Abstract
Malaria remains a major cause of mortality and morbidity worldwide. Progress has been made in recent years with the development of vaccines that could pave the way towards protection of hundreds of millions of exposed individuals. Here we used a modular repertoire approach to re-analyze a publically available microarray blood transcriptome dataset monitoring the response to malaria vaccination. We report the seminal identification of interferon signatures in the blood of subjects on days 1, 3 and 14 following administration of the third dose of the RTS,S recombinant malaria vaccine. These signatures at day 1 correlate with protection, and at days 3 and 14 to susceptibility to subsequent challenge of study subjects with live parasites. In addition we putatively link the decreased abundance of interferon-inducible transcripts observed at days 3 and 14 post-vaccination with the elicitation of an antigen specific IgE response in a subset of vaccine recipients that failed to be protected by the RTS,S vaccine.
Highlights
About 3.4 billion people, nearly half of the world’s population, live in areas at risk of malaria transmission[1]
Study subjects received the RTS,S vaccine, which consists of sequences of the Plasmodium falciparum Circum Sporozoite Protein (CSP) expressed in hepatitis B surface antigen and formulated with the proprietary adjuvant systems AS01/AS0220
The blood transcriptional profiles generated on the day of the third vaccination and at day 1, day 3 and day 14 postthird vaccination were used in our re-analysis
Summary
About 3.4 billion people, nearly half of the world’s population, live in areas at risk of malaria transmission[1]. Most notably this includes successful testing of a live vaccine consisting of radiation-attenuated sporozoites[6], and this year licensure by regulatory authorities of the first malaria vaccine, the recombinant adjuvanted vaccine developed by global pharmaceutical GSK, called RTS,S known by its commercial name, Mosquirix® This is a highly significant landmark but the efficacy of the vaccine for unknown reasons, and despite optimization attempts, remains suboptimal[7,8]. We employed an innovative approach developed earlier; including by other team members part of previous publications which consists in identification of modular transcriptional repertoires – collections of co-clustered gene sets – in order to carry out modular level “fingerprinting analyses”[16] This re-analysis led to original findings, with the identification of an interferon transcriptional signature at day 1 post-vaccination, correlating with protection as well as a second interferon signature at days 3 and 14 postvaccination correlating this time with lack of protection of study subjects from subsequent challenges with the malaria parasite
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