Current approaches to malaria vaccines

Abstract

The complex Plasmodium life cycle offers different vaccine approaches with distinct parasitological and clinical effects. The approaches and their rationales were established decades ago: vaccines targeting pre-erythrocytic (sporozoite and liver-stage) parasites prevent infection, those to blood-stage parasites reduce disease, and those to sexual-stage parasites or mosquito vector reduce transmission and eliminate malaria through herd immunity. The pre-erythrocytic RTS,S vaccine (Mosquirix, GlaskoSmithKline (GSK)), recommended by WHO in 2021, reduces clinical malaria in children. Knowledge of parasite biology, host-parasite interactions, and immune mechanisms is informing new concepts to improve on RTS,S and to target other parasite stages. This review emphasizes vaccine approaches and candidates currently in the clinic or likely to enter clinical testing soon.

Figure 1

Pre-erythrocytic Plasmodium development and immune mechanisms of leading vaccine candidates. RTS,S and R21 are similar subunit vaccines that induce antibodies and CD4 T cells against the CSP displayed on sporozoite surface and expressed by liver-stage parasites. CSP monoclonal antibodies may target sporozoites in skin (as seen for rodent parasites [71]), bloodstream [72], during hepatocyte traversal [72] and invasion [73], and liver-stage development [74]. RTS,S serology studies suggest roles for repeat- and C-terminus-specific antibodies in protection, involving antibody-dependent phagocytosis and NK cell activation [11]. Efficacy of PfSPZ vaccines is associated with CSP titers and Vδ2 γδ T-cell levels [28,30••,31•]; Vd2 cells may be required to induce protective CD8 T cells that kill intrahepatocytic parasites [37].

Figure 2

Blood-stage Plasmodium development and immune mechanisms of leading vaccine candidates. Vaccine candidates targeting merozoite antigens (PfRH2, AMA1–RON2 complex, PvDBPII) generate antibodies that inhibit nonredundant erythrocyte-invasion pathways: RH5 forms a complex with two other secreted parasite proteins (CyRPA and Rh5-interacting protein (RIPR)) targeted by growth-inhibitory antibodies [75,76], and binds to membrane-anchored P113 on the merozoite surface [77] from whence it interacts with the essential erythrocyte receptor basigin; AMA1 forms a complex with parasite antigen RON2 that has transferred to the erythrocyte plasma membrane, thereby committing the parasite to invasion [78]; PvDBP forms a dimer on the merozoite surface upon contact with the Duffy antigen receptor that is then sandwiched between two region-II (DBPRII) moieties, and neutralizing antibodies can target both the dimer and the ligand-receptor interfaces [79]. Antibodies to PfGARP (that localizes to the exofacial membrane surface of early-to-late-trophozoite-infected erythrocytes) induce programmed cell death of intraerythrocytic trophozoites [49]. Antibodies to SEA-1A (the SEA-1 N-terminal fragment upstream of its centromeric protein (CCENP-C) and dimerization domains required for chromosomal segregation [80], merozoite viability, and normal egress [81]) decreased parasite replication in one study [50] but not another [51] and SEA-1A vaccination delayed mortality in mice after challenge with lethal P. berghei parasites [50]. VAR2CSA (an integral membrane protein displayed on the exofacial surface of infected erythrocyte protrusions called knobs) uses conserved channels formed by multiple domains from its extracellular region to bind its placental receptor CSA and mediate parasite sequestration in the placenta [57]; antibodies that block parasite adhesion to CSA and opsonize CSA-binding infected erythrocytes are naturally acquired by women as they become resistant to placental malaria, forming the conceptual basis for a placental malaria vaccine.

Figure 3

Mosquito sexual-stage Plasmodium development and immune mechanisms of leading transmission-blocking vaccine candidates. TBV targeting gamete and zygote surface antigens elicit antibodies to kill or arrest parasite stages in the mosquito, thereby reducing community transmission to achieve improved malaria control or elimination through herd immunity. P. falciparum gamete surface antigens Pfs230 and Pfs48/45 and zygote surface antigen Pfs25 have all entered clinical testing in the field, while female gamete surface antigen Pfs47 showed vaccine activity in preclinical studies. In a comparative trial using the same conjugated-protein-in-adjuvant platform, Pfs230D1 delivered superior immunogenicity and serum transmission-blocking activity versus Pfs25. Pfs230D1 serum activity is enhanced by complement and lyses gametes.