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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-?B-signaling pathway and 14 to the IFN-?-signaling pathway. Post-dose 3 serum IFN-? concentrations were also correlated with protection; and N-PLS-DA of IFN-?-signaling pathway transcriptome data selected almost all (44/45) of the representative genes for predictive models of protection. Hence, the identification of the NF-?B and IFN-? pathways provides further insight into how vaccine-mediated protection may be achieved.

SUBMITTER: van den Berg RA

PROVIDER: S-EPMC5440508 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

van den Berg Robert A RA Coccia Margherita M Ballou W Ripley WR Kester Kent E KE Ockenhouse Christian F CF Vekemans Johan J Jongert Erik E Didierlaurent Arnaud M AM van der Most Robbert G RG

Frontiers in immunology 20170523

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 predi ...[more]

PMID: 28588574

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Project description:ObjectiveRTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals' proprietary Adjuvant Systems AS02(A) or AS01(B). A recent trial of the RTS,S/AS02(A) and RTS,S/AS01(B) vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02(A) and RTS,S/AS01(B) on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias.DesignThe distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine.SettingThe study was conducted in Kombewa District, western Kenya.ParticipantsSemi-immune adults from the three study arms provided isolates at baseline and during break-through infections.OutcomeParasite isolates used for determining MOI and divergence of csp T cell-epitopes were 191 at baseline and 87 from break-through infections.ResultsGrouping recipients of RTS,S/AS01(A) and RTS,S/AS02(B) together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01(B) group, but not the RTS,S/AS02(A) group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups.ConclusionsIt is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct.

Project description:The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5-56.3; p = 0.029) over the double-blind phase and of 9.0% (-30.6-36.6; p = 0.609) during the single-blind phase.Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia.ClinicalTrials.gov NCT00197041.

Dataset Information

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

Publications

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

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