Potent Antibody Protection Against P. falciparum and P. vivax Malaria

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Project Summary/Abstract Malaria remains a significant threat to global public health, causing over 600,000 deaths in 2022 alone, predominantly among African children under the age of five. Improving vaccines and implementing long-acting immune-based therapies to prevent transmission are critical to reduce malaria incidence and support global elimination efforts. Our team, and others in the field, have now identified panels of highly potent human antibodies against the pre-erythrocytic circumsporozoite protein of Plasmodium falciparum (PfCSP). The most potent of these anti-PfCSP antibodies (CIS43) shows over 85% protective efficacy in controlled human challenge studies and field trials. Deep molecular characterization of protective antibody candidates highlighted certain epitopes associated with improved antibody affinity and potency, which will be required for clinical malaria interventions. However, additional antibody potency improvements are still needed for broad deployment against P. falciparum, and the molecular mechanisms for protective antibodies against CSP of the second most significant human malaria species, Plasmodium vivax (Pv), are not well understood. Elucidating the functional molecular profiles of protective antibodies against Pf and PvCSP, particularly the relationships between affinity, targeted epitopes, and in vivo protection, is crucial to design effective, potent, and long-lasting vaccines and immunotherapies. This R01 research project builds directly on our previously published work improving antibody potency against PfCSP, and will analyze the molecular composition of protective antibody responses against both Pf and PvCSP. In particular, our goal is to identify new antibody variants with additional 5-fold or greater improvement on previous CIS43 and L9 variants to support broad medical use, and to understand the mechanisms that support exquisite protective potency for anti-malarial antibodies targeting sporozoites. In Aims 1 and 2, we will apply our validated yeast display and directed evolution platform to engineer anti-PfCSP antibodies for enhanced affinity and in vivo protection, with detailed characterization of the mechanisms behind potency improvements. We will focus on antibody lineage variants targeting the PfCSP junctional epitope (CIS43) and minor repeat (L9), which have already been validated as highly protective targets in human clinical trials. We will study the relationship between increased affinity and protective potency, with a focus on manipulating multi-epitope affinities across the highly similar CSP peptide repeat regions. In Aim 3, we will extend these approaches for multidimensional immune mapping of anti-malarial antibody repertoires elicited by recent exposure to Pv in Brazilian adults. We will identify the genetic, functional, and structural features of naturally elicited protective antibodies against PvCSP, and other sporozoite protein targets, that will guide new potential intervention mechanisms for vaccines against Pv. Successful completion of this R01 study will deepen our understanding of antibody-based malaria immunity to guide vaccine design and provide potent antibody drug candidates to help address the global burden of malaria.