A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model

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 (CSP) 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.

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

npj Vaccines ◽

10.1038/s41541-020-00274-4 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Lucie Jelínková ◽

Hugo Jhun ◽

Allison Eaton ◽

Nikolai Petrovsky ◽

Fidel Zavala ◽

...

Keyword(s):

Mouse Model ◽

Malaria Vaccine ◽

High Titer ◽

Circumsporozoite Protein ◽

Infection Model ◽

Vaccine Platform ◽

Junctional Region ◽

Mouse Infection Model ◽

Virus Like Particle ◽

Major Surface

AbstractA 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.

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

10.1101/2020.08.07.241802 ◽

2020 ◽

Author(s):

Lucie Jelínková ◽

Hugo Jhun ◽

Allison Eaton ◽

Nikolai Petrovsky ◽

Fidel Zavala ◽

...

Keyword(s):

Mouse Model ◽

Malaria Vaccine ◽

High Titer ◽

Circumsporozoite Protein ◽

Infection Model ◽

Vaccine Platform ◽

Mouse Infection Model ◽

Virus Like Particle ◽

Malaria Vaccine Candidate ◽

Major Surface

AbstractA 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 Qß 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.

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Analysis of peripheral blood B and Tfh cells as predictors of antibody responses in individuals receiving candidate blood-stage malaria vaccines in a Phase Ia clinical trial

Malaria Journal ◽

10.1186/1475-2875-13-s1-p28 ◽

2014 ◽

Vol 13 (S1) ◽

Author(s):

Sean Elias ◽

Kathryn Milne ◽

Cecilia Chui ◽

Susanne Hodgson ◽

Persephone Borrow ◽

...

Keyword(s):

Clinical Trial ◽

Peripheral Blood ◽

Antibody Responses ◽

Blood Stage ◽

Tfh Cells ◽

Malaria Vaccines ◽

Blood Stage Malaria

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Mapping Epitopes of the Plasmodium vivax Duffy Binding Protein with Naturally Acquired Inhibitory Antibodies

Infection and Immunity ◽

10.1128/iai.01036-09 ◽

2009 ◽

Vol 78 (3) ◽

pp. 1089-1095 ◽

Cited By ~ 64

Author(s):

Patchanee Chootong ◽

Francis B. Ntumngia ◽

Kelley M. VanBuskirk ◽

Jia Xainli ◽

Jennifer L. Cole-Tobian ◽

...

Keyword(s):

Plasmodium Vivax ◽

Binding Protein ◽

High Titer ◽

Blood Stage ◽

Duffy Binding Protein ◽

Linear Peptide ◽

Binding Function ◽

Blood Stage Infection ◽

Erythrocyte Binding ◽

Linear Epitopes

ABSTRACT Plasmodium vivax Duffy binding protein (DBP) is a merozoite microneme ligand vital for blood-stage infection, which makes it an important candidate vaccine for antibody-mediated immunity against vivax malaria. A differential screen with a linear peptide array compared the reactivities of noninhibitory and inhibitory high-titer human immune sera to identify target epitopes associated with protective immunity. Naturally acquired anti-DBP-specific serologic responses observed in the residents of a region of Papua New Guinea where P. vivax is highly endemic exhibited significant changes in DBP-specific titers over time. The anti-DBP functional inhibition for each serum ranged from complete inhibition to no inhibition even for high-titer responders to the DBP, indicating that epitope specificity is important. Inhibitory immune human antibodies identified specific B-cell linear epitopes on the DBP (SalI) ligand domain that showed significant correlations with inhibitory responses. Affinity-purified naturally acquired antibodies on these epitopes inhibited the DBP erythrocyte binding function greatly, confirming the protective value of specific epitopes. These results represent an important advance in our understanding of part of blood-stage immunity to P. vivax and some of the specific targets for vaccine-elicited antibody protection.

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