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

Details

Serval ID
serval:BIB_807A74E7EF22
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Transcriptional correlates of malaria in RTS,S/AS01-vaccinated African children: a matched case-control study.
Journal
eLife
Author(s)
Moncunill G., Carnes J., Chad Young W., Carpp L., De Rosa S., Campo J.J., Nhabomba A., Mpina M., Jairoce C., Finak G., Haas P., Muriel C., Van P., Sanz H., Dutta S., Mordmüller B., Agnandji S.T., Díez-Padrisa N., Williams N.A., Aponte J.J., Valim C., Neafsey D.E., Daubenberger C., McElrath M.J., Dobaño C., Stuart K., Gottardo R.
ISSN
2050-084X (Electronic)
ISSN-L
2050-084X
Publication state
Published
Issued date
21/01/2022
Peer-reviewed
Oui
Volume
11
Pages
e70393
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
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.
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.
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 <sup>+</sup> 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.
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 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.
Keywords
Antibodies, Protozoan/immunology, Antigens, Protozoan/immunology, B-Lymphocytes/immunology, B-Lymphocytes/metabolism, Case-Control Studies, Child, Preschool, Clinical Trials, Phase III as Topic, Humans, Infant, Leukocytes, Mononuclear/immunology, Leukocytes, Mononuclear/metabolism, Malaria Vaccines/immunology, Malaria, Falciparum/immunology, Malaria, Falciparum/prevention & control, Mozambique, T-Lymphocytes/immunology, T-Lymphocytes/metabolism, Tanzania, Transcriptome/genetics, Transcriptome/immunology, Vaccines, Synthetic/immunology, Plasmodium falciparum, gene expression, human, immune cell responses, immunology, infectious disease, inflammation, malaria, microbiology, vaccine
Pubmed
Web of science
Open Access
Yes
Create date
31/01/2022 12:11
Last modification date
06/05/2022 6:35
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