Avid binding by B cells to the Plasmodium circumsporozoite protein repeat suppresses responses to protective subdominant epitopes.

Deepyan Chatterjee,Xin Gao,Colin J Jackson,Henry J Sutton,Fiona J Lewis,Hayley A Mcnamara,Ian A Cockburn,Joe A Kaczmarski,Yeping Cai

doi:10.1016/j.celrep.2021.108996

Abstract

SummaryAntibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSPRepeat) can protect against malaria. However, it has also been suggested that the CSPRepeat is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSPRepeat are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions. We find that this immunodominance is driven by avid binding of the CSPRepeat to cognate B cells that are able to expand at the expense of B cells with other specificities. We further show that mice immunized with repeat-truncated CSP molecules develop responses to subdominant epitopes and are protected against malaria. These data demonstrate that the CSPRepeat functions as a decoy, but truncated CSP molecules may be an approach for malaria vaccination.

Highlights

The most advanced malaria vaccine RTS,S/AS01 aims to induce antibodies that target the repeat region of the circumsporozoite protein (CSP), which covers the surface of the Plasmodium sporozoite (Agnandji et al, 2012; Olotu et al, 2016; RTS,S Clinical Trials Partnership, 2015)
Immunoglobulin G (IgG) responses to the CSPRepeat were significantly higher than responses to either of the other domains, with a significant response developing to the CSPCterm only after 28 days (Figure 1A)
By day 7, a pronounced germinal centers (GCs) reaction developed and the number of CSPRepeat+ GL7+ B cells was again $10-fold higher than responses to the other domains, which was sustained until day 28 (Figure 1Cii)

Summary

Introduction

The most advanced malaria vaccine RTS,S/AS01 aims to induce antibodies that target the repeat region of the circumsporozoite protein (CSP), which covers the surface of the Plasmodium sporozoite (Agnandji et al, 2012; Olotu et al, 2016; RTS,S Clinical Trials Partnership, 2015). The rationale for this approach derives from the observation that immunization with radiationattenuated sporozoites confers sterile protection against malaria and that the humoral response induced by irradiated sporozoites is dominated by anti-CSP antibodies (Ishizuka et al, 2016; Nussenzweig et al, 1967; Seder et al, 2013; Zavala et al, 1985). Antibodies targeting the C-terminal domain CSP (CSPCterm) have been associated with protection by the RTS,S vaccine in clinical trials (Dobano et al, 2019; Ubillos et al, 2018), individual mAbs targeting this domain have not been found to confer protection (Triller et al, 2017)

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Conclusion