Transcriptional correlates of malaria in RTS,S/AS01-vaccinated African children: a matched case–control study

• DOI: 10.7554/elife.70393
• Publication Date: 2022-01-21T12:01:08Z
• Authors: Gemma Moncunill; Jason Carnes; William Chad Young; Lindsay Carpp; Stephen De Rosa; Joseph J Campo; Augusto Nhabomba; Maxmillian Mpina; Chenjerai Jairoce; Greg Finak; Paige Haas; Carl Muriel; Phu Van; Héctor Sanz; Sheetij Dutta; Benjamin Mordmüller; Selidji T Agnandji; Núria Díez-Padrisa; Nana Aba Williams; John J Aponte; Clarissa Valim; Daniel E Neafsey; Claudia Daubenberger; M Juliana McElrath; Carlota Dobaño; Ken Stuart; Raphael Gottardo
• Keywords: Cerebral Malaria; Circumsporozoite protein; Monocyte; Vaccine efficacy

Background: In a phase 3 trial in African infants and children, the RTS,S/AS01 vaccine (GSK) showed moderate efficacy against clinical malaria. We sought to further understand RTS,S/AS01-induced immune responses associated with protection. Methods: Applying blood transcriptional module (BTM) framework, we characterized transcriptomic response vaccination antigen-stimulated (and vehicle control) peripheral mononuclear cells sampled from subset of participants at baseline month (1-month post-third dose). Using matched case–control study design, evaluated which these ‘RTS,S/AS01 signature BTMs’ malaria case status vaccinees. Antigen-specific T-cell were analyzed by flow cytometry. also performed cross-study correlates analysis where assessed generalizability our findings across three controlled human infection studies healthy, malaria-naive adult recipients. Results: was downregulation B-cell monocyte-related BTMs upregulation T-cell-related BTMs, as well higher (vs. baseline) circumsporozoite protein-specific CD4 + responses. There few RTS,S/AS01-associated whose levels correlated risk. contrast, dendritic monocytes (among others) The cell- BTM correlations risk appeared generalize adults. Conclusions: A prevaccination associates RTS,S/AS01-vaccinated elements this may be broadly generalizable. consistent presence modules suggests that certain monocyte subsets inhibit protective Funding: Funding obtained NIH-NIAID (R01AI095789), (U19AI128914), PATH Malaria Vaccine Initiative (MVI), Ministerio de Economía y Competitividad (Instituto Salud Carlos III, PI11/00423 PI14/01422). RNA-seq project has been funded whole or part Federal funds National Institute Allergy Infectious Diseases, Institutes Health, Department Health Human Services, under grant number U19AI110818 Broad Institute. This supported Statistical Support (Bill Melinda Gates Foundation award INV-008576/OPP1154739 R.G.). C.D. recipient Ramon Cajal Contract (RYC-2008-02631). G.M. Sara Borrell–ISCIII fellowship (CD010/00156) work support Catalan Government (SLT006/17/00109). research is ISGlobal’s Program on Molecular Mechanisms partially Fundación Ramón Areces acknowledge Spanish Ministry Science Innovation through ‘Centro Excelencia Severo Ochoa 2019–2023’ (CEX2018-000806-S), Generalitat Catalunya CERCA Program.