Pre-erythrocytic malaria vaccines: identifying the targets

Abstract

Pre-erythrocytic malaria vaccines target Plasmodium during its sporozoite and liver stages, and can prevent progression to blood-stage disease, which causes a million deaths each year. Whole organism sporozoite vaccines induce sterile immunity in animals and humans and guide subunit vaccine development. A recombinant protein-in-adjuvant pre-erythrocytic vaccine called RTS,S reduces clinical malaria without preventing infection in field studies and additional antigens may be required to achieve sterile immunity. Although few vaccine antigens have progressed to human testing, new insights into parasite biology, expression profiles and immunobiology have offered new targets for intervention. Future advances require human trials of additional antigens, as well as platforms to induce the durable antibody and cellular responses including CD8+ T cells that contribute to sterile protection.

Malaria DNA vaccine gp96NTD-CSP elicits both CSP-specific antibody and CD8+ T cell response

“…Pre-erythrocytic subunit vaccines, such as peptide-in-adjuvant, DNA vaccine, and viral vector vaccine, have been developed in recent decades (Duffy et al 2012). However, peptide-in-adjuvant subunit vaccines could only elicit high levels of humoral response and low level of cellular response (Moorthy and Ballou 2009).…”

“…Additionally, vaccination safety is also the great concern, as the breakthrough of the GAS has been reported during phase I of clinical trials (Spring et al 2013). Therefore, the application of RAS and GAS is limited, and great efforts have been made to develop subunit malaria vaccines against the pre-erythrocytic stage in the past decades (Duffy et al 2012).…”

Malaria Immunity in Man and Mosquito: Insights into Unsolved Mysteries of a Deadly Infectious Disease

“…This is a likely reason why extremely high frequencies of memory CD8 + T cells are required to induce sterile immunity after immunization with irradiated sporozoites (57). RA sporozoite-induced antibodies have also been implicated as effectors in liver stage immunity in mice (reviewed in (59)) through enhancing sporozoite clearance, decreasing sporozoite motility (60) or blocking hepatocyte invasion (61). Undoubtedly, animal models will continue to inform further investigations that also take advantage of recent advances in human skin immunobiology (62) and humanized mouse liver models (63).…”

Dysfunctional Adaptive Immunity During Parasitic Infections

“…Functional recognition of this ligand (MHC-peptide) by the TCR triggers signaling cascades that culminate in the secretion of anti-microbial cytokines or degranulation of the CD8 T cell, which results in release of cytotoxic effector proteins that trigger apoptotic pathways within target cells [8]. Large bodies of experimental evidence and clinical correlates show that, with the possible exception of Babesia and blood-stage Plasmodium parasites, effective control of protozoan parasitic infections and liver stage malaria depends on the induction and maintenance of efficacious, parasite-specific CD8 T cell responses [9–11]. Babesia and blood-stage Plasmodium parasites replicate exclusively in mammalian red blood cells (RBC), which lack functional MHC expression.…”