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Cellular responses to  Plasmodium falciparum  parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites ( Pf Spz) and asexual blood-stage ( Pf RBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental  P. falciparum  infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following  in vitro  re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both  Pf Spz and  Pf RBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only ‘adaptive’ but also ‘innate’ lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for  Pf RBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO +  CD62L -  effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ + IL-2 + ) EM responses against both  Pf RBC and  Pf Spz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with  P. falciparum , with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.

Longevity and Composition of Cellular Immune Responses Following Experimental Plasmodium falciparum Malaria Infection in Humans