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1.
J Immunol ; 197(9): 3597-3606, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27683751

ABSTRACT

Despite the considerable effort that has been invested in elucidating the mechanisms of protection and immunopathogenesis associated with dengue virus infections, a reliable correlate of protection against the disease remains to be found. Neutralizing Abs, long considered the prime component of a protective response, can exacerbate disease severity when present at subprotective levels, and a growing body of data is challenging the notion that their titers are positively correlated with disease protection. Consequently, the protective role of cell-mediated immunity in the control of dengue infections has begun to be studied. Although earlier research implicated cellular immunity in dengue immunopathogenesis, a wealth of newer data demonstrated that multifunctional CD8+ T cell responses are instrumental for avoiding the more severe manifestations of dengue disease. In this article, we describe a new tetravalent vaccine candidate based on recombinant dengue virus capsid proteins, efficiently produced in Escherichia coli and purified using a single ion-exchange chromatography step. After aggregation to form nucleocapsid-like particles upon incubation with an oligodeoxynucleotide containing immunostimulatory CpG motifs, these Ags induce, in mice and monkeys, an IFN-γ-secreting cell response that significantly reduces viral load after challenge without the contribution of antiviral Abs. Therefore, this new vaccine candidate may not carry the risk for disease enhancement associated with Ab-based formulations.


Subject(s)
Antibodies, Neutralizing/immunology , CD8-Positive T-Lymphocytes/immunology , Dengue Virus/physiology , Dengue/immunology , Interferon-gamma/metabolism , Viral Vaccines/immunology , Virion/immunology , Animals , CD8-Positive T-Lymphocytes/virology , Disease Models, Animal , Haplorhini , Humans , Immunity, Cellular , Mice , Nucleocapsid Proteins/immunology , Viral Load
2.
Biotechnol Appl Biochem ; 56(3): 111-8, 2010 Jul 09.
Article in English | MEDLINE | ID: mdl-20515441

ABSTRACT

HCV (hepatitis C virus) infection is among the leading causes of chronic liver disease, but currently there is no vaccine available. Data have accumulated about the importance of targeting different HCV antigens in vaccine candidate preparations. Here, a surface response study to select the optimal ratio of recombinant HCV structural antigens in a vaccine preparation, capable of generating in vivo functional cellular immune response in mice, was performed. The immunogenicity of the selected HCV structural protein mixture (Co-E1-E2) in mice and African green monkeys, after five doses of immunization, was also demonstrated. Specific T-cell proliferative response against HCV structural antigens was induced in vaccinated mice. Moreover, on challenge with recombinant HCV VV (vaccinia virus), all mice controlled the viraemia and 80% were protected. On the other hand, monkeys immunized with Co-E1-E2 developed antibodies, specifically directed to region 412-438 of E2 protein, that include an epitope implicated in HCV neutralization, in addition to a specific proliferative response against HCV Core and E2 proteins. These results indicated that the optimal amount and ratio of HCV recombinant proteins should be taken into account to elicit a successful immune response against HCV and therefore have important implications for vaccine design.


Subject(s)
Hepatitis C, Chronic/immunology , Immunity, Cellular , Viral Core Proteins/immunology , Viral Envelope Proteins/immunology , Viral Hepatitis Vaccines/immunology , Animals , Chlorocebus aethiops , Female , Hepatitis C Antibodies/blood , Hepatitis C Antigens/immunology , Hepatitis C Antigens/pharmacology , Hepatitis C, Chronic/prevention & control , Humans , Male , Mice , Mice, Inbred BALB C , Recombinant Proteins/immunology , Recombinant Proteins/pharmacology , Viral Core Proteins/pharmacology , Viral Envelope Proteins/pharmacology
3.
Biotechnol Appl Biochem ; 51(Pt 2): 97-105, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18215116

ABSTRACT

HCV (hepatitis C virus) is a worldwide health problem nowadays. No preventive vaccine is available against this pathogen, and therapeutic treatments currently in use have important drawbacks, including limited efficacy. In the present work a recombinant fowlpox virus, FPCoE1, expressing a truncated HCV core-E1 polyprotein, was generated. FPCoE1 virus generally failed to elicit a humoral immune response against HCV antigens in BALB/c mice. By contrast, mice inoculated with FPCoE1 elicited a positive interferon-gamma secretion response against HCV core in ex-vivo ELISPOT (enzyme-linked immunospot) assays. Remarkably, mice inoculated with FPCoE1 significantly controlled viraemia in a surrogate challenge model with vvRE, a recombinant vaccinia virus expressing HCV structural antigens. In fact, 40% of the mice had no detectable levels of vvRE in their ovaries. Administration of FPCoE1 in vervet monkeys [Chlorocebus (formerly Cercophitecus) aethiops sabaeus] induced lymphoproliferative response against HCV core and E1 proteins in 50% of immunized animals. Monkeys immunized with FPCoE1 had no detectable levels of vvRE in their blood, whereas monkeys inoculated with FP9, the negative control virus, had detectable levels of vvRE in blood up to 7 days after challenge. In conclusion, recombinant fowlpox virus FPCoE1 is able to induce an anti-HCV immune response in mice and monkeys. This ability could be rationally employed to develop effective strategies against HCV infection by using FPCoE1 in combination with other vaccine candidates or antiviral treatments.


Subject(s)
Chlorocebus aethiops/immunology , Fowlpox virus/genetics , Hepatitis C/immunology , Immunization , Polymorphism, Single Nucleotide/immunology , Vaccinia virus/immunology , Viral Envelope Proteins/immunology , Animals , Chlorocebus aethiops/virology , DNA, Viral/genetics , Enzyme-Linked Immunosorbent Assay , Female , Fowlpox virus/immunology , Hepatitis C/prevention & control , Male , Mice , Mice, Inbred BALB C , Polymerase Chain Reaction , Polymorphism, Single Nucleotide/genetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Viral Envelope Proteins/administration & dosage , Viral Envelope Proteins/genetics
4.
Biotecnol. apl ; 14(3): 163-8, jul.-sept. 1997. tab, graf
Article in English | CUMED | ID: cum-11528

ABSTRACT

Se estudió la respuesta reparativa de lesiones de grosor total en cerdos ante variaciones en la frecuencia de aplicación de una formulación con factor de crecimiento epidérmico (FCE, 10 µ/g) y sulfadiacina de plata 1 porciento. Se indujeron 100 lesiones de 8 mm que se agruparon y trataron como: I, II, II, tratados con FCE cada 24, 48 y 72 h, respectivamente. Los grupos IV y V fueron controles medicado y espontáneo. Los animales se sacrificaron al octavo día y se colectaron las úlceras para estudio histológico o planimétrico (10/10). Se estudiaron los siguientes parámetros; porciento de área total reepitelizada, radio medio, factor de circularidad, perímetro, crecimiento lineal del epitelio, reconstitución dérmica, migración epitelial, e índice de contracción. Las heridas del grupo 1 mostraron un 80 porciento de reepitelización total, la que fue significativamente superior al resto de los grupos (P<0,05). Estas mostraron el mayor nivel de crecimiento lineal y los menores valores de radio medio y perímetro con respecto a los otros grupos (P<0,05). Se constató un incremento significativo de la migración en todos los grupos tratados con FCE con relación al grupo IV, (p<0,05). La circularidad fue significativamente menor en el grupo I con relación a los otros grupos (p<0,05). La reconstitución de la dermis fue significativamente superior en los grupos I y II con respecto al IV (p<0,05). No se demostraron diferencias en el nivel de contracción de las heridas. Este experimento demostró que el FCE estimula la reparación cutánea de forma frecuencia de tratamiento-dependiente (AU)


Subject(s)
Animals , Epidermal Growth Factor/pharmacology , Silver Sulfadiazine/pharmacology , Wound Healing , Swine
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