A 2-Dose AERAS-402 Regimen Boosts CD8+ Polyfunctionality in HIV-Negative, BCG-Vaccinated Recipients

Abstract

Despite the widespread use of BCG, tuberculosis (TB) remains a global threat. Existing vaccine candidates in clinical trials are designed to replace or boost BCG which does not provide satisfying long-term protection. AERAS-402 is a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis (Mtb) antigens 85A, 85B, and TB10.4. The present phase I trial assessed the safety and immunogenicity of AERAS-402 in participants living in India – a highly TB-endemic area. Healthy male participants aged 18–45 years with a negative QuantiFERON-TB Gold in-tube test (QFT) were recruited. Enrolled participants (n=12) were randomized 2:1 to receive two intramuscular injections of either AERAS-402 (3 x 1010 viral particles [vp]); (n=8) or placebo (n=4) on study days 0 and 28. Safety and immunogenicity parameters were evaluated for up to 182 days post the second injection. Immunogenicity was assessed by a flow cytometry-based intracellular cytokine staining (ICS) assay and transcriptional profiling. The latter was examined using dual-color-Reverse-Transcriptase-Multiplex-Ligation-dependent-Probe-Amplification (dc-RT MLPA) assay. AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine-induced CD8+ T-cell responses were dominated by cells co-expressing IFN-γ, TNF-α, and IL-2 (“polyfunctional” cells) and were more robust than CD4+ T-cell responses. Five genes (CXCL10, GNLY, IFI35, IL1B and PTPRCv2) were differentially expressed between the AERAS-402-group and the placebo group, suggesting vaccine-induced responses. Further, compared to pre-vaccination, three genes (CLEC7A, PTPRCv1 and TAGAP) were consistently up-regulated following two doses of vaccination in the AERAS-402-group. No safety concerns were observed for AERAS-402 in healthy Indian adult males. The vaccine-induced predominantly polyfunctional CD8+ T cells in response to Ag85B, humoral immunity, and altered gene expression profiles in peripheral blood mononuclear cells (PBMCs) indicative of activation of various immunologically relevant biological pathways.

Photochemically-Mediated Inflammation and Cross-Presentation of Mycobacterium bovis BCG Proteins Stimulates Strong CD4 and CD8 T-Cell Responses in Mice

“…Many alternatives to the M. bovis BCG vaccine are in pre-and clinical development (7,11,(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Most of these developments are aimed to improve the immunogenicity of M. bovis BCG, either by genetic modifications, by choosing effective antigen subsets from Mtb/BCG (41)(42)(43)(44)(45)(46), by adding more improved adjuvants (47), or by using prime-boost strategies (48)(49)(50). Moreover, the route for administration may also be important for of the vaccine efficacy (26,51).…”

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

“…Several studies have linked TAGAP with active TB; TAGAP was enriched for differential acetylation peaks upon Mtb infection in granulocytes 58 and TAGAP was induced upon vaccination with AERAS-402 vaccine encoding a fusion protein of Mtb antigens. 59 Furthermore, TAGAP had higher expression in TB patients compared to LTBI and healthy controls 55 and, surprisingly, lower expression in pulmonary TB compared to household controls. 60 Our data showing that TAGAP expression was significantly increased during TB treatment in patients who had a poor TB treatment outcome could indicate that TAGAP is actively involved in TB pathogenesis or that TAGAP expression is a consequence of persisting Mtb infection, potentially by enhanced T-cell activation, but this remains to be investigated.…”

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

“…Several studies have linked TAGAP with active TB; TAGAP was enriched for differential acetylation peaks upon Mtb infection in granulocytes 58 and TAGAP was induced upon vaccination with AERAS-402 vaccine encoding a fusion protein of Mtb antigens. 59 Furthermore, TAGAP had higher expression in TB patients compared to LTBI and healthy controls 55 and, surprisingly, lower expression in pulmonary TB compared to household controls. 60 Our data showing that TAGAP expression was significantly increased during anti-TB treatment in patients who had a poor treatment outcome could indicate that TAGAP is actively involved in TB pathogenesis or that TAGAP expression is a consequence of persisting Mtb infection, but this remains to be investigated.…”