Once activated, all the three pathways converge at the C3 step, leading to covalent deposition of the opsonins C3b and iC3b, generation of inflammatory anaphylatoxins C3a and C5a, and ultimately the formation of MAC [29]. == Fig. the malaria parasites and the emerging role of complement in antibodymediated protection against malaria. We emphasize that immune responses to vaccines based on complement inhibitors should not only induce complementactivating antibodies but also neutralize the escape mechanisms of the parasite. Keywords:complement, immunity, malaria,Plasmodium == Abbreviations == C1INH, C1inhibitor C3bBb, C3 convertase C4BP, C4bbinding protein CCP, complement control protein CR1, complement receptor 1 CRIg, complement receptor of immunoglobulin CSP, circumsporozoite protein DAF, decayaccelerating factor FH, factor H FHbp, factor Hbinding protein MAC, membrane attack complex MASP2, mannanbinding lectinassociated serine protease 2 MBL, mannosebinding lectin MCP, membrane cofactor protein NAI, naturally acquired immunity PfEMP1,P. falciparumerythrocyte membrane protein 1 PfGPI,P. falciparumglycosylphosphatidylinositol VSA, variant surface antigen The global burden of malaria is usually massive. In 2018 alone, an estimated 228 million cases occurred globally. There were 405 000 deaths reported; 67% occurred in children under the age of 5 years. Of all malaria deaths, 93% occurred in subSaharan Africa [1]. Malaria in humans is caused by five species ofPlasmodium:P. falciparum,P. vivax,P. LYPLAL1-IN-1 malariae, P. ovale, andP. knowlesi.P. falciparumcauses the most severe CD22 forms of malaria. The life cycle ofPlasmodiumparasites is usually complex (Fig.1) [2]. They require an anopheline mosquito vector and a vertebrate host [3]. In the human host, infection begins with the bite of an infectedAnophelesmosquito that inoculates the person with about 10100 sporozoites [4]. The sporozoites migrate to the capillaries and then travelviathe bloodstream into the liver, where they invade hepatocytes [5] and initiate the preerythrocytic cycle [6]. Upon invasion of hepatocytes, the parasites undergo replication, also called schizogony, at the end of which thousands of daughter cells are formed. These cells differentiate into invasive bloodstage parasites called merozoites that are released in batches into the bloodstream [7]. In the bloodstream, the merozoites quickly invade erythrocytes to initiate the pathogenic erythrocytic stage of the parasite life cycle, also called the asexual cycle. Within the erythrocytes, the merozoites mature to form rings, then trophozoites, and eventually schizonts with multiple parasites that burst to release a new generation of merozoites, thereby starting the process of invading new erythrocytes [8]. The asexual life cycle is accompanied by commitment to gametocytogenesis [9,10]. Thereby, a fraction of merozoites differentiate inside erythrocytes into male and female gametocytes [11] that are taken up during a mosquitos blood meal. In the mosquito midgut, male and female gametes fuse to form ookinetes that cross the midgut epithelium, where they develop into oocysts. Parasites inside oocysts differentiate ultimately into sporozoites that invade the mosquitos salivary glands [12]. == Fig. 1. == Life cycle of the LYPLAL1-IN-1 malaria parasiteP. falciparum. The complex life cycle of malaria offers multiple potential points of intervention. Malaria vaccine development has primarily focused on preerythrocytic, bloodstage, or transmissionblocking vaccine targets [13]. However, after more than 50 years of intensive research and development, only one LYPLAL1-IN-1 malaria vaccine candidate, RTS,S (Mosquirix), based on the central repeat and Cterminal epitopes of the major LYPLAL1-IN-1 sporozoite surface antigen, circumsporozoite protein (CSP), have completed phase3 trials. Results of these trials indicated that this vaccine reduced episodes of clinical malaria in children 517 months and infants 612 weeks of age by 50.4% and 30.1%, respectively, over a 1year followup [14]. Despite this positive outlook, it was apparent that this vaccine was only partially protective, and the obtained immunity waned over time, as the RTS,S vaccine efficacy was only 28% in children 517 months of age and 18% in infants 612 weeks of age when measured 2 years after vaccination [15,16]. Therefore, LYPLAL1-IN-1 innovative approaches are urgently needed to design vaccines with improved efficacies [17]. The complement system represents a major part of the innate immunity and is considered the first line of defense against pathogens. It is a cascade of soluble plasma proteins and membraneexpressed receptors and regulators, which operate in plasma and other body fluids, in tissues and on cell surfaces. Recent studies exhibited thatP. falciparumparasite has surface molecules that can capture host soluble complement regulators to inhibit complement activities and avoid cell damage [18,19,20]. Other studies described a role for complement in antibodymediated protection against malaria [21,22,23,24,25,26,27]. These findings could be exploited to design a malaria vaccine that can induce antibodies with an ability to neutralize complement evasion mechanisms and activate the complement, thus resulting in.