Inducing a cell-mediated immune response against peptides of the Plasmodium vivax circumsporozoite protein

Abstract

An attempt was made to generate an unrestricted cellular immune response against peptide antigens of the circumsporozoite protein (CSP) of Plasmodium vivax. The peptides used represent the repeat-region sequences of the type-I variant (AA and DA) or type-II variant (ANG) and the conserved region (region II) containing the hepatocyte-binding region extended to include a T-cell epitope (HBP). The study was conducted in outbred mice and two genetically unrelated inbred strains of mice. Spleen cells, recovered from mice that had been primed either with one peptide or a conjugate formed of HBP linked to one of the repeat-region peptides, were pulsed in vitro with varying amounts of individual peptides/conjugates, both in soluble and particulate form (with and without a human beta-casein bio-active fragment analogue as adjuvant). In the tests using the cells from the mice primed with an individual peptide(s), HBP showed a high proliferation index, and the repeat-region peptides, especially AA, showed T-cell activity in at least one of the mouse strains studied. In vitro, higher concentrations of the free peptides than of liposomal preparations of the peptides had to be used to elicit the optimal proliferation of the cells from each strain of mice. Interestingly, the cells from the conjugate-primed mice showed enhanced proliferation (compared with that observed in the cells from mice primed with individual peptides) when stimulated with each component, and especially the repeat-region sequence, of the relevant conjugate. In such cases there was no evidence of restriction of the immune response by the major histocompatibility complex. The major secreted cytokines were found to be from CD4(+) Th1 (interferon-gamma and interleukin-2), with relatively low levels of the Th-2 cytokines interleukin-4 and interleukin-6. The delivery of cohered 'B-T' peptide(s) sequences from the same protein, ideally with an immunostimulatory adjuvant or as a liposomal preparation, should greatly enhance the cell-mediated immune response and should improve clearance of mosquito-inoculated P. vivax sporozoites.

Analysis of Circumsporozoite Protein–specific Immune Responses Following Recent Infection With Plasmodium Vivax

“…15 Since it is believed that CSP-specific CD4 + and CD8 + T cell responses, along with CSP-specific antibodies, will be important in immunity to P. vivax sporozoite/liver stages, and because polymorphisms within the P. vivax CSP 16,17 could render a single recombinant CSP ineffective as a vaccine candidate, a major strategy is to define T and B cell epitopes and combine these in a synthetic vaccine. An epitope on P. vivax CSP recognized by a protective monoclonal antibody has been defined, 18 and vaccine constructs based on this 19 and CSP T cell epitopes 20 have been made. Other epitopes defined from monkey 21 and murine 20,22 studies may also prove useful.…”

“…An epitope on P. vivax CSP recognized by a protective monoclonal antibody has been defined, 18 and vaccine constructs based on this 19 and CSP T cell epitopes 20 have been made. Other epitopes defined from monkey 21 and murine 20,22 studies may also prove useful.…”