Immunization with full-length Plasmodium falciparum merozoite surface protein 1 is safe and elicits functional cytophilic antibodies in a randomized first-in-human trial

Abstract

A vaccine remains a priority in the global fight against malaria. Here, we report on a single-center, randomized, double-blind, placebo and adjuvant-controlled, dose escalation phase 1a safety and immunogenicity clinical trial of full-length Plasmodium falciparum merozoite surface protein 1 (MSP1) in combination with GLA-SE adjuvant. Thirty-two healthy volunteers were vaccinated at least three times with MSP1 plus adjuvant, adjuvant alone, or placebo (24:4:4) to evaluate the safety and immunogenicity. MSP1 was safe, well tolerated and immunogenic, with all vaccinees sero-converting independent of the dose. The MSP1-specific IgG and IgM titers persisted above levels found in malaria semi-immune humans for at least 6 months after the last immunization. The antibodies were variant-and strain-transcending and stimulated respiratory activity in granulocytes. Furthermore, full-length MSP1 induced memory T-cells. Our findings encourage challenge studies as the next step to evaluate the efficacy of full-length MSP1 as a vaccine candidate against falciparum malaria (EudraCT

Progress in Parasite Genomics and Its Application to Current Challenges in Malaria Control

“…MSP1 plays an important role in the invasion of erythrocytes as it binds and recruits other peripheral merozoite surface proteins to form a complex [109]. MSP1 starts off as a precursor of about 196 kDa and then cleave into four subunits before invading the erythrocytes [110]. The four subunits are held non-covalently forming a complex attached to the merozoite's GPI anchor [110].…”

“…MSP1 starts off as a precursor of about 196 kDa and then cleave into four subunits before invading the erythrocytes [110]. The four subunits are held non-covalently forming a complex attached to the merozoite's GPI anchor [110]. Once the MSP1 complex is formed, it binds with the receptors on erythrocytes and activates a spectrin-binding function to enter the erythrocytes [110].…”

“…The four subunits are held non-covalently forming a complex attached to the merozoite's GPI anchor [110]. Once the MSP1 complex is formed, it binds with the receptors on erythrocytes and activates a spectrin-binding function to enter the erythrocytes [110]. MSP1 has been shown to elicit both humoral (IgM and IgG antibodies) and cell-mediated immune responses (memory T cells) that lasted about 6 months after immunization [110].…”

“…Once the MSP1 complex is formed, it binds with the receptors on erythrocytes and activates a spectrin-binding function to enter the erythrocytes [110]. MSP1 has been shown to elicit both humoral (IgM and IgG antibodies) and cell-mediated immune responses (memory T cells) that lasted about 6 months after immunization [110]. These results are promising as MSP1 vaccine will also activate antibodies for complement fixation, induce opsonizing antibodies, and initiate secretion of reactive oxygen species by other immune cells [110].…”

Malaria vaccine research & innovation: the intersection of IA2030 and zero malaria

“…A myriad of biological and technical barriers have been encountered; however, step-by-step, these barriers have been chipped away. Advances include: new insights into the evolution of the immune response to the major pre-erythrocytic target, CSP 10 , and into the role of complementfixing antibodies in blood stage clinical immunity 11 ; the ability to express and manufacture full length versions of blood stage targets, e.g., the highly promising, highly conserved reticulocytebinding protein homolog 5 (PfRH5) 12 , as well as the 196-kDa merozoite surface protein 1 (the primary structure first described by Holder, et al in 1985 13 ), the latter of which demonstrated favorable safety and immunogenicity in a first-in human study 14 ; and, the delivery of target malaria parasite antigens by measles vectors to overcome the barrier of waning immune responses, resulting in durable memory and protection, at least in a murine model 15 .…”