Abstract
Pre-erythrocytic malaria vaccines that induce high-titer, durable antibody responses can potentially provide protection from infection. Here, we engineered a virus-like particle (VLP)-based vaccine targeting a recently described vulnerable epitope at the N-terminus of the central repeat region of the Plasmodium falciparum circumsporozoite protein that is recognized by the potently inhibitory monoclonal antibody L9 and show that immunization with L9 VLPs induces strong antibody responses that provide protection from blood-stage malaria in a mouse infection model.
Highlights
Pre-erythrocytic malaria vaccines that largely target the immunodominant central repeat (CR) region of the Plasmodium falciparum circumsporozoite protein (PfCSP)—a protein that densely covers the surface of invading sporozoites— provide moderate protection from human infection[2–4]
The recent identification of human monoclonal antibodies from human volunteers immunized with an experimental irradiated whole sporozoite vaccine developed by Sanaria (PfSPZ) that target epitopes in CSP outside of the CR and potently protect animal models from malaria infection have pointed to new sites of vulnerability in CSP that may be exploited using epitope-targeted vaccines[5–10]
We previously showed that a bacteriophage Qßbased virus-like particle (VLP) vaccine that multivalently displays a peptide representing the epitope of the CIS43 monoclonal antibodies (mAbs), which is located at the junction between the N-terminal region of CSP and the CR5, could elicit extremely durable and high-titer anti-CSP antibody responses and reduce parasite liver burden in a mouse malaria challenge model, but did not prevent blood-stage parasitemia[10]
Summary
Pre-erythrocytic malaria vaccines (such as RTS,S1) that largely target the immunodominant central repeat (CR) region of the Plasmodium falciparum circumsporozoite protein (PfCSP)—a protein that densely covers the surface of invading sporozoites— provide moderate protection from human infection[2–4]. We previously showed that a bacteriophage Qßbased virus-like particle (VLP) vaccine that multivalently displays a peptide representing the epitope of the CIS43 mAb, which is located at the junction between the N-terminal region of CSP and the CR5, could elicit extremely durable and high-titer anti-CSP antibody responses and reduce parasite liver burden in a mouse malaria challenge model, but did not prevent blood-stage parasitemia[10]. We assessed the immunogenicity and protective efficacy of VLPs displaying the epitope of the L9 mAb, a newly described antibody that is one of the most potent anti-CSP mAbs at inhibiting parasite invasion in mouse models[6]. L9 VLPs are highly immunogenic in mice; three doses of unadjuvanted L9 VLPs elicited high titer and durable anti-CSP antibodies (Fig. 2a), as was previously observed in mice immunized with. We evaluated and compared the efficacy of vaccines targeting two overlapping epitopes within the junctional/minor
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