Probing novel epitopes on the Plasmodium falciparum circumsporozoite protein for vaccine development

Pascal S Krenger; Magali Roques; Anne-Cathrine S Vogt; Alessandro Pardini; Dominik A Rothen; Ina Balke; Sophie T Schnider; Mona O Mohsen; Volker T Heussler; Andris Zeltins; Martin F Bachmann

doi:10.1038/s41541-024-01006-8

Probing novel epitopes on the Plasmodium falciparum circumsporozoite protein for vaccine development

NPJ Vaccines. 2024 Nov 18;9(1):225. doi: 10.1038/s41541-024-01006-8.

Authors

Pascal S Krenger^{1

2

3}, Magali Roques⁴, Anne-Cathrine S Vogt^{5

6

7}, Alessandro Pardini^{5

6

7}, Dominik A Rothen^{5

6

7}, Ina Balke⁸, Sophie T Schnider^{5

6}, Mona O Mohsen^{5

6}, Volker T Heussler⁴, Andris Zeltins^{8

9}, Martin F Bachmann^{10

11

12}

Affiliations

¹ Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. [email protected].
² Department for Rheumatology and Immunology, University Hospital of Bern, Bern, Switzerland. [email protected].
³ Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland. [email protected].
⁴ Institute of Cell Biology, University of Bern, Bern, Switzerland.
⁵ Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
⁶ Department for Rheumatology and Immunology, University Hospital of Bern, Bern, Switzerland.
⁷ Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland.
⁸ Latvian Biomedical Research and Study Centre, Riga, Latvia.
⁹ Saiba AG, Pfäffikon, Switzerland.
¹⁰ Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. [email protected].
¹¹ Department for Rheumatology and Immunology, University Hospital of Bern, Bern, Switzerland. [email protected].
¹² Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology (CCMP), The Jenner Institute, University of Oxford, Oxford, UK. [email protected].

Abstract

RTS,S and R21 are the only vaccines recommended by the WHO to protect children from Plasmodium falciparum (Pf) clinical malaria. Both vaccines target the Pf sporozoite surface protein circumsporozoite protein (CSP). Recent studies showed that human antibodies neutralize Pf sporozoites most efficiently when simultaneously binding to the PfCSP NANP repeat and the NPDP junction domain. However, neither RTS,S nor R21 targets this junction domain. To test the potential of the NPDP junction domain and other sites of PfCSP as innovative vaccine targets, we developed multiple vaccine candidates based on cucumber mosaic virus-like particles (CuMV_TT-VLPs). These candidates vary in several aspects: the number of targeted NANP repeats, the presence or absence of the junction domain, the cleavage site, and up to three NVDP repeats within the target sequence. Immunogenicity and efficacy studies were conducted in BALB/c mice, utilizing chimeric Plasmodium berghei (Pb) sporozoites, in which the endogenous CSP has been replaced by PfCSP (Pb/PfCSP). We observed a positive association between the number of targeted NANP repeats and the induction of specific IgM/IgG antibodies. Elevated humoral responses led to enhanced protection against parasitemia after Pb/PfCSP sporozoite challenge. Especially high-avidity/affinity antibody formation and vaccine protection were NANP repeat-dependent. Intriguingly, vaccine efficacy was not enhanced by targeting sites on PfCSP other than the NANP repeats. Our data emphasize the dominant role of the NANP repeat region for induction of protective antibodies. Furthermore, we present here novel malaria vaccine candidates with an excellent immunogenic profile that confer sterile protection in mice, even in absence of adjuvants.

Abstract

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