An epitope-based malaria vaccine targeting the junctional region of circumsporozoite protein

Lucie Jelínková,Bryce Chackerian,Hugo Jhun,Allison Eaton,Nikolai Petrovsky,Fidel Zavala

doi:10.1038/s41541-020-00274-4

Lucie Jelínková, Bryce Chackerian + Show 4 more

Open Access

https://doi.org/10.1038/s41541-020-00274-4

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Abstract

A malaria vaccine that elicits long-lasting protection and is suitable for use in endemic areas remains urgently needed. Here, we assessed the immunogenicity and prophylactic efficacy of a vaccine targeting a recently described epitope on the major surface antigen on Plasmodium falciparum sporozoites, circumsporozoite protein (CSP). Using a virus-like particle (VLP)-based vaccine platform technology, we developed a vaccine that targets the junctional region between the N-terminal and central repeat regions of CSP. This region is recognized by monoclonal antibodies, including mAb CIS43, that have been shown to potently prevent liver invasion in animal models. We show that CIS43 VLPs elicit high-titer and long-lived anti-CSP antibody responses in mice and is immunogenic in non-human primates. In mice, vaccine immunogenicity was enhanced by using mixed adjuvant formulations. Immunization with CIS43 VLPs conferred partial protection from malaria infection in a mouse model, and passive transfer of serum from immunized macaques also inhibited parasite liver invasion in the mouse infection model. Our findings demonstrate that a Qβ VLP-based vaccine targeting the CIS43 epitope combined with various adjuvants is highly immunogenic in mice and macaques, elicits long-lasting anti-CSP antibodies, and inhibits parasite infection in a mouse model. Thus, the CIS43 VLP vaccine is a promising pre-erythrocytic malaria vaccine candidate.

Highlights

Malaria is a major global public health concern, causing 228 million infections and 405,000 deaths worldwide in 20181. malaria can be caused by several species of the parasitic organism Plasmodium, Plasmodium falciparum is responsible for causing a severe form of the disease with the highest morbidity and mortality, and is one of the leading causes of death in children under 5 years old[1]
We evaluated the efficacy of a novel vaccine targeting a highly conserved epitope[14,34,36] within the junctional region of P. falciparum circumsporozoite protein (CSP) that is recognized by several potent inhibitory monoclonal antibodies (mAbs), including mAb CIS43
We showed that a virus-like particle (VLP)-based vaccine that displays the CIS43 epitope elicited high-titer antibodies against CSP in both mice and non-human primates and that vaccination inhibited parasite invasion in a mouse Plasmodium challenge model

Summary

INTRODUCTION

Malaria is a major global public health concern, causing 228 million infections and 405,000 deaths worldwide in 20181. MGG4, CIS43, and L9 are mAbs that were isolated from human volunteers immunized with an experimental irradiated whole sporozoite vaccine (PfSPZ); these mAbs are highly effective at inhibiting liver invasion in mouse models of malaria infection[13,14,15]. These three mAbs bind to overlapping epitopes within the junctional region, a region of CSP that is not included in the RTS,S vaccine[4]. CIS43, e.g., has recently entered Phase I trials for prophylactic prevention of clinical malaria in humans[17] These data suggest that the junctional region of CSP is a promising target for vaccine development. Scale bar (in white) represents 100 nm. d Binding of the CIS43 mAb to CIS43 VLPs (red) or wild-type (unmodified) Qβ VLPs (blue) as measured by ELISA

RESULTS

DISCUSSION

METHODS

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