An Epitope-based Malaria Vaccine Targeting the Junctional Domain of Circumsporozoite Protein

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 domains 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 non-human primates. Immunization with CIS43 VLPs confers partial protection from malaria infection in a mouse model, and both immunogenicity and protection were enhanced when mice were immunized with CIS43 VLPs in combination with adjuvants including delta inulin polysaccharide particles and TLR9 agonists. 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.

Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria

“…Although the junctional and minor repeat regions of PfCSP are known to be sites of neutralization due to mAb characterization [ 31 , 32 , 34 ], this result is one of the first demonstrations that peptides spanning these epitopes could elicit neutralizing antibodies. The data presented here are in agreement with a recent study by Jelinkova et al, which showed that peptide 21 elicited partial protection when displayed on Qβ bacteriophage VLPs [ 48 ]. Similarly, a tetra-branched peptide covering the junctional region has been shown to reduce liver burden following mosquito bite challenge [ 49 ].…”

“…Interestingly, CHIK-p21-23 N /p21-23 B elicited higher titers against the NANP major repeats and lower responses to the junctional and minor repeat epitopes, more closely resembling mAbs like 317, which are cross-reactive but have preferred binding to the major repeats. These data lend credence to the idea that eliciting cross-reactivity across the various epitopes in the repeat region may be the best strategy to induce protection [ 48 , 50 ]. Interestingly, CHIK-p21-23 N /p21-23 B does not display the “NPNA” structural motif bound by mAbs targeting the major repeats [ 26 , 51 ].…”