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

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.

Transgenic Parasites Stably Expressing Full-Length Plasmodium falciparum Circumsporozoite Protein as a Model for Vaccine Down-Selection in Mice Using Sterile Protection as an Endpoint

“…The protection was dependent on the antigen dose and the nature of the CSP immunogen. In support of our observations, it is noteworthy that, during the course of our study, Kaba et al reported using the same Tr P. berghei parasite line to monitor protection induced in mice following immunization with a nanoparticle vaccine expressing B-cell and CD8 ϩ T-cell epitopes from the PfCSP (23). Although the biological relevance of this mouse protection model with respect to human vaccine development remains to be confirmed, sterile protection as the efficacy endpoint provides a means to evaluate PfCSP-based vaccines rapidly for future human trials.…”

“…Additionally, it is noteworthy that several mice with low repeat-specific antibody titers were protected in the present study, as is often observed with RTS,S-immunized humans. Although cellular immune responses to CSP were not measured, T-cell epitopes in the N-and C-terminal regions of CSP might have contributed to protection (6,19), as observed by others using CSP-transgenic parasite models (11,23).…”

Pre-Erythrocytic Vaccine Candidates in Malaria

“…Self-assembling proteins that form nanoparticles (S"PNs) have also been examined in murine studies [132,133]. The S"PN is comprised of 60 monomers of a recombinant linear protein containing trimeric and pentameric coiled-coil domains separated by a lexible linker with T and " cell epitopes expressed at N-or C-terminus.…”

Applications of nanomaterials as vaccine adjuvants

“…For example, 15-30 nm VLNs mimic the structure of viruses, and their size and surface structure facilitate tissue penetration and lymph node (LN) targeting and also activate toll-like receptor (TLR) signaling. 23,24 Based on the function and application, adjuvants can be divided into three major categories: immunomodulatory molecules, non-immunostimulatory delivery systems, and combinations of the former two. A number of immunomodulatory molecules have been applied in widespread experimental use or clinical trials.…”

“…[29][30][31][32][33][34][35][36][37] To further facilitate antigen entry into a cell, cell-penetrating peptides (CPPs) and viral-like nanosurfaces have been applied. 23,24,[38][39][40] More recently, smart nanoparticles have been manufactured using pH-sensitive or redox-sensitive materials; 23,24,[40][41][42][43] these environment-responsive nanoparticles enable controlled release of antigens at target sites and more adequate release of antigens from endo-lysosomal compartments, thus enhancing antigen presentation. In addition to their delivery function, a great number of nanoparticles have shown immunomodulatory effects, particularly for innate immune signaling.…”