Effect of polymorphism of sporozoite antigens on T-cell activation

One of the most studied candidate antigens for vaccines directed against the sporozoite stage of the malaria life-cycle is the circumsporozoite (CS) protein. This is a protein covering the surface of the sporozoite whose apparent function is to mediate binding to the sporozoite to a hepatocyte ligand prior to cell penetration. The focus of this paper will be on the CS protein of Plasmodium falciparum. This report shows a schematic representation of this protein, the most notable characteristic of which is the four-mer NANP repeated up to 51 times in the central region. The second and fourth repeats are always the variant repeat NVDP, which may occur twice more throughout the repeat region. The repeats have proven to be immunodominant epitopes for B cells. While specific antibody has been shown to be able to interfere with sporozoite motility, vaccine trials based on the repeats have found that humoral immunity is often not sufficient to provide complete protection. Immune T cells targeting the intrahepatocytic sporozoite are also required for the sterile immunity demanded by an effective anti-sporozoite vaccine. CD4 super(+) and CD8 super(+) T cells specific for the CS protein have been shown to be able to protect mice from sporozoite challenge. Research into a subunit vaccine based on the CS protein of P. falciparum has identified several serious impediments for vaccine development. These include immunological non-responsiveness, subversion of protective immune responses by prior exposure to cross-reactive non-malaria antigens and polymorphism of T-cell determinants, among others. The CS protein of P. falciparum has regions of amino acid sequence diversity, as illustrated in figure 1, and this section aims to describe the effect of such polymorphism on T-cell immunity, focusing particularly on the non-repeat regions of this protein. While the repeats vary in number and location of minor repeats, the repeat region is largely invariant, and problems of epitope variation are unlikely to affect repeat-specific T-cell immunity. Further, the repeats tend not to be immunodominant T-cell determinants, although a peptide encompassing the minor repeats has been found to be a T-cell epitope for T cells from people immunized with sporozoites, and the NANP repeats are frequently recognized by T cells from naturally exposed Thais and Indonesians.