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1.
Nat Commun ; 14(1): 8507, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38129388

RESUMO

Tuberculosis remains an international health threat partly because of limited protection from pulmonary tuberculosis provided by standard intradermal vaccination with Bacillus of Calmette and Guérin (BCG); this may reflect the inability of intradermal vaccination to optimally induce pulmonary immunity. In contrast, respiratory Mycobacterium tuberculosis infection usually results in the immune-mediated bacillary containment of latent tuberculosis infection (LTBI). Here we present RNA-Seq-based assessments of systemic and pulmonary immune cells from LTBI participants and recipients of intradermal and oral BCG. LTBI individuals uniquely display ongoing immune activation and robust CD4 T cell recall responses in blood and lung. Intradermal BCG is associated with robust systemic immunity but only limited pulmonary immunity. Conversely, oral BCG induces limited systemic immunity but distinct pulmonary responses including enhanced inflammasome activation potentially associated with mucosal-associated invariant T cells. Further, IL-9 is identified as a component of systemic immunity in LTBI and intradermal BCG, and pulmonary immunity following oral BCG.


Assuntos
Tuberculose Latente , Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculose , Humanos , Vacina BCG , Mycobacterium tuberculosis/genética , Transcriptoma , Tuberculose/prevenção & controle , Vacinação
2.
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
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