Evaluating antidisease immunity to malaria and implications for vaccine design

Abstract

Immunity to malaria could be categorized broadly as antiparasite or antidisease immunity. While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria. The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses. This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it. Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals.

Keywords: inflammation; malaria; tolerance.

Figure 1

Mechanisms associated with reduced inflammatory responses at high exposure levels. (a) Direct immunosuppression of immune cells: hemozoin (Hz)‐laden immune cells [including dendritic cells (DCs), monocytes and macrophages (Mϕ)] exhibit impaired effector functions, such as reduced cytokine secretion and reduced expression of costimulatory molecules. (b) Loss of immune cells: repeated exposure is associated with the loss of immune cells, such as the Vδ2 subset of γδ T cells, which would normally secrete high levels of interferon (IFN)‐γ. (c) Exhausted or refractory immune cells: T cells (including CD4⁺ and CD8⁺) may display high levels of programmed cell death 1 (PD)‐1, a marker of an exhausted phenotype, at high levels of exposure. Similarly, innate immune cells may have become refractory to stimulation by lower antigen (parasitaemia) levels, and require high antigen loads to become stimulated.

Figure 2

Schematic depiction of the processes leading to differences in parasite tolerance at different levels of exposure. (a) Continuous high levels of exposure mimics a chronic state of infection (low Δt between infections), whereas low exposure levels are characterized by intermittent infections, separated by intervals of no exposure (high Δt between infection). (b) Each infection is therefore a distinct acute event at low levels of exposure, which induce a strong inflammatory response, requiring comparatively lower parasitaemia. A strong inflammatory response is associated with increased immunopathology, and consequently results in a high predisposition to clinical symptoms. However, higher parasite densities are required to stimulate immune cells at high exposure levels (as there is usually low‐level parasitaemia without clinical symptoms), and this stimulation leads to milder inflammatory responses. Mild proinflammatory responses result in reduced immunopathology, which may preclude the manifestation of clinical symptoms.