A highly effective malaria vaccine remains the ultimate tool for malaria control and elimination. The front runner
is RTS,S/AS01, a recombinant protein comprising portions of Plasmodium falciparum (Pf) circumsporozoite
protein (CSP). However, the observed vaccine efficacy to clinical malaria in children living in malaria endemic
settings is only 36%. In order to understand how to improve upon this vaccine, a comprehensive evaluation of
baseline and cumulative factors that impede malaria vaccine performance, in direct contrast to factors
associated with protection from malaria, is needed. We have recently defined stronger correlates of protection
based on functional antibody activity using a systems serology approach. To date, these system serology
studies have been conducted only for adults from non-endemic regions. Here, we aim to test the overall
hypothesis that children living in malaria endemic areas who have less mature or aberrant immune cells are
unable to develop the breadth of functional antibodies and T cells elicited by RTS,S in order to become
protected against malaria. Drawing on the WHO Malaria Vaccine Implementation Program in a high-
transmission region in Kenya, we will employ an intensive longitudinal cohort study design to follow children
during their 4-dose RTS,S vaccination schedule, with active and passive follow-up for Pf infections and
episodes of clinical malaria until they reach 4 years of age. Our overall hypothesis will be tested by the
following specific aims: SA1: To comprehensively characterize baseline and peri-vaccination factors that
correlate with vaccine hyporesponsiveness. Using an integrated systems immunology and machine
learning approach, we will determine the effects of ongoing exposures to malaria, systemic inflammation, pre-
existing anti-malarial immunity, and immaturity of cellular immune signatures on RTS,S vaccine hypo-
responsiveness, defined as the inability to develop a core group of functional anti-CSP antibodies. SA2: To
comprehensively characterize the post-vaccination immune signatures in children that correlate with
protection from malaria. Using a systems immunology approach, we will determine the function of vaccine-
elicited anti-CSP antibodies and their correlation with age, cellular immune signatures, and protection from
malaria. Functional in vitro studies will assess antibody opsonization of sporozoites and antibody-dependent
cellular cytotoxicity with and without innate immune cells; assess the phenotype and function of vaccine-
elicited CSP-specific T cells; and explore the potential for epigenetic modifications of monocytes (trained
immunity) to influence vaccine performance. Using a computational modeling/machine learning approach, we
will integrate deep immunoprofiling features to predict correlates with protection from malaria. Together, this
study aims to inform the next generation of malaria vaccines and vaccination programs that could include
immune-modulatory components or recommendations to combine antimalarial prophylaxis/treatment within the
vaccine schedule.
