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1.
EBioMedicine ; 7: 278-86, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27322481

RESUMO

BACKGROUND: We report a first-in-human trial evaluating safety and immunogenicity of a recombinant BCG, AERAS-422, over-expressing TB antigens Ag85A, Ag85B, and Rv3407 and expressing mutant perfringolysin. METHODS: This was a randomized, double-blind, dose-escalation trial in HIV-negative, healthy adult, BCG-naïve volunteers, negative for prior exposure to Mtb, at one US clinical site. Volunteers were randomized 2:1 at each dose level to receive a single intradermal dose of AERAS-422 (>10(5)-<10(6)CFU=low dose, ≥10(6)-<10(7)CFU=high dose) or non-recombinant Tice BCG (1-8×10(5)CFU). Randomization used an independently prepared randomly generated sequence of treatment assignments. The primary and secondary outcomes were safety and immunogenicity, respectively, assessed in all participants through 182days post-vaccination. ClinicalTrials.gov registration number: NCT01340820. FINDINGS: Between Nov 2010 and Aug 2011, 24 volunteers were enrolled (AERAS-422 high dose, n=8; AERAS-422 low dose, n=8; Tice BCG, n=8); all were included in the safety and immunogenicity analyses. All 24 subjects had at least one adverse event, primarily expected local reactions. High dose AERAS-422 vaccination induced Ag85A- and Ag85B-specific lymphoproliferative responses and marked anti-mycobacterial activity in a whole blood bactericidal activity culture assay (WBA), but was associated with varicella zoster virus (VZV) reactivation in two vaccinees. These volunteers displayed high BCG-specific IFN-γ responses pre- and post-vaccination possibly predisposing them to autocrine/paracrine negative regulation of immune control of latent VZV. A systems biology transcriptomal approach identified positive correlations between post-vaccination T cell expression modules and WBA, and negative correlations between post-vaccination monocyte expression modules and WBA. The expression of one key macrophage marker (F4/80) was constitutively elevated in the two volunteers with zoster. INTERPRETATION: The unexpected development of VZV in two of eight healthy adult vaccine recipients resulted in discontinuation of AERAS-422 vaccine development. Immunological and transcriptomal data identified correlations with the development of TB immunity and VZV that require further investigation. FUNDING: Aeras, FDA, Bill and Melinda Gates Foundation.


Assuntos
Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Herpesvirus Humano 3/fisiologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Aciltransferases/imunologia , Aciltransferases/metabolismo , Adulto , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Vacina BCG/efeitos adversos , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Proteínas Hemolisinas/imunologia , Proteínas Hemolisinas/metabolismo , Humanos , Masculino , Vacinas Sintéticas/efeitos adversos , Ativação Viral , Adulto Jovem
2.
Vaccine ; 33(33): 4130-40, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26095509

RESUMO

BACKGROUND: H56:IC31 is a candidate tuberculosis vaccine comprising a fusion protein of Ag85B, ESAT-6 and Rv2660c, formulated in IC31 adjuvant. This first-in-human, open label phase I trial assessed the safety and immunogenicity of H56:IC31 in healthy adults without or with Mycobacterium tuberculosis (M.tb) infection. METHODS: Low dose (15 µg H56 protein in 500 nmol IC31) or high dose (50 µg H56, 500 nmol IC31) vaccine was administered intramuscularly thrice, at 56-day intervals. Antigen-specific T cell responses were measured by intracellular cytokine staining and antibody responses by ELISA. RESULTS: One hundred and twenty-six subjects were screened and 25 enrolled and vaccinated. No serious adverse events were reported. Nine subjects (36%) presented with transient cardiovascular adverse events. The H56:IC31 vaccine induced antigen-specific IgG responses and Th1 cytokine-expressing CD4(+) T cells. M.tb-infected vaccinees had higher frequencies of H56-induced CD4(+) T cells than uninfected vaccinees. Low dose vaccination induced more polyfunctional (IFN-γ(+)TNF-α(+)IL-2(+)) and higher frequencies of H56-specific CD4(+) T cells compared with high dose vaccination. A striking increase in IFN-γ-only-expressing CD4(+) T cells, displaying a CD45RA(-)CCR7(-) effector memory phenotype, emerged after the second high-dose vaccination in M.tb-infected vaccinees. TNF-α(+)IL-2(+) H56-specific memory CD4(+) T cells were detected mostly after low-dose H56 vaccination in M.tb-infected vaccinees, and predominantly expressed a CD45RA(-)CCR7(+) central memory phenotype. Our results support further clinical testing of H56:IC31.


Assuntos
Anticorpos Antibacterianos/sangue , Linfócitos T CD4-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Profilaxia Pós-Exposição/métodos , Subpopulações de Linfócitos T/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Aciltransferases/administração & dosagem , Aciltransferases/imunologia , Adolescente , Adulto , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/imunologia , Citocinas/biossíntese , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos/administração & dosagem , Oligopeptídeos/administração & dosagem , Resultado do Tratamento , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/efeitos adversos , Adulto Jovem
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