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1.
PLoS One ; 11(4): e0153579, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27088239

RESUMO

Significant genetic variability in the head region of the influenza A hemagglutinin, the main target of current vaccines, makes it challenging to develop a long-lived seasonal influenza prophylaxis. Vaccines based on the conserved hemagglutinin stalk domain might provide broader cross-reactive immunity. However, this region of the hemagglutinin is immunosubdominant to the head region. Peptide-based vaccines have gained much interest as they allow the immune system to focus on relevant but less immunogenic epitopes. We developed a novel influenza A hemagglutinin-based display platform for H1 hemagglutinin stalk peptides that we identified in an epitope mapping assay using human immune sera and synthetic HA peptides. Flow cytometry and competition assays suggest that the identified stalk sequences do not recapitulate the epitopes of already described broadly neutralizing stalk antibodies. Vaccine constructs displaying 25-mer stalk sequences provided up to 75% protection from lethal heterologous virus challenge in BALB/c mice and induced antibody responses against the H1 hemagglutinin. The developed platform based on a vaccine antigen has the potential to be either used as stand-alone or as prime-vaccine in combination with conventional seasonal or pandemic vaccines for the amplification of stalk-based cross-reactive immunity in humans or as platform to evaluate the relevance of viral peptides/epitopes for protection against influenza virus infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Epitopos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Infecções por Orthomyxoviridae/prevenção & controle , Sequência de Aminoácidos , Animais , Feminino , Citometria de Fluxo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Conformação Proteica , Homologia de Sequência de Aminoácidos
2.
Vaccine ; 32(3): 355-62, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24262313

RESUMO

Human infections with a novel influenza A H7N9 subtype virus were reported in China recently. The virus caused severe disease with high mortality rates and it raised concerns over its pandemic potential. Here, we assessed in the mouse model protective efficacy of single immunisations with low vaccine doses of insect cell-derived H7 virus-like particles, consisting of hemagglutinin and matrix protein. Vaccinated mice were fully protected and survived a stringent lethal challenge (100 mLD50) with H7N9, even after a single, unadjuvanted, low vaccine dose (0.03 µg). Serum analysis revealed broad reactivity and hemagglutination inhibition activity across a panel of divergent H7 strains. Moreover, we detected significant levels of cross-reactivity to related group 2 hemagglutinins. These data demonstrate that virus-like particle vaccines have the potential to induce broadly protective immunity against the novel H7N9 virus and a variety of other H7 strains.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Subtipo H7N9 do Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Vacinação/métodos , Vacinas de Partículas Semelhantes a Vírus/imunologia , Proteínas da Matriz Viral/imunologia , Animais , Anticorpos Antivirais/sangue , Reações Cruzadas , Modelos Animais de Doenças , Feminino , Testes de Inibição da Hemaglutinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/genética , Camundongos , Camundongos Endogâmicos BALB C , Células Sf9 , Spodoptera , Análise de Sobrevida , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/genética , Proteínas da Matriz Viral/administração & dosagem , Proteínas da Matriz Viral/genética
3.
Biotechnol Lett ; 36(4): 743-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24375231

RESUMO

PURPOSE OF WORK: A comparative analysis of new and established insect cell lines, in regard to process relevant parameters, provide data that can be exploited for designing more robust and effective protein production processes. The baculovirus-insect cell expression system has been efficiently used for the production of heterologous proteins. Three different insect cell lines Tnao38, High Five and Sf9 were compared in terms of virus susceptibility, baculovirus production and product yield of an intra-cellularly (YFP) and extra-cellularly (influenza A virus hemagglutinin)-expressed recombinant protein. The Tnao38 and High Five cell lines exhibited higher (tenfold) susceptibility to baculovirus infection than Sf9 cells, whereas Sf9 cells showed a higher (100-fold) capacity for production of infectious virus particles. Analysis of recombinant protein expression revealed considerably higher product yields in Tnao38 and High Five cells as compared to Sf9 cells, for both model proteins. Overall, the two Trichoplusia ni-derived cell lines, High Five and Tnao38, were significantly more efficient in terms of secreting proteins such as the glycoprotein hemagglutinin of influenza A virus.


Assuntos
Baculoviridae/crescimento & desenvolvimento , Interações Hospedeiro-Parasita , Proteínas Recombinantes/biossíntese , Animais , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Baculoviridae/genética , Linhagem Celular , Glicoproteínas de Hemaglutininação de Vírus da Influenza/biossíntese , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Insetos , Proteínas Luminescentes/biossíntese , Proteínas Luminescentes/genética , Proteínas Recombinantes/genética
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