HVTN 602 data repo: Adolescent BCG revaccination induces a phenotypic shift in CD4+ T cell responses to Mycobacterium tuberculosis

Data supporting submitted manuscript:<b>Title: Adolescent BCG revaccination induces a phenotypic shift in CD4+ T cell responses to </b><b><i>Mycobacterium tuberculosis</i></b><br><b>One sentence summary:</b> Transcriptional and protein profiling reveal diverse subsets of effector memory CD4+ T-cell boosted by BCG revaccination that may be responsible for the partial protection conferred by this vaccination regimen.<br><b>Authors:</b> One B. Dintwe^1,2,^†, Lamar Ballweber Fleming^1,^†, Valentin Voillet^1,2,^†, John McNevin¹, Aaron Seese¹, Anneta Naidoo², Saleha Omarjee², Linda-Gail Bekker³, James G. Kublin¹, Stephen C. De Rosa^1,4, Evan W. Newell¹, Andrew Fiore-Gartland^1,^‡, Erica Andersen-Nissen^1,2,*,^‡, and M. Juliana McElrath^1,5,*,^‡<br><b>Affiliations:</b>¹Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America²Cape Town HVTN Immunology Laboratory, Hutchinson Centre Research Institute of South Africa, Cape Town, South Africa³The Desmond Tutu HIV Centre, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa⁴University of Washington School of Medicine, Department of Laboratory Medicine and Pathology, Seattle, Washington, United States of America⁵University fo Washington School of Medicine, Department of Medicine, Seattle, Washington, United States of America*Corresponding authors:E-mail: [e-mail] (EAN) and [e-mail] (MJM)^†These authors contributed equally to this work.^‡These authors contributed equally to this work.<br><b>Abstract:</b>A recent clinical trial demonstrated that Bacille Calmette-Guérin (BCG) revaccination of South African adolescents reduced the risk of sustained infection with <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>). In a companion phase 1b trial, HVTN 602/Aeras A-042, we performed an in-depth characterization of cellular responses to BCG revaccination or to a H4:IC31 protein subunit vaccine boost to identify T-cell subsets that could be responsible for the protection observed. High-dimensional clustering analysis of cells profiled using a 26-color flow cytometric analysis with intracellular cytokine staining showed marked increases in five effector memory CD4+ T-cell subpopulations (T_EM) after BCG revaccination, two of which were highly polyfunctional. CITE-Seq single cell analysis revealed that the activated subsets included an abundant cluster of Th1 cells with migratory potential. In addition, we identified a small cluster of Th17 T_EM cells induced by BCG revaccination that expressed high levels of CD103, suggesting these cells may represent recirculating tissue-resident memory cells that could provide immune protection in the lung. Together, these results identify novel populations of CD4+ T cells for their potential as immune correlates of protection conferred by BCG revaccination.