Predicting RTS,S Vaccine-Mediated Protection from Transcriptomes in a Malaria-Challenge Clinical Trial

Abstract

The RTS,S candidate malaria vaccine can protect against controlled human malaria infection (CHMI), but how protection is achieved remains unclear. Here, we have analyzed longitudinal peripheral blood transcriptome and immunogenicity data from a clinical efficacy trial in which healthy adults received three RTS,S doses 4 weeks apart followed by CHMI 2 weeks later. Multiway partial least squares discriminant analysis (N-PLS-DA) of transcriptome data identified 110 genes that could be used in predictive models of protection. Among the 110 genes, 42 had known immune-related functions, including 29 that were related to the NF-κB-signaling pathway and 14 to the IFN-γ-signaling pathway. Post-dose 3 serum IFN-γ concentrations were also correlated with protection; and N-PLS-DA of IFN-γ-signaling pathway transcriptome data selected almost all (44/45) of the representative genes for predictive models of protection. Hence, the identification of the NF-κB and IFN-γ pathways provides further insight into how vaccine-mediated protection may be achieved.

Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans

“…Since these kits were not validated, qualification was performed internally to establish their cutoff values, which were subsequently set at 0.822 pg/mL for IL-1β, IL-6, TNF-α, IL-5, and IL-10, 40 pg/mL for IP-10 and MCP-1, and 7.407 pg/mL for IFN-γ. Of note, the latter cutoff for IFN-γ was higher than the limit of quantitation of the IFN-γ ELISA used in a recent study, i.e., 1.0 pg/mL ( 35 ). Concentrations below these assay cutoffs were given an arbitrary value of one-half of the cutoff value.…”

“…To further explore our hypothesis to the gene expression level, we quantified the expression of 14 genes encoding major cytokines or transcription factors implicated in inflammation, cell proliferation, and the IFN pathway (listed in Table S1 in Supplementary Material), by whole blood qPCR for a subset of subjects ( N = 112). This selection was based on published literature describing either innate responses to different AS-containing vaccines and other vaccines in humans ( 31 , 35 , 37 , 38 ) and animal models ( 25 – 27 ), or early IFN-related responses to AS01-adjuvanted candidate vaccines in humans ( 32 , 35 , 39 ) and animals ( 40 ).…”

Systems vaccinology and big data in the vaccine development chain

“…125 Interestingly, for the prediction of protection induced by malaria (RTS,S) immunization, NK cells correlated negatively whereas positive correlations were detected for molecular signatures of B-cells and plasma cells 122 factor-jB and interferon-c pathways. 123 These findings indicate that different vaccine-adjuvant combinations may induce different immune (non)effective responses.…”

“…Recent studies show that the application of systems vaccinology is especially interesting for investigating complex or dangerous pathogens such as Ebola virus, HIV, malaria-causing Plasmodium spp. and M. tuberculosis where phase 3 studies are challenging or even impossible, [120][121][122][123][124] heterologous or non-specific effects that vaccines induce against other diseases. 141 These promising changes call for the inclusion of systems vaccinology as early as possible in the vaccine development chain to better understand why some vaccines work and others do not.…”

“…In the public-private project BIOVACSAFE, systems approaches are applied to investigate markers correlating to vaccine safety in human and animal models potentially providing novel markers. 119 Investigators have conducted systems-based studies in humans investigating vaccine candidates against Ebola (rVSV-ZEBOV), 120 HIV-1, 121 malaria (RTS,S) 122,123 and M. tuberculosis (M72/ AS01). 124 For Ebola (rVSV-ZEBOV), IP-10 and CXCR6 + natural killer (NK) cells were independently correlating with antibody titers, suggesting that IP-10 could be a potential target to influence vaccine-induced responses.…”