A CD4+ T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease

Abstract

Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-gamma-secreting CD4(+) T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells. These findings provide direct evidence for a protective role for CD4(+) T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.

Advancement Towards an Approved Vaccine to Target Plasmodium Falciparum Malaria

“…48,50 One triggers cytolytic activity via recognition of infected cells displaying parasite fragments associated with major histocompatibility complex class I. 51 Recognition induces secretion of cytotoxins and perforins, which cause cell death, thereby killing the parasite.…”

“…51 IFN-γ demonstrates both immunostimulatory and immunomodulatory properties and its production is considered to play a more significant role than cytolytic activity toward infected hepatocytes. 48,50 One particular mechanism of action is based on induction of the nitric oxide pathway, which is viewed as mainly responsible for destroying infected hepatocytes. 50,52 Although CD8 + T cells are important, quantities in sporozoite-infected persons are insufficient to account for IFN-γ concentrations detected.…”

“…48,50 One particular mechanism of action is based on induction of the nitric oxide pathway, which is viewed as mainly responsible for destroying infected hepatocytes. 50,52 Although CD8 + T cells are important, quantities in sporozoite-infected persons are insufficient to account for IFN-γ concentrations detected. 42 Other IFN-γ-producing cells are therefore principally responsible for its production; CD4 + T cells, natural killer cells, natural killer T cells and γδ T cells (a rare form of T lymphocyte).…”

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

“…Individual cytokine-secreting cells were expressed as spot-forming-units (SFU) per million PBMC. Positive cytokine responses (p<0.05) were based on a chi-square comparison of the odds ratio of positive cells in the test well and control well [18,38] assuming a binomial distribution of 4 Â 10 5 cells/well. This method of determining a significant positive response is as powerful as non-parametric or parametric comparison of the means or medians of replicate wells.…”

“…Naive T cell expansion and conversion into conventional memory T cells, as well as central (proliferation) and effector (IFN-c secretion) memory T cell effector functions were also affected. In liver-stage malaria, protective immunity can be associated with specific central or effector memory T cell subpopulations [17,18]. The existence and selection of these novel multi-level (naive, memory-central and memory-effector) antagonistic T cell epitopes within MSP-1 therefore offers an unusual and powerful immune evasion strategy for the malaria parasite.…”