This also applies to CHMI studies. Controlled human malaria infections (CHMI) CHMI by either sporozoite or blood-stage inoculation of healthy malaria-na? ve volunteers can accelerate candidate vaccine development by providing rapid and robust efficacy readouts.5,96 These studies are performed in a small number of centers worldwide.97 Whether efficacy in CHMI predicts field efficacy in target populations remains an open question, since so few candidates JDTic dihydrochloride have demonstrated convincing efficacy in CHMIs, but the indications are that CHMI can accurately down-select potential candidates, since very few phase IIb studies have detected efficacy in the absence of an efficacy signal in a phase IIa CHMI5 (the only possible exception is the Combination B vaccine28,71). the utility of GIA for blood-stage vaccine development. malaria is the pre-eminent tropical parasitic infection, causing approximately 300 million infections and around 800,000 deaths per year (World Malaria Report, WHO, 2010). Effective control strategies such as insecticide-treated bed-nets (ITNs), and artemesinin-combination therapies (ACT) have contributed to considerable and impressive reductions in malaria incidence in some countries,1 prompting renewed calls for malaria eradication.2 Yet the development of parasite resistance to medicines3 and vector resistance to insecticides4 continues to challenge control attempts, and the development of an effective malaria vaccine is a global public health priority.5,6 While a partially effective vaccine is aiming for licensure in 2015, 7 a highly effective vaccine against malaria remains elusive. There are numerous difficulties to overcome,8,9 including substantial parasite genetic diversity, a lack of suitable animal models, and an incomplete understanding of the effector mechanisms that determine natural immunity in humans.10 A variety of vaccine strategies focusing on all stages of the parasite lifecycle have been pursued, including recombinant protein-in-adjuvant preparations,11 replication-deficient viral vectors encoding malaria antigens12 and attenuated whole parasites.13 Fewer than 0.5% of malaria proteins have been explored as potential candidate vaccine antigens,9 but the presence of naturally acquired immunity (in contrast to other important pathogens such as HIV), together with evidence of experimentally-induced immunity in humans, 14 offers the promise that better understanding of protective immune effector mechanisms might accelerate the vaccine development course of action. 9 With so many potential vaccine candidates and platforms, strong down-selection strategies are required for candidate antigens. In the case of vaccines to the asexual blood-stage, the most commonly employed strategy for candidate antigen down-selection has been the detection of antibody with in vitro activity in growth inhibition assays (GIA).15,16 In primate challenge models induced antibodies with high levels of GIA activity against blood-stage antigens such as apical membrane antigen-1 (AMA-1) and merozoite surface protein-1 (MSP-1) have been associated with safety against lethal challenge.17,18 SHH But can the in vitro GIA activity of induced antibodies forecast blood-stage vaccine effectiveness JDTic dihydrochloride in humans? Here we attempt to address this query using data from published immunoepidemiological, CHMI, and field effectiveness studies. Parasite growth and invasion The malaria lifecycle is definitely complex, involving several phases. Infected mosquitoes inject sporozoites of present in their salivary glands when taking a blood meal. These sporozoites migrate JDTic dihydrochloride to and invade liver cells, setting up the liver (or pre-erythrocytic) stage of illness. After around seven days each infected liver cell releases approximately 30,000 merozoites into the bloodstream. These merozoites invade and replicate asexually within reddish blood cells (erythrocytes), leading to an exponential increase in parasites in the blood (parasitemia). This is the blood-stage of illness – the only stage at which medical disease occurs. Later on in blood-stage replication a few parasites develop into male and female gametocytes, and these in turn may become taken up by feeding mosquitoes, leading to sexual reproduction in the mosquito that generates a new generation of sporozoites. Invasion of erythrocytes by merozoites is definitely quick19 and entails three main phases: 1) attachment, 2) apical re-orientation and 3) invasion.20 Various merozoite antigens are involved in these processes; such as the merozoite surface proteins (MSPs, particularly MSP-1) in attachment; the apical membrane antigen 1 (AMA-1) in re-orientation; and two family members termed the erythrocyte binding antigens (EBAs) and the Rh proteins in invasion.21 Some of these proteins are leading BS vaccine targets (e.g., AMA-1 and MSP-1), although many more are untested.15 Blood-stage immunity Although the precise immunological mechanisms underpinning malaria immunity are unresolved, its natural history is well established.22 Immunity develops over time with repeated exposure to the malaria parasite (providing death does not occur), 1st to severe disease in babies, then to clinical disease in children and young adults. Immunity is rarely.