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Human Gene Set: HOFT_PBMC_TICE_BCG_RBCG_AG85A_AG85B_AGE
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| Standard name | HOFT_PBMC_TICE_BCG_RBCG_AG85A_AG85B_AGE_18_40YO_CORRELATED_WITH_WHOLE_BLOOD_BACTERICIDAL_ACTIVITY_NEGATIVE |
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| 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. 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. |
| 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 |
| Exact source | Fig 7A |
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| External links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909487/figure/f0035/ |
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| Source species | Homo sapiens |
| Contributed by | HIPC SIGNATURES (NIAID/HIPC SIGNATURES) |
| Source platform or identifier namespace |
HUMAN_GENE_SYMBOL |
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| Version history | 7.3: First Introduced. |
