Gates Package — page 1296

: VACCINES wu) TBRU Summary September 20, 2018 Research Highlights: VACCINES • Development and Publication of a Novel Response Spectrum Assay (RSA). [ASTRa] The 60-Mtb antigen "Response Spectrum Assay (RSA)" performed on whole blood has been developed by the TBRU-ASTRa team and validated in Emory Vaccine Center laboratories. Assay development and optimization of the a 7-day diluted whole blood assay to measure antigen-specific T cell responses was of this novel assay was recently published in The Journal of Immunology (J Immunol 2018; 200(8):3008-3019) with Cheryl Day (co-PD of Project 1) as the senior author. Interim data analysis from a cohort of patients with latent TB infection (LTBI) that accepted treatment at the DeKalb County Board of Health were presented at NIAID at the TBRU-Network Meeting in April 2018 and further data analysis from this cohort as well as patients enrolled at a clinical site in Kenya is ongoing in collaboration with the TBRU-ASTRa Data Management Center (DMC). • Completion of enrollment and follow up of the LTBI "Accepted Treatment" Cohort. [ASTRa] A total of 112 study subjects with latent TB infection (LTBI) who accepted treatment for LTBI (with the weekly isoniazid plus rifapentine regimen delivered by the DeKalb County Board of Health via directly observed therapy for 12 weeks [3HP]) were enrolled into TBRU-ASTRa Project 1. Enrollment occurred at the DeKalb County Board of Health clinics in Metro Atlanta and was completed in March 2017; the final 12-month follow-up visits completed for all enrolled participants in March 2018. The 60-antigen Response Spectrum Assay (RSA) was performed on each blood sample collected at baseline, and 3-, 6-, 9- and 12-month follow-ups. PBMCs were isolated and cryopreserved, and EDTA and Sodium Heparin plasma aliquots stored at Emory Vaccine Center/Yerkes site. PAXgene blood DNA tubes were also collected from each participant enrolled. In total, 72 participants with LTBI completed LTBI treatment and all 5 study visits including 4 follow-up visits with blood sample collection for the RSA and PBMC cryopreservation. Data analyses are ongoing. • Tetramer Production and Development. [ASTRa] Dr. John Altman (TBRU ASTRa Immunology Core PD) in collaboration with the NIH-funded Emory Tetramer Facility (PI: Altman) and Drs. Michael Glickman and Jeffrey Aube of the Tri-I TBRU in New York who provided key ligands for MR1 tetramers has generated mouse, human, and rhesus macaque MR1/5-OP-RU tetramers. These reagents have been made available to the research community via the NIAID Tetramer Facility. HLA typing was performed on specimens from 68 subjects from the DeKalb County "Accepted Treatment" cohort and the TBRUASTRa Immunology Core is currently using the allele frequency data, with a focus on class II, to reprioritize tetramer development plans. We anticipate that a recent discovery by the Altman lab/Tetramer Facility that soluble HLA-DM greatly accelerates peptide loading to a wide-range of class II MHC alleles from humans (including HLA-DR and -DQ alleles), at least one class II allele from rhesus macaques (Mamu-DRB-w201), and one class II allele from mice will help us accelerate tetramer development. We expect that DM will significantly assist loading for most class II alleles, and that HLA-DM will work in a cross-species manner on alleles from rhesus macaques. • Human responses to MR1 and CD1 reactive T cells [LIMAA] Whereas most vaccine work focuses on MHC-restricted T cells, we are studying the in vivo human responses to MR1 and CD1 reactive T cells, including tests of T cell expansion during acute and chronic TB infections. We are seeking diagnostic tests that rely on antigens (tuberculosinyl adenosine, sulfoglycolipid) that are present in M. tuberculosis but absent in BCG. This approach could minimize false positive diagnostic tests in the setting of BCG vaccination, especially in the setting of NIH interest in new approaches to systemic BCG vaccination via routes other than skin, as well as renewed interest in other experimental whole cell vaccines. • Immune responses of the earliest point of initial TB infection [Tri-I] To develop a vaccine that may prevent infection, we need to understand the immune responses that occur at the earliest point of initial TB infection, yet this phase of infection has received much less attention than latent or active disease. Our studies of genetics, transcriptomics and microbiomics in defined clinical cohorts can shed light on this phase.