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1.
Vaccine ; 27(33): 4412-23, 2009 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-19500523

RESUMO

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has infected approximately two billion individuals worldwide with approximately 9.2 million new cases and 1.6 million deaths annually. Current efforts are focused on making better BCG priming vaccines designed to induce a comprehensive and balanced immunity followed by booster(s) targeting a specific set of relevant antigens in common with the BCG prime. We describe the generation and immunological characterization of recombinant BCG strains with properties associated with lysis of the endosome compartment and over-expression of key Mtb antigens. The endosome lysis strain, a derivative of BCG SSI-1331 (BCG(1331)) expresses a mutant form of perfringolysin O (PfoA(G137Q)), a cytolysin normally secreted by Clostridium perfringens. Integration of the PfoA(G137Q) gene into the BCG genome was accomplished using an allelic exchange plasmid to replace ureC with pfoA(G137Q) under the control of the Ag85B promoter. The resultant BCG construct, designated AERAS-401 (BCG(1331) DeltaureC::OmegapfoA(G137Q)) secreted biologically active Pfo, was well tolerated with a good safety profile in immunocompromised SCID mice. A second rBCG strain, designated AFRO-1, was generated by incorporating an expression plasmid encoding three mycobacterial antigens, Ag85A, Ag85B and TB10.4, into AERAS-401. Compared to the parental BCG strain, vaccination of mice and guinea pigs with AFRO-1 resulted in enhanced immune responses. Mice vaccinated with AFRO-1 and challenged with the hypervirulent Mtb strain HN878 also survived longer than mice vaccinated with the parental BCG. Thus, we have generated improved rBCG vaccine candidates that address many of the shortcomings of the currently licensed BCG vaccine strains.


Assuntos
Antígenos de Bactérias/imunologia , Vacina BCG/imunologia , Toxinas Bacterianas/imunologia , Proteínas Hemolisinas/imunologia , Epitopos Imunodominantes/imunologia , Tuberculose/prevenção & controle , Animais , Vacina BCG/administração & dosagem , Vacina BCG/genética , Toxinas Bacterianas/genética , Linhagem Celular , Eritrócitos/microbiologia , Feminino , Genes Bacterianos , Cobaias , Proteínas Hemolisinas/genética , Hemólise , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Plasmídeos , Ovinos , Tuberculose/imunologia
2.
Infect Immun ; 75(8): 4105-15, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17526747

RESUMO

There is an urgent need for an efficacious vaccine against tuberculosis (TB). Cellular immune responses are key to an effective protective response against TB. Recombinant adenovirus (rAd) vectors are especially suited to the induction of strong T-cell immunity and thus represent promising vaccine vehicles for the prevention of TB. We have previously reported on rAd vector serotype 35, the serotype of choice due to low preexisting immunity worldwide, which expresses a unique fusion protein of Mycobacterium tuberculosis antigens Ag85A, Ag85B, and TB10.4 (Ad35-TBS). Here, we demonstrate that Ad35-TBS confers protection against M. tuberculosis when administered to mice through either an intranasal or an intramuscular route. Histological evaluation of lung tissue corroborated the protection and, in addition, demonstrated differences between two mouse strains, with diffuse inflammation in BALB/c mice and distinct granuloma formation in C57BL/6 mice. Epitope mapping analysis in these mouse strains showed that the major T-cell epitopes are conserved in the artificial fusion protein, while three novel CD8 peptides were discovered. Using a defined set of T-cell epitopes, we reveal differences between the two mouse strains in the type of protective immune response, demonstrating that different antigen-specific gamma interferon (IFN-gamma)-producing T cells can provide protection against M. tuberculosis challenge. While in BALB/c (H-2(d)) mice, a dominant CD8 T-cell response was detected, in C57BL/6 (H-2(b)) mice, more balanced CD4/CD8 T-cell responses were observed, with a more pronounced CD4 response in the lungs. These results unify conflicting reports on the relative importance of CD4 versus CD8 T-cell responses in protection and emphasize the key role of IFN-gamma.


Assuntos
Epitopos de Linfócito T/imunologia , Interferon gama/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinas Virais/imunologia , Aciltransferases/genética , Aciltransferases/imunologia , Adenoviridae/genética , Administração Intranasal , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Mapeamento de Epitopos , Feminino , Vetores Genéticos , Injeções Intramusculares , Fígado/microbiologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Baço/microbiologia , Vacinas contra a Tuberculose/genética , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/genética
3.
Vaccine ; 23(29): 3836-42, 2005 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-15893622

RESUMO

Receptor-mediated gene transfer using an M cell ligand has been shown to be an efficient method for mucosal DNA immunization. To investigate further into alternative M cell ligands, the plant lectin, Ulex europaeus agglutinin I (UEA-1), was tested. UEA-1 binds to human intestinal Caco-2 cells, and these cells can be transfected with poly-l-lysine (PL)-conjugated UEA-1 for expression of reporter cDNAs. When tested in vivo, mice nasally immunized with UEA-1-PL complexed to plasmid encoding HIV-1 envelope showed elevated systemic and mucosal antibody responses, and these were supported by tissue antibody-forming cells. Likewise, elevated envelope-specific CTLs were induced. Thus, UEA-1 mediated DNA delivery represents an alternative mucosal formulation for inducing humoral and cellular immunity against HIV-1.


Assuntos
Vacinas contra a AIDS/imunologia , Proteína gp160 do Envelope de HIV/imunologia , HIV-1/imunologia , Imunidade nas Mucosas , Lectinas de Plantas/imunologia , Ulex , Vacinas de DNA/imunologia , Administração Intranasal , Animais , Células CACO-2 , Anticorpos Anti-HIV/análise , Proteína gp160 do Envelope de HIV/genética , Humanos , Imunoglobulina A/análise , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Mucosa/imunologia , Lectinas de Plantas/administração & dosagem , Lectinas de Plantas/química , Linfócitos T Citotóxicos/imunologia , Transfecção , Vacinas Sintéticas
4.
J Immunol ; 171(9): 4717-25, 2003 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-14568947

RESUMO

To facilitate invasion, reovirus has evolved to attach to M cells, a specialized epithelium residing within the follicle-associated epithelium that covers mucosal inductive tissues. Thus, we questioned adapting reovirus protein sigma1 to ferry DNA vaccines to the mucosa to immunize against HIV. Three expression plasmids encoding HIV(Ba-L) gp160, cytoplasmic gp140, and secreted gp140 were tested in mice as protein sigma1-poly-L-lysine-DNA complexes (formulated vaccine) via the intranasal route. Evaluation of cell-mediated immunity showed that the formulated gp160 DNA vaccine was more effective for stimulating envelope (Env)-specific CTL responses in lungs, lower respiratory lymph nodes (LN), cervical LN, submaxillary gland LN, and spleens. Three doses of vaccine were required for CTL responses, and intranasal naked DNA immunizations were ineffective. The greatest CTL activity was observed between weeks 8 and 10 for gp160-vaccinated mice, and activity remained detectable by week 16. These Env-specific CTL responses were perforin dependent in peripheral tissues, but mostly Fas dependent in the lungs. These Env-specific CTLs also produced IFN-gamma. Mice vaccinated with the formulated gp160 DNA vaccine showed potent antiviral immunity against vaccinia virus-env replication in ovaries. Thus, compared with live vectors, protein sigma1-mediated DNA delivery represents an alternative mucosal formulation for inducing cellular immunity against HIV-1.


Assuntos
Vacinas contra a AIDS/imunologia , Citotoxicidade Imunológica/genética , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas de DNA/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Administração Intranasal , Animais , Proteínas do Capsídeo/administração & dosagem , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , DNA Viral/administração & dosagem , DNA Viral/imunologia , Relação Dose-Resposta Imunológica , Feminino , HIV-1/genética , HIV-1/imunologia , Imunidade nas Mucosas/genética , Esquemas de Imunização , Interferon gama/fisiologia , Ativação Linfocitária/genética , Masculino , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Perforina , Proteínas Citotóxicas Formadoras de Poros , Vacinas de DNA/administração & dosagem , Vaccinia virus/genética , Vaccinia virus/imunologia , Proteínas do Envelope Viral/biossíntese , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia
5.
Vaccine ; 20(15): 1968-74, 2002 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-11983256

RESUMO

Given the increasing incidence of HIV-1 infection world-wide, an affordable, effective vaccine is probably the only way that this virus will be contained. Accordingly, our group is developing an oral prime-boost strategy with the primary goal of eliciting broadly neutralizing antibodies against HIV-1 to provide sterilizing immunity for this virus. Our secondary goal is to elicit broadly cross-reactive anti-viral CD8(+) T cells by this strategy to blunt any breakthrough infections that occur after vaccination of individuals who fail to develop sterilizing immunity. This article describes our progress in the use of the live attenuated intracellular bacteria, Salmonella and Shigella, as oral delivery vehicles for DNA vaccines and the development of conformationally constrained HIV-1 Env immunogens that elicit broadly neutralizing antibodies.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Imunização Secundária , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Vacinas contra a AIDS/imunologia , Administração Oral , Animais , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Antígenos CD4/química , Antígenos CD4/metabolismo , Linfócitos T CD8-Positivos/imunologia , Anticorpos Anti-HIV/biossíntese , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Imunidade nas Mucosas , Macaca mulatta , Camundongos , Modelos Moleculares , Conformação Proteica , Mapeamento de Interação de Proteínas , Estrutura Terciária de Proteína , Receptores CCR5/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/imunologia , Salmonella typhi/imunologia , Salmonella typhimurium/imunologia , Shigella flexneri/imunologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vacinas de DNA/imunologia
6.
J Hum Virol ; 5(1): 17-23, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12352264

RESUMO

The antigenic diversity, rapid genetic integration into host cell DNA, and immune evasion tactics of human immunodeficiency virus type 1 (HIV-1) create formidable obstacles to the development of an effective vaccine against it. In spite of this, the advent of conformationally constrained HIV-1 Env and gp120 immunogens has made it feasible to formulate HIV-1 vaccines that induce broadly cross-reactive neutralizing antibodies and afford protection through humoral mechanisms. This paper reviews recent advances made by the authors toward the development of an HIV-1 vaccine that elicits such antibodies in both the mucosal and systemic immune compartments.


Assuntos
Vacinas contra a AIDS/imunologia , Desenho de Fármacos , Anticorpos Anti-HIV/biossíntese , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Imunidade nas Mucosas , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , Humanos , Testes de Neutralização
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