Investigating the Protective Antibody‐Circumsporozoite Complex of Plasmodium falciparum and its Role in Vaccine Development

Abstract

Malaria is a parasitic disease associated with high fevers, shaking chills, and flu‐like symptoms. It is typically spread by mosquitoes and caused by infection with Plasmodium falciparum (Pf). Due to its high transmission rate and metastatic properties, malaria is a major public health concern. Insecticide resistance has led to alternative methods of disease management, such as vaccine development. The circumsporozoite protein of Plasmodium falciparum malaria is the foundation for many malaria vaccines, which are designed to block the transmission of Pf. The most promising vaccine candidate is RTS,S, a recombinant protein designed around the central NANP repeat and C‐terminal region of circumsporozoite protein. The repeat region consists of 19 repeating NANP amino acid sequences, allowing multiple antibodies to bind simultaneously. Molecular dynamics simulations and crystallography structures show the importance of the NANP amino acid sequences for binding. The Summit Country Day School MSOE Center for Biomolecular Modeling MAPS Team used 3D modeling and printing technology to examine the structure‐function relationship of the human Fab688 circumsporozoite complex and its associated binding of NANP repeat peptides to protective antibodies. Antibodies that bind to the fully extended peptide are perpendicular to the heavy chain‐light chain interface and rely on the first NANP repeat that follows the only NPDP sequence in the junctional region of Pf circumsporozoite protein, as this arrangement favors free energy contributions and results in superior protection. Junctional peptide antibody protection may relate to the ability to cross‐react with the NANP repeat region. Amino acids Asn11 and Asn13 on the junctional peptide form a hydrogen bond network with Fab668. This web of hydrogen bonds, which connects the residues that form the binding pocket, stabilizes it and contributes to stronger binding.Fab688 binds to the NANP repeat region with equal or better affinity, shedding light on the affinity and specificity for the junctional region of circumsporozoite. This research lays the framework for future advancements in vaccines by revealing important targets and thereby limiting the spread of infectious diseases.