Protective Antibody and CD8+ T-Cell Responses to the Plasmodium falciparum Circumsporozoite Protein Induced by a Nanoparticle Vaccine

Stephen A Kaba,Clara Brando,David E Lanar,Margaret E Mccoy,Debleena Dasgupta,Peter Burkhard,Roberta Spaccapelo,Tais A P F Doll,Christian Mittelholzer,Andrea Crisanti,Yongkun Yang,Qin Guo

doi:10.1371/journal.pone.0048304

Abstract

BackgroundThe worldwide burden of malaria remains a major public health problem due, in part, to the lack of an effective vaccine against the Plasmodium falciparum parasite. An effective vaccine will most likely require the induction of antigen specific CD8+ and CD4+ T-cells as well as long-lasting antibody responses all working in concert to eliminate the infection. We report here the effective modification of a self-assembling protein nanoparticle (SAPN) vaccine previously proven effective in control of a P. berghei infection in a rodent model to now present B- and T-cell epitopes of the human malaria parasite P. falciparum in a platform capable of being used in human subjects.Methodology/Principal FindingsTo establish the basis for a SAPN-based vaccine, B- and CD8+ T-cell epitopes from the P. falciparum circumsporozoite protein (PfCSP) and the universal CD4 T-helper epitope PADRE were engineered into a versatile small protein (∼125 amino acids) that self-assembles into a spherical nanoparticle repetitively displaying the selected epitopes. P. falciparum epitope specific immune responses were evaluated in mice using a transgenic P. berghei malaria parasite of mice expressing the human malaria full-length P. falciparum circumsporozoite protein (Tg-Pb/PfCSP). We show that SAPN constructs, delivered in saline, can induce high-titer, long-lasting (1 year) protective antibody and poly-functional (IFNγ+, IL-2+) long-lived central memory CD8+ T-cells. Furthermore, we demonstrated that these Ab or CD8+ T–cells can independently provide sterile protection against a lethal challenge of the transgenic parasites.ConclusionThe SAPN construct induces long-lasting antibody and cellular immune responses to epitope specific sequences of the P. falciparum circumsporozoite protein (PfCSP) and prevents infection in mice by a transgenic P. berghei parasite displaying the full length PfCSP.

Highlights

The worldwide burden of malaria remains a major public health problem due to the lack of an effective vaccine against Plasmodium falciparum, the causative agent of the deadliest human malaria [1]
We have previously reported using the basic properties of amino acids and the tenets of structural biology to design a short linear protein monomer that combines with identical monomers to form a self-assembling protein nanoparticle (SAPN) with predictable and controllable conformation and presentation of epitopes
We report here modifications of that original SAPN design to make a vaccine that could be used in humans against the malaria parasite P. falciparum

Summary

Introduction

The worldwide burden of malaria remains a major public health problem due to the lack of an effective vaccine against Plasmodium falciparum, the causative agent of the deadliest human malaria [1]. Nanoparticle based vaccines have been shown to be effective in the induction of immune responses in animal models without the need for an adjuvant [5,6,7,8,9,10]. Most of these particles are based on polymers that encapsulate antigen or create a solid support to which protein antigens are chemically coupled and do not necessarily have control over an ordered array presentation of epitopes. The worldwide burden of malaria remains a major public health problem due, in part, to the lack of an effective vaccine against the Plasmodium falciparum parasite. We report here the effective modification of a self-assembling protein nanoparticle (SAPN) vaccine previously proven effective in control of a P. berghei infection in a rodent model to present B- and T-cell epitopes of the human malaria parasite P. falciparum in a platform capable of being used in human subjects

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Conclusion