A high-affinity antibody against the CSP N-terminal domain lacks Plasmodium falciparum inhibitory activity.

Elaine Thai,Nicholas C Wu,Jean-Philippe Julien,Anna Weyrich,Yevel Flores-Garcia,Stephen W Scally,David Oyen,Tossapol Pholcharee,Katherine Prieto,Alexandre Bosch,Elena A Levashina,Rajagopal Murugan,Angelo Valleriani,Hedda Wardemann,Ian A Wilson,Giulia Costa

doi:10.1084/jem.20200061

Abstract

Malaria is a global health concern, and research efforts are ongoing to develop a superior vaccine to RTS,S/AS01. To guide immunogen design, we seek a comprehensive understanding of the protective humoral response against Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). In contrast to the well-studied responses to the repeat region and the C-terminus, the antibody response against the N-terminal domain of PfCSP (N-CSP) remains obscure. Here, we characterized the molecular recognition and functional efficacy of the N-CSP-specific monoclonal antibody 5D5. The crystal structure at 1.85-Å resolution revealed that 5D5 binds an α-helical epitope in N-CSP with high affinity through extensive shape and charge complementarity and the unusual utilization of an antibody N-linked glycan. Nevertheless, functional studies indicated low 5D5 binding to live Pf sporozoites and lack of sporozoite inhibition in vitro and in vivo. Overall, our data do not support the inclusion of the 5D5 N-CSP epitope into the next generation of CSP-based vaccines.

Highlights

Malaria is a vector-borne disease of global importance
Plasmodium falciparum circumsporozoite protein (PfCSP) residues 83-91 formed an α-helix when bound by 5D5 Fab (Fig. 1B), in line with secondary structure predictions based on the primary sequence (Drozdetskiy et al, 2015)
While structures of a variety of polypeptides derived from PfCSP have been solved in complex with a broad range of antibodies (Oyen et al, 2017; Imkeller et al, 2018; Scally et al, 2018; Tan et al, 2018; Kisalu et al, 2018; Julien and Wardemann, 2019; Murugan et al, 2019), our crystal structure of the 5D5 Fab in complex with PfCSP81-98 provides the first insight into the subdomain architecture of Plasmodium falciparum (Pf) N-terminal domain of PfCSP (N-circumsporozoite protein (CSP))

Summary

Introduction

Malaria is a vector-borne disease of global importance. In 2017, an estimated 219 million cases were reported, resulting in 435,000 deaths (WHO, 2018). The majority of deaths are caused by Plasmodium falciparum (Pf), making this parasite a central focus of research efforts for the development of effective therapeutic interventions. Anti-infection vaccines target the sporozoite stage of the Pf life cycle as parasites are transmitted to the human host by infected female. It has been established four decades ago that mAbs targeting the sporozoite surface circumsporozoite protein (CSP) are capable of neutralizing. Plasmodium infection (Potocnjak et al, 1980; Yoshida et al, 1980; Yoshida et al, 1981; Cochrane et al, 1982) This year, the current leading anti-infection CSP-based vaccine against Pf malaria, RTS,S/AS01, has begun pilot implementation in Ghana, Malawi and Kenya. Notwithstanding, RTS,S/AS01 has shown to only provide rapidly waning protection in 50% of children and intense research efforts are underway towards designing a more efficacious and durable anti-CSP vaccine (RTS,S Clinical Trials Partnership, 2015; Julien and Wardemann, 2019)

Methods

Results

Conclusion