Safety and Immunogenicity of the Recombinant BCG Vaccine AERAS-422 in Healthy BCG-naïve Adults: A Randomized, Active-controlled, First-in-human Phase 1 Trial

• Novel rBCG first-in-human trial overexpressing 3Mtb Ags induces a more potent human immune response than standard BCG.
• Transcriptomal studies demonstrated correlations between mycobacterial growth inhibition growth and potent T cell responses.
• rBCG was associated with varicella-zoster reactivation and associated with high interferon gamma and EMR1 expression.A first-in-human trial evaluating safety and immune responses of a recombinant BCG vaccine was reported. The new vaccine expresses additional TB antigens and escapes from seclusion to induce a better immune response in CD8 T cells. The immune response produced in humans could inhibit the growth of the TB pathogen. Unfortunately the vaccine was associated with shingles and studies were done to explore the reasons why that occurred.

BackgroundWe 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.MethodsThis 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 (> 105–< 106 CFU = low dose, ≥ 106– < 107 CFU = high dose) or non-recombinant Tice BCG (1–8 × 105 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 182 days post-vaccination. ClinicalTrials.gov registration number: NCT01340820.FindingsBetween 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.InterpretationThe 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.FundingAeras, FDA, Bill and Melinda Gates Foundation.