Systematic name M41034
Brief description Genes negatively correlated with whole blood bactericidal activity in peripheral blood mononuclear cell in adults (18-40) after exposure to Tice BCG/rBCG-Ag85A/Ag85B , time point 14D
Full description or abstract 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. 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.
Collection C7: Immunologic Signature
      VAX: HIPC Vaccine Response
Source publication Pubmed 27322481   Authors: Hoft DF,Blazevic A,Selimovic A,Turan A,Tennant J,Abate G,Fulkerson J,Zak DE,Walker R,McClain B,Sadoff J,Scott J,Shepherd B,Ishmukhamedov J,Hokey DA,Dheenadhayalan V,Shankar S,Amon L,Navarro G,Podyminogin R,Aderem A,Barker L,Brennan M,Wallis RS,Gershon AA,Gershon MD,Steinberg S
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Organism Homo sapiens
Source platform HUMAN_GENE_SYMBOL
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