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

Abstract

Abstract. CD8+ and CD4 + T cells are involved in immunity to the pre-erythrocytic stage of malaria. This study has been undertaken to define T cell epitopes on the Plasmodium vivax circumsporozoite protein (CSP) and to analyze the early induction of immune response following infection. We identified CD4 + and CD8 + T epitopes recognized by different strains of mice as well as by humans. The CD4 + T cell response in mice was found to be similar in all strains, but variation between strains was evident. Five H-2 d -restricted CD8 + cytotoxic T lymphocyte (CTL) epitopes, but no H-2 k -or H-2 b -restricted epitopes, could be defined. Non-H-2 genes were also able to regulate the response. In recently infected Thai adults, poor immunoresponsiveness was demonstrated. CTL activity and proliferative responses of T cells from malaria-exposed donors were very low. In contrast, exposed individuals had specific antibodies against the immunodominant repeats of both common strains of the P. vivax CSP; however, titers decreased following treatment.

A Novel ChimericPlasmodium vivaxCircumsporozoite Protein Induces Biologically Functional Antibodies That Recognize both VK210 and VK247 Sporozoites

“…Also, the N-terminal region (between the signal sequence and region I) of the CS protein of P. falciparum has been shown to be important in hepatocyte binding (39), and antibodies against this region prevent sporozoite invasion of liver cells (38). In addition, CD4 epitopes have been mapped to the first 60 amino acids in the N-terminal domain (2,48).…”

“…Although all sequenced strains of P. falciparum have a common and highly conserved repeat sequence, P. vivax has two distinct forms of the CS protein designated VK210 (type 1) and VK247 (type 2), which differ in the sequence of the central repeat region. The majority of the field infections caused by P. vivax are attributed to VK210-type sporozoites; however, a significant number of VK247-type parasites either as single or mixed (along with VK210) infections have been observed (48,54).…”

“…When a yeast-expressed recombinant protein was used, the percentage of subjects positive for antibodies ranged from 15% in Peru (17), 63% in Thailand (48), and 20 to 37.5% in Papua New Guinea (7), and with synthetic peptides it was ca. 68 to 75% in different parts of Columbia (3).…”

“…The higher immunogenicity of our construct could be explained by the fact that it is larger than the one used in the above studies and incorporates additional helper epitopes present in the N-and C-terminal regions of the CS protein (2,48), which may provide additional B-cell help. While H-2 d mice do not respond as well as the other strains tested, the presence of the additional epitopes is possibly the reason that these mice are able to overcome genetic restriction and, compared to the other strains, show the maximum amount of increase in antibody titers after booster immunizations (data not shown).…”

“…This region has been thought to be a part of an immunologically cryptic epitope that is not recognized in the context of the entire protein but is able to induce invasion-inhibitory antibodies when used as an immunogen (38). Sporozoite infection leads to low levels of antibodies to the C-terminal region of the molecule in very few of the exposed individuals (7,48). This has been attributed to poor availability of the epitope (8), epitope competition (45), or sequence homology to thrombospondin.…”