{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:54:31Z","timestamp":1790830471384,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\u00a0<jats:italic>M. tuberculosis (Mtb)<\/jats:italic>\u00a0antigens 85A, 85B, and TB10.4.\u00a0The present phase I trial assessed the safety and immunogenicity of AERAS-402 in participants living in India \u2013 a highly TB-endemic area. Healthy male participants aged 18\u201345 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 10<jats:sup>10<\/jats:sup>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<jats:sup>+<\/jats:sup>\u00a0T-cell responses were dominated by cells co-expressing IFN-\u03b3, TNF-\u03b1, and IL-2 (\u201cpolyfunctional\u201d cells) and were more robust than CD4<jats:sup>+<\/jats:sup>\u00a0T-cell responses.\u00a0Five genes (<jats:italic>CXCL10, GNLY, IFI35, IL1B<\/jats:italic>and<jats:italic>PTPRCv2<\/jats:italic>) were differentially expressed between the AERAS-402-group and the placebo group, suggesting vaccine-induced responses. Further, compared to pre-vaccination, three genes (<jats:italic>CLEC7A, PTPRCv1<\/jats:italic>and<jats:italic>TAGAP)<\/jats:italic>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<jats:sup>+<\/jats:sup>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.<\/jats:p>","DOI":"10.3389\/fimmu.2021.673532","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T16:42:51Z","timestamp":1623429771000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["A 2-Dose AERAS-402 Regimen Boosts CD8+ Polyfunctionality in HIV-Negative, BCG-Vaccinated Recipients"],"prefix":"10.3389","volume":"12","author":[{"given":"Dhanasekaran","family":"Sivakumaran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretta","family":"Blatner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Bakken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hokey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Synne","family":"Jenum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harleen M. 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