Advances and challenges in malaria vaccine development

Abstract

Malaria remains one of the most devastating infectious diseases that threaten humankind. Human malaria is caused by five different species of Plasmodium parasites, each transmitted by the bite of female Anopheles mosquitoes. Plasmodia are eukaryotic protozoans with more than 5000 genes and a complex life cycle that takes place in the mosquito vector and the human host. The life cycle can be divided into pre-erythrocytic stages, erythrocytic stages and mosquito stages. Malaria vaccine research and development faces formidable obstacles because many vaccine candidates will probably only be effective in a specific species at a specific stage. In addition, Plasmodium actively subverts and escapes immune responses, possibly foiling vaccine-induced immunity. Although early successful vaccinations with irradiated, live-attenuated malaria parasites suggested that a vaccine is possible, until recently, most efforts have focused on subunit vaccine approaches. Blood-stage vaccines remain a primary research focus, but real progress is evident in the development of a partially efficacious recombinant pre-erythrocytic subunit vaccine and a live-attenuated sporozoite vaccine. It is unlikely that partially effective vaccines will eliminate malaria; however, they might prove useful in combination with existing control strategies. Elimination of malaria will probably ultimately depend on the development of highly effective vaccines.

Figure 1. Mechanisms of protective immunity against Plasmodium-infected hepatocytes

In the protective model of live-attenuated sporozoite vaccines [irradiated sporozoites (irrSPZs) or genetically attenuated parasites (GAPs)], elimination of pre-erythrocytic-stage parasites is primarily dependent on antigen-specific and major histocompatability complex (MHC)-restricted CD8⁺ T cells, whereas recombinant vaccines, such as the CSP-based RTS,S vaccine, are primarily dependent on CD4⁺ T cells. Naive CD8⁺ T cells can be primed by dendritic cells (DCs) that encounter SPZs at skin-draining lymph nodes, by parasite-traversed or -infected hepatocytes in the liver (direct priming), or by other DCs that uptake antigens provided by traversed and infected hepatocytes, or hepatocytes that die in the liver (crosspriming). Primed CD8⁺ T cells will then proliferate and differentiate to effector (TEM) or central memory (TCM) CD8⁺ T cells. CD8⁺ T cells can mediate killing of liver stage (LS)-infected hepatocytes via several mechanisms: (a) release of perforin and granzyme B, which causes necrosis of the infected hepatocyte; (b) apoptosis, a programmed cell death through the Fas–FasL signalling pathway; (c) release of IFN-γ, via signal transducers associated with transcription (STAT) to activate inducible nitric oxide synthase (iNOS), which then induces the NO pathway to destroy the infected hepatocyte; (d) IFN-γ can also promote IL-12 release from DCs, macrophages or other cells to activate the natural killer (NK) and CD4⁺ T cells that consequently increase the IFN-γ-dependent killing of LS-infected hepatocytes

Figure 2. Mechanisms of protective immunity during blood-stage infection

Erythrocyte invasion occurs rapidly, within ~30–60 seconds (Ref. 100), and once inside the erythrocyte, the parasite appears to be relatively inaccessible to antibodies until approximately 14–16 h after invasion, when new parasite proteins, such as the P.falciparum erythrocyte, membrane protein 1 (EMP1), begins to appear on the infected erythrocyte (IE) surface. (a) Erythrocyte invasion is a complex process that has been divided into four steps: (1) attachment, (2) reorientation, (3) tight junction formation, and (4) entry. MSP1 is the most abundant protein on the merozoite surface and may function at initial attachment (Ref. 105), AMA1 at parasite reorientation and entry (Ref. 106) and P. vivax DBP during tight junction formation for P. vivax (Refs 107, 108). P. vivax DBP is a member of the erythrocyte-binding protein (EBP) family, which has undergone gene expansion in P. falciparum, leading to functional differences with P. vivax. Antibodies may directly block invasion by inhibiting parasite binding, preventing protein–protein interactions on the merozoite surface, or interfering with proteolytic processing or shedding of invasion ligands. There is also evidence for Fc-dependent mechanisms of protection against MSP1 (Ref. 121). (b) In pregnancy malaria, P. falciparum-infected erythrocytes sequester in the intervillous spaces of the maternal placenta, but are absent in fetal blood vessels. Infected erythrocytes are found directly adjacent to syncytiotrophoblast cells and also fill the intervillous space. Monocytes are recruited to infected placentas and frequently contain residual hemozoin pigment that may result from ingestion of infected erythrocytes. Potential antibody mechanisms are adhesion blocking or opsonising infected erythrocytes for phagocytosis by monocytes or activated macrophages that were recruited to the infected placenta.