Advances and challenges in malaria vaccine development

Abstract

Malaria caused by Plasmodium falciparum remains a major public health threat, especially among children and pregnant women in Africa. An effective malaria vaccine would be a valuable tool to reduce the disease burden and could contribute to elimination of malaria in some regions of the world. Current malaria vaccine candidates are directed against human and mosquito stages of the parasite life cycle, but thus far, relatively few proteins have been studied for potential vaccine development. The most advanced vaccine candidate, RTS,S, conferred partial protection against malaria in phase II clinical trials and is currently being evaluated in a phase III trial in Africa. New vaccine targets need to be identified to improve the chances of developing a highly effective malaria vaccine. A better understanding of the mechanisms of naturally acquired immunity to malaria may lead to insights for vaccine development.

Figure 1. The P. falciparum life cycle.

The P. falciparum life cycle in humans includes the pre-erythrocytic stage, which initiates the infection; the asexual blood stage, which causes disease; and the gametocyte stage, which infects mosquitoes that transmit the parasite. At each of these stages, the parasite expresses proteins that are targets of malaria vaccine candidates (Tables 1–3). The pre-erythrocytic stage begins when a female Anopheles mosquito inoculates sporozoites into the skin or directly into the bloodstream. Sporozoites migrate to the liver and infect a small number of hepatocytes. A single sporozoite gives rise to tens of thousands of asexual parasites called merozoites. Merozoites exit the liver into the bloodstream approximately one week later, leaving no residual parasites in the liver. The pre-erythrocytic stage does not cause disease, and complete immunity to this stage is not induced through natural P. falciparum infection. Merozoites entering the bloodstream begin a cycle of erythrocyte invasion, replication, erythrocyte rupture, and merozoite release that repeats approximately every 48 hours. Symptoms of malaria only occur during the blood stage of infection. Immunity that protects against disease but not infection per se can be acquired by individuals who are repeatedly infected in endemic areas. A small percentage of blood-stage asexual parasites convert to sexual forms, or gametocytes, which can infect mosquitoes. The mosquito stage is a potential target for transmission-blocking vaccines, as the parasite in the mosquito midgut is present extracellularly and in relatively small numbers. Possible immune mechanisms at each stage are indicated.

Figure 2. Schematic representation of the CSP and the RTS,S vaccine.

The CSP is the predominant surface antigen on sporozoites. CSP is composed of an N-terminal region that binds heparin sulfate proteoglycans (RI), a central region containing a four-amino-acid (NANP) repeat, and a GPI-anchored C-terminal region containing a thrombospondin-like domain (RII). The region of the CSP included in the RTS,S vaccine includes the last 16 NANP repeats and the entire flanking C-terminus. HBsAg particles serve as the matrix carrier for RTS,S, 25% of which is fused to the CSP segment. The central repeat region contains the immunodominant B cell epitope, which induces antibodies that block sporozoite infection of liver cells in vitro (111, 112). RTS,S immunization induces antibodies to the central repeat region that correlate with protection from P. falciparum infection (46, 47) but not clinical disease (41, 45, 46). RTS,S also includes the thrombospondin domain, which binds receptors on liver cells (113). Monoclonal antibodies to the thrombospondin domain also block sporozoite invasion of liver cells, but to a lesser degree than antibodies to the repeat region (112). The CSP contains three known T cell epitopes: a highly variable CD4⁺ T cell epitope before the thrombospondin domain (114), a highly variable CD8⁺ T cell epitope within the thrombospondin domain (115), and a conserved “universal” CD4⁺ T cell epitope at the C-terminus (116). RTS,S induces a moderate CS-specific CD4⁺ T cell response that weakly correlates with protection from infection (37, 38), but RTS,S does not appear to induce a substantial CS-specific CD8⁺ T cell response (37, 117, 118).