Systems biological assessment of vaccination-induced protective immunity in African children

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. The project proposes 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 the well-characterized cohort, detailed immunological characterization of host responses, and state-of-the-art computational models of immunity, the project will in Aim 1 perform a systems analysis of baseline signatures that predict immunogenicity and protection from primary vaccination against Pf. The project 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. The 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, A systems analysis of vaccine-induced signatures will be performed that predict immunogenicity and protection from primary and booster vaccination against Pf. The project 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. An integrated analysis of these datasets will be performed 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.

Project details

Monitoring & Evaluation
Vaccines (Immune Correlates)

Feb 2022 — Jan 2027

$1.6M

Malawi