Blood Interferon Signatures Putatively Link Lack of Protection Conferred by the RTS,S Recombinant Malaria Vaccine to an Antigen-specific IgE Response

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. Furthermore, profiling of antigen-specific levels of IgE in a Mozambican cohort of malaria-exposed children vaccinated with RTS,S identified an association between elevated baseline IgE levels and subsequent development of naturally acquired malaria infection during follow up. Taken together these findings warrant further investigation of the role of antigen-specific IgE in conferring susceptibility to malaria infection.

Repeated clinical malaria episodes are associated with modification of the immune system in children

“…In a recent study, a modular transcriptional repertoire analysis was used to find markers for malarial immunity following an RTS,S study [ 34 ]. In contrast to modular expression, which describes changes over entire categories of children, we also defined modular response ( r ) for individuals as: where r c,M is the response of child c in module M , | M | is the number of genes in module M, g i,c is the rlog gene expression of gene i in child c , and μ i is the median gene expression of gene i in high and low malaria episode children.…”

Using ‘collective omics data’ for biomedical research training

“…But once the potential for addressing a gap in biomedical knowledge has been identified that process becomes hypothesis‐driven and fairly similar to what most readers would have experienced in their younger days. Furthermore, downstream discovery work would be likely to require, at some point, de novo data generation, which was the case for our COD3 proof of principle study …”

“…The only relevant point here is that it is an approach that was not employed by the primary investigators who conducted and published the seminal study . This gap between the approaches used for primary and secondary analyses is what permitted the identification of distinct but potentially complementary signatures associated with protection conferred by the RTS,S vaccine …”

“…A proof of principle was recently obtained with one trainee completing all three modules . Five other scientists having completed at least one training module …”

Development of quantitative suspension array assays for six immunoglobulin isotypes and subclasses to multiple Plasmodium falciparum antigens

“…However, it needs to be better established whether non-cytophilic IgG2 and IgG4 antibodies, despite being present at low levels in exposed individuals, could be induced in detriment of cytophilic subclasses considered as protective, and to what extent their increase could be associated with risk of malaria. Furthermore, the role of IgM and IgE in malaria immunity has been less studied and merits more attention according to recent data associating those responses to protection 19 or risk 20–22 , respectively. Therefore, an appropriate understanding of the magnitude and antigenic specificity of each of the Ig isotypes and subclasses is very important for the development of a new generation of effective vaccines.…”