T cell responses to repeat and non-repeat regions of the circumsporozoite protein detected in volunteers immunized with Plasmodium falciparum sporozoites

Abstract

The design of a malarial vaccine based on the circumsporozoite (CS) protein, a major surface antigen of the sporozoite stage of the malaria parasite, requires the identification of T and B cell epitopes for inclusion in recombinant or synthetic vaccine candidates. We have investigated the specificity and function of a series of T cell clones, derived from volunteers immunized with Plasmodium falciparum sporozoites, in an effort to identify relevant epitopes in the immune response to the pre-erythrocytic stages of the parasite. CD4+ T cell clones were obtained which specifically recognized a repetitive epitope located in the 5' repeat region of the CS protein. This epitope, when conjugated to the 3' repeat region in a synthetic MAPs construct, induced high titers of antisporozoite antibodies in C57BL mice. A second T cell epitope, which mapped to aa 326-345 of the carboxy terminal, was recognized by lytic, as well as non-lytic, CD4+ T cells derived from the sporozoite-immunized volunteers. The demonstration of CD4+ CTL in the human volunteers, and the recent studies in the rodent model (Renia et al., 1991; Tsuji et al., 1990), suggest that CS-specific CD4+ T cells, in addition to their indirect role as helper cells in the induction of antibody and CD8+ effector cells, may also play a direct role in protection against sporozoite challenge by targeting EEF within the liver.

Naturally Exposed Populations Differ in Their T1 and T2 Responses to the Circumsporozoite Protein ofPlasmodium falciparum

“…ϩ (27) and CD4 ϩ (19) T cells specific to the circumsporozoite protein (CS) of Plasmodium are important mediators of protection in animal models of malaria (16,21,30). Attempts to understand pre-erythrocytic immunity to infection in humans have led many researchers to focus on T cells specific for CS epitopes from P. falciparum CS.…”

Plasmodium falciparum-Specific Cellular Immune Responses after Immunization with the RTS,S/AS02D Candidate Malaria Vaccine in Infants Living in an Area of High Endemicity in Mozambique

“…In vaccines based on irradiated sporozoites and CSP in human and mouse models, antibodies to circulating sporozoites, followed by cell-mediated responses to the protein after invasion of hepatocytes, have been described as crucial for the generation of protective responses (7,11,13,28,29).…”

Interethnic differences in the humoral response to non-repetitive regions of the Plasmodium falciparum circumsporozoite protein.

“…[5][6][7][8] The involvement of CSP in the invasion of sporozoites into hepatocytes has been shown by Cerami and others. 9 The flanking non-repeat regions of CSP contain several epitopes recognized not only by antibodies, [10][11][12][13][14][15][16][17] but also by CD4 ϩ T helper cells [18][19][20] and CD8 ϩ cytotoxic T lymphocytes. [21][22][23][24] Vaccine candidates based on the immunodominant, repetitive domain of the P. falciparum CSP (Pf CSP) gave unsatisfactory results in terms of protection of human volunteers.…”