The future for blood‐stage vaccines against malaria

Abstract

Malaria is a leading cause of mortality and morbidity globally, and effective vaccines are urgently needed. Malaria vaccine approaches can be broadly grouped as pre-erythrocytic, blood stage and transmission blocking. This review focuses on bloodstage vaccines, and considers the evidence supporting the development of blood-stage vaccines, the advantages and challenges of this approach, potential targets, human vaccine studies and future directions. There is a strong rationale for the development of vaccines based on antigens of blood-stage parasites. Symptomatic malaria is caused by blood-stage parasitemia and acquired immunity in humans largely targets blood-stage antigens. Several candidate vaccines have proved efficacious in animal models and at least one vaccine showed partial efficacy in a clinical trial. At present, all leading candidate blood-stage antigens are merozoite proteins, located on the merozoite surface or within the apical organelles. Major challenges and priorities include overcoming antigenic diversity, identification of protective epitopes, understanding the nature and targets of protective immune responses, and defining antigen combinations that give the greatest efficacy. Additionally, objective criteria and approaches are needed to prioritize the large number of candidate antigens, and strong candidates need to be tested in clinical trials as quickly as possible.

Passive Immunoprotection of Plasmodium falciparum-Infected Mice Designates the CyRPA as Candidate Malaria Vaccine Antigen

“…Our data show that CyRPA clearly fulfills three key criteria applied to select asexual blood-stage Ags as vaccine candidates (97): 1) the protein is conserved; 2) Abs against the Ag inhibit parasite growth in vitro and 3) are protective in animal models. To validate further CyRPA as a blood-stage vaccine Ag, one ought to demonstrate that 1) CyRPA is essential for parasite survival, 2) growth inhibitory anti-CyRPA Abs can be induced by active immunization with recombinant CyRPA, 3) immunization is safe, and 4) growth inhibitory anti-CyRPA Abs confer protection against clinical malaria in humans.…”

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

“…The development of effective malaria vaccines is a high priority for malaria control and elimination, particularly in light of increasing drug resistance (2,3), as well as the declining efficacy of vector control interventions in some populations that is compromising current control efforts (4). Effective immunity develops naturally in humans following exposure to P. falciparum infection, which has long provided a strong rationale that the development of malaria vaccines is achievable and highlights the importance of understanding the targets and mechanisms of immunity (5). Therefore, an important criterion for objectively identifying and prioritizing Ags for malaria vaccine development is the demonstration that a specific Ag is a target of acquired human immunity and that the immune response is associated with protection from symptomatic disease (6).…”

“…Acquired human immunity predominantly targets the blood stage of infection, and Ags expressed by the merozoite, the extracellular form of Plasmodium that infects erythrocytes, are especially important immune targets and vaccine candidates (5). Erythrocyte invasion occurs over several steps, with multiple interactions involving proteins on the merozoite surface and proteins contained within dedicated invasion organelles, the micronemes and rhoptries (8).…”

Characterization of Plasmodium falciparum Proteome at Asexual Blood Stages for Screening of Effective Vaccine Candidates: An Immunoinformatics Approach

“…29 Overall, our predicted data provide a strong rationale for developing asexual blood-stage vaccine component as part of a multivalent effective malaria vaccine that may need to incorporate antigens of several life-cycle stages including liver stage. [64][65][66][67] …”