PROJECT SUMMARY/ABSTRACT
The most advanced malaria vaccine candidate, RTS,S, provides only partial efficacy against clinical malaria
episodes when given to young children. Furthermore, efficacy wanes within 12-18 months post vaccination,
with many children having low magnitude and/or rapidly waning immune responses, and booster doses are
only partially efficacious. The immunologic mechanisms underlying sub-optimal and waning immune responses
and vaccine efficacy remain unclear. We propose to utilize a multi-omics, systems biology approach to
define baseline, and vaccine-induced signatures that predict immunogenicity and protection, following
RTS,S vaccination of young children in Malawi. This project will take advantage of an extraordinary
opportunity to comprehensively study baseline and vaccine-induced immune responses to RTS,S in young
children through a collaboration with the Malawi International Centers of Excellence in Malaria Research
(ICEMR). The Malawi ICEMR is studying the effectiveness of RTS,S to prevent malaria infection and
transmission in a longitudinal cohort of children as part of a World Health Organization-sponsored
implementation study. By leveraging our well-characterized cohort, detailed immunological characterization of
host responses, and state-of-the-art computational models of immunity, we will in Aim 1 perform a systems
analysis of baseline signatures that predict immunogenicity and protection from primary vaccination
against Pf. We will use a multi-omics approach, using bulk RNA-seq, metabolomics of serum, cytometry by
time of flight with epigenetic profiling (EpiTOF), and single cell epigenetic profiling to profile baseline
signatures prior to primary RTS,S vaccination in 300 Malawian children. Our goal will be to perform an
integrated analysis of these orthogonal datasets to define a baseline signature that can be used to predict the
immunogenicity and efficacy of RTS,S vaccination. In Aim 2, we will perform a systems analysis of
vaccine-induced signatures that predict immunogenicity and protection from primary and booster
vaccination against Pf. We will use a multi-omics approach, using bulk RNA-seq, metabolomics of serum,
multiplex analysis of serum cytokines and CSP-specific T cell assays, to comprehensively profile vaccine-
induced signatures following RTS,S vaccination in Malawian children. We will perform an integrated analysis
of these datasets to define vaccine-induced signatures that can be used to predict the immunogenicity and
efficacy of RTS,S vaccination. The successful completion of these aims will provide deep insight into the
molecular mechanisms underlying suboptimal immunity to RTS,S vaccination, and yield biomarkers of vaccine-
induced immunity and protection.