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We sought to further understand RTS,S\/AS01-induced immune responses associated with vaccine protection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Applying the blood transcriptional module (BTM) framework, we characterized the transcriptomic response to RTS,S\/AS01 vaccination in antigen-stimulated (and vehicle control) peripheral blood mononuclear cells sampled from a subset of trial participants at baseline and month 3 (1-month post-third dose). Using a matched case\u2013control study design, we evaluated which of these \u2018RTS,S\/AS01 signature BTMs\u2019 associated with malaria case status in RTS,S\/AS01 vaccinees. Antigen-specific T-cell responses were analyzed by flow cytometry. We also performed a cross-study correlates analysis where we assessed the generalizability of our findings across three controlled human malaria infection studies of healthy, malaria-naive adult RTS,S\/AS01 recipients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      RTS,S\/AS01 vaccination was associated with downregulation of B-cell and monocyte-related BTMs and upregulation of T-cell-related BTMs, as well as higher month 3 (vs. baseline) circumsporozoite protein-specific CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell responses. There were few RTS,S\/AS01-associated BTMs whose month 3 levels correlated with malaria risk. In contrast, baseline levels of BTMs associated with dendritic cells and with monocytes (among others) correlated with malaria risk. The baseline dendritic cell- and monocyte-related BTM correlations with malaria risk appeared to generalize to healthy, malaria-naive adults.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>A prevaccination transcriptomic signature associates with malaria in RTS,S\/AS01-vaccinated African children, and elements of this signature may be broadly generalizable. The consistent presence of monocyte-related modules suggests that certain monocyte subsets may inhibit protective RTS,S\/AS01-induced responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>Funding was obtained from the NIH-NIAID (R01AI095789), NIH-NIAID (U19AI128914), PATH Malaria Vaccine Initiative (MVI), and Ministerio de Econom\u00eda y Competitividad (Instituto de Salud Carlos III, PI11\/00423 and PI14\/01422). The RNA-seq project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant number U19AI110818 to the Broad Institute. This study was also supported by the Vaccine Statistical Support (Bill and Melinda Gates Foundation award INV-008576\/OPP1154739 to R.G.). C.D. was the recipient of a Ramon y Cajal Contract from the Ministerio de Econom\u00eda y Competitividad (RYC-2008-02631). G.M. was the recipient of a Sara Borrell\u2013ISCIII fellowship (CD010\/00156) and work was performed with the support of Department of Health, Catalan Government grant (SLT006\/17\/00109). This research is part of the ISGlobal\u2019s Program on the Molecular Mechanisms of Malaria which is partially supported by the Fundaci\u00f3n Ram\u00f3n Areces and we acknowledge support from the Spanish Ministry of Science and Innovation through the \u2018Centro de Excelencia Severo Ochoa 2019\u20132023\u2019 Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.70393","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T08:15:20Z","timestamp":1640074520000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.70393","source":"Crossref","is-referenced-by-count":13,"title":["Transcriptional correlates of malaria in RTS,S\/AS01-vaccinated African children: a matched case\u2013control study"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5105-9836","authenticated-orcid":true,"given":"Gemma","family":"Moncunill","sequence":"first","affiliation":[{"name":"ISGlobal, Hospital Cl\u00ednic - Universitat de Barcelona","place":["Barcelona, Spain"]},{"name":"CIBER de Enfermedades Infecciosas","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Carnes","sequence":"additional","affiliation":[{"name":"Center for Global Infectious Disease Research, Seattle Children's Research Institute","place":["Seattle, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Chad Young","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center","place":["Seattle, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0333-5925","authenticated-orcid":true,"given":"Lindsay","family":"Carpp","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center","place":["Seattle, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center","place":["Seattle, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J","family":"Campo","sequence":"additional","affiliation":[{"name":"Antigen Discovery Inc","place":["Irvine, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augusto","family":"Nhabomba","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Sa\u00fade de Manhi\u00e7a (CISM), Rua 12, Cambeve, Vila de Manhi\u00e7a","place":["Maputo, Mozambique"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxmillian","family":"Mpina","sequence":"additional","affiliation":[{"name":"Ifakara Health Institute. 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