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

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, 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

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.

Trial registration: ClinicalTrials.gov NCT00866619.

Keywords: Plasmodium falciparum; gene expression; human; immune cell responses; immunology; infectious disease; inflammation; malaria; microbiology; vaccine.

Conflict of interest statement

GM, JC, WC, LC, SD, AN, MM, CJ, GF, PH, CM, PV, HS, SD, BM, SA, ND, NW, JA, CV, DN, CD, MM, CD, KS, RG No competing interests declared, JC is an employee of Antigen Discovery Inc. The author declare that no other competing interests exist

Figures

Figure 1.. Schematic showing vaccination and sampling…
Figure 1.. Schematic showing vaccination and sampling schedule.
Participants received RTS,S/AS01 (or comparator) at months 0, 1, and 2; peripheral blood mononuclear cells (PBMCs) were collected for fresh stimulations and RNA-sequencing and for cryopreservation at months 0 and 3 (1-month postfinal primary vaccination dose). Stim, stimulation.
Figure 2.. Transcriptional responses and antigen-specific transcriptional…
Figure 2.. Transcriptional responses and antigen-specific transcriptional responses at 1-month postfinal dose associated with RTS,S/AS01 vaccination.
(A) Comparison 1: month 3 (M3) peripheral blood mononuclear cells (PBMC), RTS,S/AS01 vs. comparator; (B) Comparison 2: M3 PBMC vs. month 0 (M0) PBMC, RTS,S/AS01 recipients only. Cell color intensity represents the significance of the difference in the relevant comparison, expressed as signed log10 false discovery rate (FDR); blood transcriptional modules (BTMs) with significantly different expression (FDR ≤0.2) between the two compared groups are outlined in black. |FDR| < 0.2 (*), <0.05 (**), <0.01 (***). Red, higher expression in RTS,S/AS01 recipients vs. comparator recipients at M3 (Comparison 1) or higher expression in RTS,S/AS01 recipients at M3 vs. M0 (Comparison 2); blue, lower expression in RTS,S/AS01 recipients vs. comparator recipients at M3 (Comparison 1) or lower expression in RTS,S/AS01 recipients at M3 vs. M0 (Comparison 2). High-level BTM annotation groups are shown in the left-most color bar. Numbers of participants in each analysis are: (A) Vehicle: 348 (131 comparator, 217 RTS,S/AS01), CSP: 355 (135 comparator, 220 RTS,S/AS01), HBS: 353 (132 comparator, 221 RTS,S/AS01), and AMA1: 351 (132 comparator, 219 RTS,S/AS01). (B) Vehicle: 221, CSP: 224 (221 vehicle, 219 CSP), HBS: 225 (221 vehicle, 211 HBS), AMA1: 223 (221 vehicle, 195 AMA1). Numbers include participants not part of the case–control cohort, and thus exceed the numbers in Table 1. Each ‘vehicle’ column displays the vaccine effect in vehicle; each ‘stimulation’ column displays the vaccine effect for that stimulation compared to vehicle, that is adjusted for vehicle. Detailed equations are given in Methods.
Figure 3.. Associations of month 3 levels…
Figure 3.. Associations of month 3 levels of RTS,S/AS01 signature blood transcriptional modules (BTMs) with malaria case status in RTS,S/AS01 recipients.
Heatmap showing downselected signature BTMs (Comparison 1) with significantly different expression (false discovery rate [FDR] ≤0.2) in month 3 peripheral blood mononuclear cells (PBMC) from RTS,S/AS01 malaria cases vs. nonmalaria controls, in at least one stimulation condition. Cell color intensity represents the significance of the difference in the relevant comparison, expressed as signed log10 FDR; BTMs with significantly different expression in the comparison are outlined in black. |FDR| < 0.2 (*), <0.05 (**), <0.01 (***). Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls. High-level BTM annotation groups are shown in the left-most color bar. Numbers of participants in each analysis are: vehicle: 122, CSP: 123 (122 vehicle, 122 CSP), HBS: 123 (122 vehicle, 115 HBS), AMA1: 123 (122 vehicle, 97 AMA1). The ‘vehicle’ column displays the vaccine effect in vehicle; each ‘stimulation’ column displays the vaccine effect for that stimulation compared to vehicle, that is adjusted for vehicle. Detailed equations are given in Methods.
Figure 3—figure supplement 1.. Associations of month…
Figure 3—figure supplement 1.. Associations of month 3 levels of RTS,S/AS01 signature blood transcriptional modules (BTMs) with malaria case status in comparator recipients.
Heatmap showing which of the 68 downselected RTS,S/AS01 signature BTMs (Comparison 1) showed significantly different expression (false discovery rate [FDR] ≤ 0.2) in month 3 peripheral blood mononuclear cells (PBMC) between comparator cases vs. nonmalaria controls in vehicle-stimulated PBMC from comparator recipients. |FDR| 10 FDR. Red, higher expression in comparator cases vs. controls; blue, lower expression in comparator cases vs. controls. High-level BTM annotation groups are shown in the left-most color bar.
Figure 4.. RTS,S/AS01 vaccination elicits circumsporozoite protein…
Figure 4.. RTS,S/AS01 vaccination elicits circumsporozoite protein (CSP)-specific polyfunctional T-cell responses that do not correlate with clinical malaria risk.
Boxplots show (A) polyfunctionality score and (B) magnitude (% CD4+ T cells expressing IL2 or TNF-α or CD154) of CSP-specific CD4+ T-cell responses in RTS,S/AS01 recipients as assessed by intracellular cytokine staining of peripheral blood mononuclear cells (PBMC) collected at month 0 (M0) or at month 3 (M3). Each dot represents a single participant. Data plotted include all available months 0 and 3 samples, that is paired months 0–3 samples were not required for plotting. (C) Polyfunctionality score and (D) magnitude of CSP-specific CD4+ T-cell responses in RTS,S/AS01 vaccine recipients at month 3, stratified by case–control status. In panels A and B, p values were obtained using a mixed-effects model with participant as a random effect. In panels C and D, p values were obtained using a mixed-effects model with match_id as a random effect. Number of participants in each panel is: (A) 213 (73 M0 and 182 M3), (B) 194 (61 M0, 175 M3), (C) 37 cases and 145 controls, and (D) 36 cases and 139 controls.
Figure 5.. Correlations of month 3 transcriptional…
Figure 5.. Correlations of month 3 transcriptional and adaptive responses in RTS,S/AS01 vaccine recipients.
Heatmap showing correlations between month 3 levels of RTS,S/AS01 signature blood transcriptional modules (BTMs) in vehicle-treated peripheral blood mononuclear cells (PBMC) and month 3 antibody responses. Cell color intensity represents the strength of the correlation; BTM/response pairs with significant correlations (false discovery rate [FDR] ≤0.2) are outlined in black. Cell color represents correlation direction: red, positive correlation; blue, negative correlation. High-level BTM annotation groups are shown in the left-most color bar. Number of participants: 30–42.
Figure 5—figure supplement 1.. Correlations of transcriptional…
Figure 5—figure supplement 1.. Correlations of transcriptional and adaptive responses in comparator vaccine recipients.
Heatmap showing significant correlations between month 3 levels of RTS,S/AS01 signature blood transcriptional modules (BTMs) in vehicle-treated peripheral blood mononuclear cells (PBMC) and month 3 antibody responses in comparator recipients. Cell color intensity represents the strength of the correlation; BTM/response pairs with significant correlations (false discovery rate [FDR] ≤0.2) are outlined in black. Cell color represents correlation direction: red, positive correlation; blue, negative correlation. High-level BTM annotation groups are shown in the left-most color bar. No correlations with month 3 cellular responses were seen.
Figure 6.. Associations of ( A )…
Figure 6.. Associations of (A) month 3 or (B) month 0 levels of downselected blood transcriptional modules (BTMs) with malaria case status RTS,S/AS01 vaccine recipients across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
(A) Heatmap showing the difference in month 3 peripheral blood mononuclear cell (PBMC) BTM expression between RTS,S/AS01 cases vs. controls, in each of three controlled human malaria infection (CHMI) studies, of the seven BTMs whose month 3 levels in vehicle-stimulated PBMC associated with malaria case status in MAL067 (Figure 3). ‘Month 3’ = 21-day postfinal dose in MAL068 and MAL071, and 14-day postfinal dose in WRAIR 1032. BTMs with significantly different expression (false discovery rate [FDR] ≤0.2, with adjustment done across the five BTMs) are outlined in black. |FDR| < 0.2 (*), <0.05 (**), <0.01 (***). (B) Heatmap showing the 45 BTMs whose month 0 levels showed significantly different expression in MAL067 RTS,S/AS01 malaria cases vs. nonmalaria controls. These 45 BTMs were also examined as potential correlates of challenge outcome in each of the 3 CHMI studies. Significantly different expression is defined as FDR ≤0.2, with adjustment across the 45 BTMs. All data shown are from participants who received the same vaccine regimen: a dose of RTS,S/AS01 at months 0, 1, and 2. Cell color intensity represents the significance of the difference in the case vs. control comparison, expressed as signed log10 FDR; BTMs with significantly different expression (FDR ≤0.2) between the two compared groups are outlined in black. |FDR| < 0.2 (*), <0.05 (**), <0.01 (***). Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls. High-level BTM annotation groups are shown in the left-most color bar. Numbers of participants in each analysis are: (A) MAL067, 122; WRAIR 1032, 39; MAL068 RRR, 21; MAL071 RRR, 16. (B) MAL067, 37; WRAIR 1032, 39; MAL068 RRR, 21; MAL071 RRR, 16. Detailed equations are given in Methods.
Figure 6—figure supplement 1.. Association of month…
Figure 6—figure supplement 1.. Association of month 0 level of each gene in the ‘cell cycle and transcription (M4.0)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls. The red-outlined portion of the heatmap in the lower right corresponds to an expanded view of the red-outlined portion of the heatmap on the left, for increased legibility of gene names.
Figure 6—figure supplement 2.. Association of month…
Figure 6—figure supplement 2.. Association of month 0 level of each gene in the ‘Resting dendritic cell surface signature (S10)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls.
Figure 6—figure supplement 3.. Association of month…
Figure 6—figure supplement 3.. Association of month 0 level of each gene in the ‘DC surface signature (S5)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls.
Figure 6—figure supplement 4.. Association of month…
Figure 6—figure supplement 4.. Association of month 0 level of each gene in the ‘Enriched in dendritic cells (M168)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls.
Figure 6—figure supplement 5.. Association of month…
Figure 6—figure supplement 5.. Association of month 0 level of each gene in the ‘Myeloid cell enriched receptors and transporters (M4.3)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls.
Figure 6—figure supplement 6.. Association of month…
Figure 6—figure supplement 6.. Association of month 0 level of each gene in the ‘Enriched in monocytes (II) (M11.0)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls.
Figure 6—figure supplement 7.. Association of month…
Figure 6—figure supplement 7.. Association of month 0 level of each gene in the ‘Enriched in monocytes (I) (M4.15)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls.
Figure 6—figure supplement 8.. Association of month…
Figure 6—figure supplement 8.. Association of month 0 level of each gene in the ‘Monocyte surface signature (S4)’ module with malaria case status across studies sharing a common months 0, 1, and 2 RTS,S/AS01 arm.
Cell color intensity represents the strength of the difference in the case vs. control comparison, expressed as signed log10 p value; genes with significantly different expression (false discovery rate ≤0.2) between the two compared groups are outlined in black. Red, higher expression in RTS,S/AS01 cases vs. controls; blue, lower expression in RTS,S/AS01 cases vs. controls.
Figure 6—figure supplement 9.. Correlations of month…
Figure 6—figure supplement 9.. Correlations of month 0 blood transcriptional module (BTM) expression in vehicle-treated peripheral blood mononuclear cells (PBMC) with month 3 T-cell responses in RTS,S/AS01 vaccine recipients.
Heatmap showing significant correlations between month 0 levels of RTS,S/AS01 signature BTMs and month 3 cellular responses (no significant correlations were seen with any month 3 antibody responses). Cell color intensity represents the strength of the correlation; BTM/response pairs with significant correlations (false discovery rate [FDR] ≤0.2) are outlined in black. Cell color represents correlation direction: red, positive correlation; blue, negative correlation. High-level BTM annotation groups are shown in the left-most color bar. No significant correlations were seen with month 3 antibody responses. PFS, polyfunctionality score.
Figure 6—figure supplement 10.. No significant differences…
Figure 6—figure supplement 10.. No significant differences in monocyte frequencies in cases vs. controls in RTS,S/AS01 vaccinees at either month 0 or 3.
(A) Monocyte frequency, (B) inflammatory monocyte frequency, and (C) inflammatory monocyte/lymphocyte ratio, stratified by case/control status, in RTS,S/AS01 recipients. Flow cytometry data were analyzed using the gating strategy defined in Moncunill et al., 2017a. ‘Inflammatory monocytes’ refers to ‘HLA-DR+ CD14+ CD16++’ cells. The p values at the bottom of each panel are from testing for a significant difference in controls vs. cases within each panel, and were modeled using a mixed-effects model (using lmer) with match ID as a random effect.

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