Antigen-stimulated PBMC transcriptional signatures of protection upon malaria sporozoite and RTS,S/AS01E immunizations
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PROVIDER: PRJNA605110 | ENA |
REPOSITORIES: ENA
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Project description:Identifying immune correlates of protection and mechanisms of immunity accelerates and streamlines the development of vaccines. RTS,S/AS01E, the most advanced malaria vaccine, has moderate efficacy in African children. In contrast, immunization with sporozoites under antimalarial chemoprophylaxis (CPS immunization) can provide 100% sterile protection in naïve adults. We used systems biology approaches to identify correlates of vaccine-induced immunity based on transcriptomes of peripheral blood mononuclear cells from subjects immunized with RTS,S/AS01E or chemo-attenuated sporozoites stimulated with parasite antigens in vitro. Specifically, we used samples of subjects from two age cohorts and 3 African countries participating in an RTS,S/AS01E pediatric phase 3 trial and malaria-naïve subjects participating in a CPS trial. We identified both pre-immunization and post-immunization transcriptomic signatures correlating with protection. Signatures were validated in independent children and infants from the RTS,S/AS01E phase 3 trial and subjects from an independent CPS trial with high accuracies (>70%). Transcription modules revealed interferon, NF-B, TLR, and monocyte-related signatures associated with protection. Pre-immunization signatures suggest the potential for strategies to prime the immune system before vaccination towards improving vaccine immunogenicity and efficacy. Finally, signatures of protection could be useful to determine efficacy in clinical trials, accelerating vaccine candidate testing. Nevertheless, signatures should be tested more extensively across multiple cohorts and trials to demonstrate their universal predictive capacity.
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Project description:RTS,S is the sole candidate vaccine shown to provide protection against infection to malaria-naive adults challenged with mosquito-borne homologous falciparum malaria and protection against infection and clinical and severe disease to volunteers in malaria-endemic Africa who were exposed to diverse Plasmodium falciparum strains. In this experiment we profiled gene expression in PBMCs after vaccination with the RTS,S candidate malaria vaccine in a controlled human malaria infection study. Subjects were vaccinated with three doses of the RTS,S candidate malaria vaccine. Blood samples for PBMC isolation and subsequent gene expression analysis were taken on day 0 (0m), day of the third vaccination (8w), 1 day post third vaccination (8w1d), 3 days post third vaccination (8w3d), the day of the infection (10w), 1 day post infection (10w1d), and 5 days post infection (10w5d). After infection the subjects were closely monitored for parasitemia. The response to the controlled infection was recorded as follows: no parasitemia (P, protected), parasitemia in the same time frame as the control group (NP, not protected), parasitemia later than the control group (DL, delayed). In addition to the experimental factors, a confounding factor was identified in the data analysis related to the use of a specific kit batch (Kit A or B).
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Project description:In a phase 3 trial in African infants/children, the RTS,S/AS01 (GSK) vaccine showed moderate efficacy against clinical malaria. We aimed to identify RTS,S/AS01-induced signatures associated with clinical malaria by analyzing antigen-stimulated peripheral blood mononuclear cells sampled from a subset of trial participants at baseline and month 3 (one month post-final dose). RTS,S/AS01 vaccination was associated with downregulation of B-cell and monocyte-related blood transcriptional modules (BTMs) and upregulation of T-cell related BTMs, as well as higher month 3 (vs baseline) (CSP)-specific CD4+ T-cell responses. For some RTS,S/AS01-associated BTMs, month 3 levels correlated with anti-circumsporozoite protein (CSP) IgM and inversely with anti-CSP IgG responses. There were few RTS,S/AS01-associated BTMs whose month 3 levels correlated with malaria risk. In contrast, baseline levels of dendritic cell and monocyte RTS,S/AS01-associated BTMs correlated with malaria risk. A cross-study analysis supported generalizability of these correlations to healthy, malaria-naïve adults, suggesting inflammatory monocytes may inhibit protective RTS,S/AS01-induced responses.
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