A Safety and Efficacy Study of Concomitant Administration of ChAd63/MVA ME-TRAP + RTS,S
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103874 | GEO | 2020/09/01
REPOSITORIES: GEO
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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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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:Sterile immunity to Plasmodium falciparum infection can be induced experimentally in humans after few exposures. An example is the induction of immunity using whole parasites by exposure of malaria-naive volunteers to infectious mosquito bites while using chloroquine prophylaxis (CPS immunization). Chloroquine kills blood-stage parasites but leaves liver-stage parasites unaffected, thereby exposing the liver-stage and early blood-stage antigens to the immune system. Upon subsequent challenge, volunteers are completely protected from infection, but protective efficacy decreases when fewer infectious mosquito bites are used for CPS immunization. Efforts to understand the mechanisms of this immunity, and how it differs from naturally-acquired immunity, may provide critical insights that could aid malaria vaccine development. In this pilot study, transcriptomic features are derived from blood samples collected before and after challenge with infectious mosquito bites.
2013-09-18 | GSE50957 | GEO
Project description:<p>Description:<br/> Experimental exposure to malaria parasites can lead to development of protective immunity, providing a foothold for the development of a malaria vaccine. The goal of this study is to investigate immune transcriptional profiles associated with malaria protective immune responses induced by experimental Chemo-Prophylaxis and Sporozoites (CPS) immunization of P. <i>falciparum</i>-naive human volunteers. Samples for this study were obtained from a CPS-immunization study conducted in 2011 (ClinicalTrials.gov Identifier: NCT01218893), where healthy volunteers received CPS-immunization with bites from different numbers of P. <i>falciparum</i>-infected mosquitoes (three times 15 (n=5), 10 (n=9) or 5 (n=10)). Five control subjects received uninfected mosquito bites under chloroquine prophylaxis. Fifteen weeks after discontinuation of chloroquine prophylaxis, all volunteers were challenged by exposure to infected mosquito bites. </p> <p>Study Design:<br/> A maximum of 30 volunteers were divided into four groups. All volunteers received weekly chloroquine prophylaxis for a period of 13 weeks (91 days). During these 13 weeks, on days 8, 36 and 64 they were exposed to the bites of 15 mosquitoes. Group 1 (n=5, positive control) received three CPS immunizations by 15 mosquitoes infected with P. falciparum sporozoites. Group 2 (n=10) received three times 10 bites from infected mosquitoes and 5 bites from uninfected mosquitoes. Group 3 (n=10) received three times 5 bites from infected mosquitoes and 10 bites from uninfected mosquitoes. Group 4 (n=5), the negative control, received three placebo immunizations with 15 bites of uninfected mosquitoes. Fifteen weeks after discontinuation of chloroquine prophylaxis, all 30 volunteers were challenged at day 196 by the bites of 5 infectious mosquitoes and followed for 21 days. All subjects were treated with chloroquine 21 days after challenge or whenever they had a positive thick smear during that period. </p>
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Project description:Systems biology has the potential to identify gene signatures associated with vaccine immunogenicity or protective efficacy. The main objective of our study was to identify optimal post-vaccination time points for evaluating blood RNA-expression profiles in recipients of the candidate tuberculosis vaccine M72/AS01. In this phase II open-label study (NCT01669096), healthy Bacillus Calmette-Guérin (BCG)-primed, HIV-negative adults were administered two doses (30-days apart) of M72/AS01. Blood samples were collected pre-dose 1, pre-dose 2 and 1, 7, 10, 14, 17 and 30 days post-dose 2. RNA expression in blood and peripheral-blood mononuclear cells (PBMCs) was quantified using microarray technology. The data analysis used as a reference, a PBMC-gene signature that was associated with the protective efficacy of a similarly adjuvanted candidate malaria vaccine. Peripheral-blood CD4+ T-cell reactivity, serum interferon-gamma (IFNG) concentrations and safety were also assessed. Twenty subjects completed the study and 18 subjects received two doses. The observed safety profile was similar to previous trials. Serum IFNG responses and M72-specific CD4+ T cell responses to vaccination were detected as expected, based on previous trial experience. PBMC and whole-blood RNA-expression data at day 14 post-dose 2 relative to pre-vaccination and whole-blood RNA-expression data at 7, 10, and 17 days post-dose 2 relative to pre-vaccination could be used to classify vaccine recipients into gene-signature positive or gene-signature negative groups. In conclusion, whole blood sampled from the 7, 10, 14, or 17 day post-vaccination time points, in addition to pre-vaccination, could be selected to assess potentially clinically relevant responses to M72/AS01 using transcriptome analysis.
2018-03-19 | GSE102459 | GEO
Project description:Gene expression analysis in lymph nodes and site of injection (intradermal) after vaccination with adenovirus (Ad), modified vaccinia Ankara (MVA) or a mixed formulation of Ad+MVA. The hypothesis tested in the present study was that co-administration of two viral vectors induce a differential gene expression in the site of vaccination (dermis) and the draining lymph nodes that ultimately influences the protective ability of a vaccine against pre-erythrocytic malaria.
2012-12-01 | GSE30564 | GEO
Project description:Gene expression analysis in lymph nodes and site of injection (intradermal) after vaccination with adenovirus (Ad), modified vaccinia Ankara (MVA) or a mixed formulation of Ad+MVA. The hypothesis tested in the present study was that co-administration of two viral vectors induce a differential gene expression in the site of vaccination (dermis) and the draining lymph nodes that ultimately influences the protective ability of a vaccine against pre-erythrocytic malaria. Total RNA was isolated from the vaccination site (dermis) and lymph nodes after vaccination with adenovirus, MVA or Ad+MVA mixed co-administration after 6h and 24h (ear biopsies) and 9h, 24h and 72h for lymph nodes. Differential gene expression was assessed between vaccinated and non-immunized mice. Four ear biopsy samples did not pass quality control, and are not included in this submission.
2012-12-01 | E-GEOD-30564 | biostudies-arrayexpress
Project description:Identification of gene signatures that are associated with protection in RTS,S malaria vaccination study
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