas/inmunología , Infecciones Meningocócicas/microbiología , Vacunas Meningococicas/genética , Vacunas Meningococicas/inmunología , Neisseria meningitidis Serogrupo B/genética

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A fully synthetic MUC1-based cancer vaccine was designed and chemically synthesized containing an endogenous helper T-epitope (MHC class II epitope). The vaccine elicited robust IgG titers that could neutralize cancer cells by antibody-dependent cell-mediated cytotoxicity (ADCC). It also activated cytotoxic T-lymphocytes. Collectively, the immunological data demonstrate engagement of helper T-cells in immune activation. A synthetic methodology was developed for a penta-glycosylated MUC1 glycopeptide, and antisera of mice immunized by the new vaccine recognized such a structure. Previously reported fully synthetic MUC1-based cancer vaccines that elicited potent immune responses employed exogenous helper T-epitopes derived from microbes. It is the expectation that the use of the newly identified endogenous helper T-epitope will be more attractive, because it will activate cognate CD4+ T-cells that will provide critical tumor-specific help intratumorally during the effector stage of tumor rejection and will aid in the generation of sustained immunological memory.

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Vacunas contra el Cáncer/síntesis química , Vacunas contra el Cáncer/inmunología , Glicopéptidos/inmunología , Mucina-1/inmunología , Vacunas Sintéticas/inmunología , Animales , Vacunas contra el Cáncer/química , Glicopéptidos/química , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Conformación Molecular , Mucina-1/química , Linfocitos T Citotóxicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Vacunas Sintéticas/química

RESUMEN

Porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2 (PCV2) and swine influenza virus (SIV) are three of the most economically important swine pathogens, causing immense economic losses to the global swine industry. Monovalent commercial vaccines against each of the three viruses are routinely used in pig farms worldwide. A trivalent vaccine against all three pathogens would greatly simplify the vaccination programme and reduce the financial burden to the swine industry. In this study, by using an attenuated strain of PRRSV (strain DS722) as a live virus vector, we generated a multi-component vaccine virus, DS722-SIV-PCV2, which expresses the protective antigens from SIV and PCV2. The DS722-SIV-PCV2 trivalent vaccine virus replicates well, and expresses PCV2 capsid and SIV HA proteins in vitro. A subsequent vaccination and challenge study in 48 pigs revealed that the DS722-SIV-PCV2-vaccinated pigs had significantly reduced lung lesions and viral RNA loads when challenged with PRRSV. Upon challenge with PCV2, the vaccinated pigs had partially reduced lymphoid lesions and viral DNA loads, and when challenged with SIV the vaccinated pigs had significantly reduced acute respiratory sign scores. The results from this study demonstrate the potential of DS722-SIV-PCV2 as a candidate trivalent vaccine, and also shed light on exploring PRRSV as a potential live virus vaccine vector.

Asunto(s)

Anticuerpos Antivirales/biosíntesis , Infecciones por Circoviridae/veterinaria , Infecciones por Orthomyxoviridae/veterinaria , Síndrome Respiratorio y de la Reproducción Porcina/prevención & control , Enfermedades de los Porcinos/prevención & control , Vacunación , Vacunas Virales/biosíntesis , Animales , Antígenos Virales/química , Antígenos Virales/inmunología , Infecciones por Circoviridae/inmunología , Infecciones por Circoviridae/prevención & control , Infecciones por Circoviridae/virología , Circovirus/genética , Circovirus/inmunología , Inmunogenicidad Vacunal , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/virología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/virología , Síndrome Respiratorio y de la Reproducción Porcina/inmunología , Síndrome Respiratorio y de la Reproducción Porcina/virología , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , Virus del Síndrome Respiratorio y Reproductivo Porcino/inmunología , Porcinos , Enfermedades de los Porcinos/inmunología , Enfermedades de los Porcinos/virología , Potencia de la Vacuna , Vacunas Atenuadas , Vacunas de Subunidad , Carga Viral/efectos de los fármacos , Vacunas Virales/administración & dosificación , Vacunas Virales/genética

RESUMEN

We have reported that attenuated Salmonella (S) carrying plasmids encoding the cysteine protease cruzipain (Cz) protects against Trypanosoma cruzi infection. Here, we determined whether immunoprotection could be improved by the oral coadministration of 3 Salmonella carrying the plasmids that encode the antigens Cz, Tc52, and Tc24. SCz+STc52+STc24-immunized mice presented an increased antibody response against each antigen compared with those in the single antigen-immunized groups, as well as higher trypomastigotes antibody-mediated lyses and cell invasion inhibition compared with controls. SCz+STc52+STc24-immunized and -challenged mice rendered lower parasitemia. Weight loss after infection was detected in all mice except those in the SCz+STc52+STc24 group. Moreover, cardiomyopathy-associated enzyme activity was significantly lower in SCz+STc24+STc52-immunized mice compared with controls. Few or no abnormalities were found in muscle tissues of SCz+STc24+STc52-immunized mice, whereas controls presented with inflammatory foci, necrosis, and amastigote nests. We conclude that a multicomponent approach that targets several invasion and metabolic mechanisms improves protection compared with single-component vaccines.

Asunto(s)

Enfermedad de Chagas/prevención & control , Portadores de Fármacos , Vacunas Antiprotozoos/inmunología , Salmonella/genética , Trypanosoma cruzi/inmunología , Vacunas de ADN/inmunología , Animales , Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/genética , Antígenos de Protozoos/inmunología , Peso Corporal , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/patología , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos C3H , Miocardio/patología , Parasitemia/prevención & control , Vacunas Antiprotozoos/administración & dosificación , Vacunas Antiprotozoos/genética , Resultado del Tratamiento , Trypanosoma cruzi/genética , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética