Malaria pre-erythrocytic (PE) stage. Although it takes years,

Malaria still remains a serious challenge to human health as millions of lives are at the risk of infection, particularly the children residing in South-East Asia and Sub-Saharan Africa. In 2016, an estimated 216 million cases of malaria occurred worldwide, there were an estimated 445 000 deaths from malaria globally (WHO, 2016). Malaria is caused by the protozoan parasite of the genus Plasmodia which is transmitted to humans by the bites of female Anopheles mosquitos infected with Plasmodia parasite. There are five Plasmodia species known to infect humans: P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowelsi; all of which have a distinct geographical distribution and clinical manifestation, further there are two Plasmodia species in mice P. berghei, and P. yoelii. Among these human malaria species, P. falciparum is deadliest and most prevalent species responsible for malaria associated disease symptoms and mortality. Despite tremendous development in healthcare system, malaria in 21st century still remains a serious challenge to human health particularly to children below 5 years old. Use of drugs including artemisinin-based combinational therapy (ACT) and vector control measures e.g.  insecticide treated nets (ITN) has resulted in mixed outcome. In certain regions of Africa, while these interventions have been linked with temporary 50% reduction in incidence, other regions of Africa and some parts of the world, such as, Amazonia, have noticed the malaria incidence is static or increasing (O’ Meara et al., 2009; Carbal et al., 2010). Further, P. falciparum has been shown to be acquiring and rapidly spreading resistance to anti-malarial drugs (Dondorp et al., 2010). At present we have to deal with multi-drug-resistant parasites against most potent drug including chloroquine and artemisinin, and emergence of insecticide-resistant mosquitoes making it very difficult to control malaria. Given the enormous genetic plasticity of the parasite, the emergence of antimalarial drug resistance is inevitable and thus a major concern (Miller et al., 2013). Therefore, it is critical to have an effective vaccine to control or possibly eradicate malaria.To develop a potent anti-malaria vaccine there is need of good understanding of immune response generated at pre-erythrocytic (PE) stage. Although it takes years, people living in the malaria endemic areas naturally acquire immunity against severe life threatening P. falciparum infection, whereas immunity to mild disease is not typically acquired until late adolescence (Crompton et al., 2014). However, they lose protection to Plasmodia if they stay away from the endemic area for 2 to 3 years (Baird et al., 1991; Doolan et al., 2009). This has prompted us to look deeper into the problem. More than 10 vaccines designed to induce protective antibody-or cell-mediated immune responses against the liver-stage (LS) infection have been evaluated in humans, only a small number of volunteers are shown to be protected (Hill et al., 2010). Further, malaria vaccine development is hindered due to the complexity of the parasite and its life cycle (Gardner et al., 2002, Florens et al., 2002), extensive antigenic variation (Scherf et al., 2008), and a poor understanding of the interaction between P. falciparum and the human immune system (Langhorne et al., 2008). Although tremendous efforts have been made for the development of effective vaccines, only RTS, S (Mosquirix), a subunit pre-erythrocytic (PE) stage malaria vaccine was licensed to go for phase-III clinical trials. The most promising subunit vaccine candidate to date, RTS, S (Stoute et al., 1997), induces antibody and CD4+T cell responses against the dominant sporozoite-expressed surface protein, the circum sporozoite protein (CSP) (Kester et al., 2009). When RTS, S mixed with potent adjuvant AS01/02 was injected to volunteers, it achieved respectable levels (30-50%) of sterilizing protection against experimental sporozoite challenge?(Peifang et al., 2003; Kester et al., 2009). Similarly, in phase I, II and III clinical trials, RTS, S vaccination was shown to reduce the rate of clinical malaria by 30-50% (Selidji et al., 2012). However, the protection generated by RTS, S remains short lived (Alaso et al., 2005; Guinovart et al., 2009). The protection conferred by the RTS,S was efficient but was not long-lasting and perdurable as it is reportedly seen for less than 6 months (Agnandji et al., 2011; Rts et al., 2012). The radiation attenuated sporozoites (RAS) vaccination has been seen promising for inducing sterile immunity against LS infection (Butler et al., 2012; Link et al., 1990; Nussenzweig et al., 1967). However, the protection is still short lived seen in the rodents as well as in humans even after receiving multiple frequent dosages of RAS (Epstein et al., 2017; Van Braeckel-Budimir and Harty, 2014; Zarling et al., 2013). Similarly, repeated immunizations with genetically attenuated parasite (GAP) has shown the maintenance of partial sterile protection (20-40%) (Haussig et al., 2014). We have shown that the protection could be extended up-to 18 months in the mice through  intermittent challenge by infectious sporozoites (Inf. Spz) (Krzych et al., 2010) (Meeting abstract) (manuscript in preparation). It is also reportedly shown that repeated exposure to malaria parasite leave people immune in endemic areas (Doolan et al., 2009; Griffin et al., 2015). The results obtained from experimental models including ours demonstrate that protection is dependent upon the presence of effector CD8+T cells in the liver. Moreover, we have shown that the loss of CD8+T cells in the liver of RAS immune mice is rescued following the infectious sporozoite (Inf. Spz) challenge. It has been shown that host (rodent as well as human) immunized with sporozoites under the cover of chloroquine are protected up to 28 months. Collectively, above findings suggest that infectious status of sporozoites may be playing a pivotal role in modulating CD8+T cell response that ensue longer-lived protection against Plasmodia LS infection. The danger signals host perceives from the pathogen would dictate the nature of innate immune response. Moreover, infectious status of sporozoites might influence the innate immune effectors which eventually modulate the CD8+T cell response. Dendritic cells (DCs) are shown to be involved in the induction of protective immunity against various pathogens including Plasmodia.