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

Author:

Moncunill Gemma12ORCID,Carnes Jason3,Chad Young William4,Carpp Lindsay4ORCID,De Rosa Stephen4,Campo Joseph J5,Nhabomba Augusto6,Mpina Maxmillian7,Jairoce Chenjerai6,Finak Greg4,Haas Paige3,Muriel Carl4,Van Phu4,Sanz Héctor1,Dutta Sheetij8,Mordmüller Benjamin29,Agnandji Selidji T910,Díez-Padrisa Núria1,Williams Nana Aba1,Aponte John J1,Valim Clarissa11,Neafsey Daniel E1213ORCID,Daubenberger Claudia1415,McElrath M Juliana416,Dobaño Carlota12ORCID,Stuart Ken341718ORCID,Gottardo Raphael419ORCID

Affiliation:

1. ISGlobal, Hospital Clínic - Universitat de Barcelona

2. CIBER de Enfermedades Infecciosas

3. Center for Global Infectious Disease Research, Seattle Children's Research Institute

4. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center

5. Antigen Discovery Inc

6. Centro de Investigação em Saúde de Manhiça (CISM), Rua 12, Cambeve, Vila de Manhiça

7. Ifakara Health Institute. Bagamoyo Research and Training Centre

8. Walter Reed Army Institute of Research (WRAIR)

9. Institute of Tropical Medicine and German Center for Infection Research

10. Centre de Recherches Médicales de Lambaréné (CERMEL), BP 242

11. Department of Global Health, Boston University School of Public Health

12. Broad Institute of Massachusetts Institute of Technology and Harvard

13. Harvard T.H. Chan School of Public Health

14. Swiss Tropical and Public Health Institute

15. University of Basel

16. Departments of Laboratory Medicine and Medicine, University of Washington

17. Department of Pediatrics, University of Washington

18. Department of Global Health, University of Washington

19. University of Lausanne and Centre Hospitalier Universitaire Vaudois

Abstract

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 vaccine protection.Methods: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–control study design, we evaluated which of these ‘RTS,S/AS01 signature BTMs’ 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.Results: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+ 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.Conclusions: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.Funding:Funding was obtained from the NIH-NIAID (R01AI095789), NIH-NIAID (U19AI128914), PATH Malaria Vaccine Initiative (MVI), and Ministerio de Economía 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 Economía y Competitividad (RYC-2008-02631). G.M. was the recipient of a Sara Borrell–ISCIII 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’s Program on the Molecular Mechanisms of Malaria which is partially supported by the Fundación Ramón Areces and we acknowledge support from the Spanish Ministry of Science and Innovation through the ‘Centro de Excelencia Severo Ochoa 2019–2023’ Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.

Funder

National Institute of Allergy and Infectious Diseases

PATH Malaria Vaccine Initiative

Instituto de Salud Carlos III

Departament de Salut, Generalitat de Catalunya

Bill and Melinda Gates Foundation

Ministerio de Economía, Industria y Competitividad, Gobierno de España

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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